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  • Associations among peripheral and central kynurenine pathway metabolites and inflammation in depression
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-15
    Ebrahim Haroon; James R. Welle; Bobbi J. Woolwine; David R. Goldsmith; Wendy Bear; Trusharth Patel; Jennifer C. Felger; Andrew H. Miller

    Kynurenine pathway (KP) metabolites are believed to be a link between inflammation and depression through effects on brain glutamate receptors. However, neither the relationship between plasma and cerebrospinal fluid (CSF) KP metabolites nor their association with inflammatory mediators is well-established in depression. Moreover, the clinical profile associated with combined activation of plasma inflammatory and kynurenine pathways is unknown. Accordingly, plasma and CSF-KP metabolites and inflammatory markers along with depressive symptoms and antidepressant treatment response were measured in 72 unmedicated depressed patients. Following bivariate analyses, component factors representing immune and kynurenine variables in the plasma and CSF were extracted and were used to examine directionality of associations in a path model. In addition, patients were clustered using individual markers that most accounted for the association between plasma immune and KP systems. Path analysis revealed a directional association extending from plasma inflammatory markers to plasma kynurenines, to CSF kynurenines. Among immune markers, plasma tumor necrosis factor (TNF) was robustly associated with plasma kynurenine (KYN) and KYN/tryptophan (TRP), which was in turn significantly associated with CSF KYN, kynurenic acid, and quinolinic acid. Clustering of patients based on plasma TNF and KYN/TRP yielded subgroups of high (N = 17) and low (N = 55) TNF-KYN/TRP groups. High TNF-KYN/TRP subjects exhibited greater depression severity, anhedonia, and treatment nonresponse. In conclusion, plasma-KP metabolites may mediate an inflammation-associated depressive symptom profile via CNS KP metabolites that can serve as a target for intervention at the level of inflammation, peripheral KYN metabolism, KYN transport to the brain, or effects of KP metabolites on glutamate receptors.

  • Dorsal and ventral striatal dopamine D1 and D2 receptors differentially modulate distinct phases of serial visual reversal learning
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-15
    Júlia Sala-Bayo; Leanne Fiddian; Simon R. O. Nilsson; Mona El-Sayed Hervig; Colin McKenzie; Alexis Mareschi; Maria Boulos; Peter Zhukovsky; Janet Nicholson; Jeffrey W. Dalley; Johan Alsiö; Trevor W. Robbins

    Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human and animal studies have implicated striatal D2-like and D1-like receptors (D2R; D1R) in this form of flexibility, less is known about the contribution they make within distinct sub-regions of the striatum and the different phases of visual reversal learning. The present study investigated the involvement of D2R and D1R during the early (perseverative) phase of reversal learning as well as in the intermediate and late stages (new learning) after microinfusions of D2R and D1R antagonists into the nucleus accumbens core and shell (NAcC; NAcS), the anterior and posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) on a touchscreen visual serial reversal-learning task. Reversal learning was improved after dopamine receptor blockade in the nucleus accumbens; the D1R antagonist, SCH23390, in the NAcS and the D2R antagonist, raclopride, in the NAcC selectively reduced early, perseverative errors. In contrast, reversal learning was impaired by D2R antagonism, but not D1R antagonism, in the dorsal striatum: raclopride increased errors in the intermediate phase after DMS infusions, and increased errors across phases after DLS infusions. These findings indicate that D1R and D2R modulate different stages of reversal learning through effects localised to different sub-regions of the striatum. Thus, deficits in behavioral flexibility observed in disorders linked to dopamine perturbations may be attributable to specific D1R and D2R dysfunction in distinct striatal sub-regions.

  • The acute effects of nicotine on corticostriatal responses to distinct phases of reward processing
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-13
    Kainan S. Wang; Maya Zegel; Elena Molokotos; Lauren V. Moran; David P. Olson; Diego A. Pizzagalli; Amy C. Janes

    Nicotine enhances the reinforcement of non-drug rewards by increasing nucleus accumbens (NAcc) reactivity to anticipatory cues. This anticipatory effect is selective as no clear evidence has emerged showing that nicotine acutely changes reward receipt reactivity. However, repeated rewarding experiences shifts peak brain reactivity from hedonic reward outcome to the motivational anticipatory cue yielding more habitual cue-induced behavior. Given nicotine’s influence on NAcc reactivity and connectivity, it is plausible that nicotine acutely induces this shift and alters NAcc functional connectivity during reward processing. To evaluate this currently untested hypothesis, a randomized crossover design was used in which healthy non-smokers were administered placebo and nicotine (2-mg lozenge). Brain activation to monetary reward anticipation and outcome was evaluated with functional magnetic resonance imaging. Relative to placebo, nicotine induced more NAcc reactivity to reward anticipation. Greater NAcc activation during anticipation was significantly associated with lower NAcc activation to outcome. During outcome, nicotine reduced NAcc functional connectivity with cortical regions including the anterior cingulate cortex, orbitofrontal cortex, and insula. These regions showed the same negative relationship between reward anticipation and outcome as noted in the NAcc. The current findings significantly improve our understanding of how nicotine changes corticostriatal circuit function and communication during distinct phases of reward processing and critically show that these alterations happen acutely following a single dose. The implications of this work explain nicotinic modulation of general reward function, which offer insights into the initial drive to smoke and the subsequent difficulty in cessation.

  • Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-13
    Elissar Andari; Shota Nishitani; Gopinath Kaundinya; Gabriella A. Caceres; Michael J. Morrier; Opal Ousley; Alicia K. Smith; Joseph F. Cubells; Larry J. Young

    The role of oxytocin in social cognition has attracted tremendous interest in social neuroscience and psychiatry. Some studies have reported improvement in social symptoms following oxytocin treatment in autism spectrum disorders (ASD), while others point to endogenous factors influencing its efficiency and to mixed results in terms of long-term clinical benefits. Epigenetic modification to the oxytocin receptor gene (OXTR) in ASD could be an informative biomarker of treatment efficacy. Yet, little is known about the relationship between OXTR methylation, clinical severity, and brain function in ASD. Here, we investigated the relationship between OXTR methylation, ASD diagnosis (in N = 35 ASD and N = 64 healthy group), measures of social responsiveness, and resting-state functional connectivity (rsFC) between areas involved in social cognition and reward processing (in a subset of ASD, N = 30). Adults with ASD showed higher OXTR methylation levels in the intron 1 area compared with healthy subjects. This hypermethylation was related to clinical symptoms and to a hypoconnectivity between cortico-cortical areas involved in theory of mind. Methylation at a CpG site in the exon 1 area was positively related to social responsiveness deficits in ASD and to a hyperconnectivity between striatal and cortical brain areas. Taken together, these findings provide initial evidence for OXTR hypermethylation in the intron area as a potential biomarker for adults with ASD with less severe developmental communication deficits, but with impairments in theory of mind and self-awareness. Also, OXTR methylation in the exon 1 area could be a potential biomarker of sociability sensitive to life experiences.

  • Fast-acting antidepressant-like effects of Reelin evaluated in the repeated-corticosterone chronic stress paradigm
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-11
    Kyle J. Brymer; Jenessa Johnston; Justin J. Botterill; Raquel Romay-Tallon; Milann A. Mitchell; Josh Allen; Graziano Pinna; Hector J. Caruncho; Lisa E. Kalynchuk

    The present report examines the effects of repeated or single intrahippocampal reelin infusions on measures of depressive-like behavior, cognition, and hippocampal neurogenesis in the repeated-corticosterone (CORT) paradigm. Rats received subcutaneous injections of CORT for 3 weeks and reelin was infused through an inserted canula in the left hippocampus on days 7, 14, and 21, or only on day 21 of CORT injections. CORT increased immobility in the forced-swim test and impaired object-location memory. Notably, these effects were reversed by both repeated and single-reelin infusions. CORT decreased both the number and complexity of doublecortin-labeled maturing newborn neurons in the dentate gyrus subgranular zone, and a single-reelin infusion increased the number but not complexity of newborn neurons, while repeated reelin infusions restored both. Injection of the AMPA antagonist CNQX blocked the rescue of the behavioral phenotype by Reelin but did completely block the effects of Reelin on hippocampal neurogenesis. Reelin is able to rescue the deficits in AMPA, NMDA, GABAA receptors, mTOR and p-mTOR induced by CORT. These novel results demonstrate that a single intrahippocampal Reelin infusion into the dorsal hippocampus has fast-acting antidepressant-like effects, and that some of these effects may be at least partially independent of Reelin actions on hippocampal neurogenesis.

  • Polygenic prediction and GWAS of depression, PTSD, and suicidal ideation/self-harm in a Peruvian cohort
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-11
    Hanyang Shen; Bizu Gelaye; Hailiang Huang; Marta B. Rondon; Sixto Sanchez; Laramie E. Duncan

    Genome-wide approaches including polygenic risk scores (PRSs) are now widely used in medical research; however, few studies have been conducted in low- and middle-income countries (LMICs), especially in South America. This study was designed to test the transferability of psychiatric PRSs to individuals with different ancestral and cultural backgrounds and to provide genome-wide association study (GWAS) results for psychiatric outcomes in this sample. The PrOMIS cohort (N = 3308) was recruited from prenatal care clinics at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. Three major psychiatric outcomes (depression, PTSD, and suicidal ideation and/or self-harm) were scored by interviewers using valid Spanish questionnaires. Illumina Multi-Ethnic Global chip was used for genotyping. Standard procedures for PRSs and GWAS were used along with extra steps to rule out confounding due to ancestry. Depression PRSs significantly predicted depression, PTSD, and suicidal ideation/self-harm and explained up to 0.6% of phenotypic variation (minimum p = 3.9 × 10−6). The associations were robust to sensitivity analyses using more homogeneous subgroups of participants and alternative choices of principal components. Successful polygenic prediction of three psychiatric phenotypes in this Peruvian cohort suggests that genetic influences on depression, PTSD, and suicidal ideation/self-harm are at least partially shared across global populations. These PRS and GWAS results from this large Peruvian cohort advance genetic research (and the potential for improved treatments) for diverse global populations.

  • Aggression based genome-wide, glutamatergic, dopaminergic and neuroendocrine polygenic risk scores predict callous-unemotional traits
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-09
    I. Hyun Ruisch; Andrea Dietrich; Marieke Klein; Stephen V. Faraone; Jaap Oosterlaan; Jan K. Buitelaar; Pieter J. Hoekstra

    Aggression and callous, uncaring, and unemotional (CU) traits are clinically related behavioral constructs caused by genetic and environmental factors. We performed polygenic risk score (PRS) analyses to investigate shared genetic etiology between aggression and these three CU-traits. Furthermore, we studied interactions of PRS with smoking during pregnancy and childhood life events in relation to CU-traits. Summary statistics for the base phenotype were derived from the EAGLE-consortium genome-wide association study of children’s aggressive behavior and were used to calculate individual-level genome-wide and gene-set PRS in the NeuroIMAGE target-sample. Target phenotypes were ‘callousness’, ‘uncaring’, and ‘unemotional’ sumscores of the Inventory of Callous-Unemotional traits. A total of 779 subjects and 1,192,414 single-nucleotide polymorphisms were available for PRS-analyses. Gene-sets comprised serotonergic, dopaminergic, glutamatergic, and neuroendocrine signaling pathways. Genome-wide PRS showed evidence of association with uncaring scores (explaining up to 1.59% of variance; self-contained Q = 0.0306, competitive-P = 0.0015). Dopaminergic, glutamatergic, and neuroendocrine PRS showed evidence of association with unemotional scores (explaining up to 1.33, 2.00, and 1.20% of variance respectively; self-contained Q-values 0.037, 0.0115, and 0.0473 respectively, competitive-P-values 0.0029, 0.0002, and 0.0045 respectively). Smoking during pregnancy related to callousness scores while childhood life events related to both callousness and unemotionality. Moreover, dopaminergic PRS appeared to interact with childhood life events in relation to unemotional scores. Our study provides evidence suggesting shared genetic etiology between aggressive behavior and uncaring, and unemotional CU-traits in children. Gene-set PRS confirmed involvement of shared glutamatergic, dopaminergic, and neuroendocrine genetic variation in aggression and CU-traits. Replication of current findings is needed.

  • Circulating PACAP peptide and PAC1R genotype as possible transdiagnostic biomarkers for anxiety disorders in women: a preliminary study
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-07
    Rachel A. Ross; Susanne S. Hoeppner; Samantha N. Hellberg; Emily B. O’Day; Peter L. Rosencrans; Kerry J. Ressler; Víctor May; Naomi M. Simon

    Pituitary adenylate cyclase activating polypeptide (PACAP, gene Adcyap1) is a neuropeptide and hormone thought to play a critical role in stress response (Stroth et al., Ann NY Acad Sci 1220:49−59, 2011; Hashimoto et al., Curr Pharm Des 17:985-989, 2011). Research in humans implicates PACAP as a useful biomarker for the severity of psychiatric symptoms in response to psychological stressors, and work in rodent models suggests that PACAP manipulation exerts downstream effects on peripheral hormones and behaviors linked to the stress response, providing a potential therapeutic target. Prior work has also suggested a potential sex difference in PACAP effects due to differential estrogen regulation of this pathway. Therefore, we examined serum PACAP and associated PAC1R genotype in a cohort of males and females with a primary diagnosis of generalized anxiety disorder (GAD) and nonpsychiatric controls. We found that, while circulating hormone levels were not associated with a GAD diagnosis overall (p = 0.19, g = 0.25), PACAP may be associated with GAD in females (p = 0.04, g = 0.33). Additionally, among patients with GAD, the risk genotype identified in the PTSD literature (rs2267735, CC genotype) was associated with higher somatic anxiety symptom severity in females but lower somatic anxiety symptom severity in males (−3.27, 95%CI [−5.76, −0.77], adjusted p = 0.03). Taken together, the associations between the risk genotype, circulating PACAP, and somatic anxiety severity were stronger among females than males. These results indicate a potential underlying biological etiology for sex differences in stress-related anxiety disorders that warrants further study.

  • Integration analysis of methylation quantitative trait loci and GWAS identify three schizophrenia risk variants
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-07
    Hao Yu; Weiqiu Cheng; Xiao Zhang; Xin Wang; Weihua Yue

    Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with schizophrenia (SCZ). However, prioritizing risk variants and regulatory elements for follow-up functional studies remains a major challenge. Therefore, we performed an integrated analysis to identify variants who affect methylation levels of nearby genes and contribute to the risk of SCZ, and to explore the potential role of these variants in SCZ pathogenesis. First, we used the Summary data-based Mendelian Randomization (SMR) method to integrate GWAS and methylation quantitative trait loci data. Then, the SNP-methylation combinations as associated with SCZ were replicated across multiple samples. Totally, we identified and replicated 14 and one SNP-methylation combinations in blood and brain tissues, respectively, that significantly associated with SCZ. Furthermore, our expression quantitative trait loci analysis, differential methylation analysis, neuroimaging genetics, and cognitive genetics analysis consistently supported the potential roles of these 15 SNPs in the pathogenesis of SCZ. Finally, using the convergent functional genomics method, we prioritized three risk SNPs, including rs3765971 (RERE, PSMR = 3.87 × 10−8), rs55742290 (ARL6IP4, PSMR = 1.50 × 10−7), and rs7293091 (CENPM, PSMR = 5.09 × 10−7), may represent promising risk variants in SCZ. These convergent lines of evidence suggest that three risk variants may be involved in the pathogenesis of SCZ. Further investigation of the roles of these variants in the pathogenesis of SCZ is warranted.

  • Lower brain fatty acid amide hydrolase in treatment-seeking patients with alcohol use disorder: a positron emission tomography study with [C-11]CURB
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-07
    Laura M. Best; Belinda Williams; Bernard Le Foll; Esmaeil Mansouri; Richard P. Bazinet; Lin Lin; Vincenzo De Luca; Dina Lagzdins; Pablo Rusjan; Rachel F. Tyndale; Alan A. Wilson; Christian S. Hendershot; Markus Heilig; Sylvain Houle; Junchao Tong; Stephen J. Kish; Isabelle Boileau

    The endocannabinoid enzyme, fatty acid amide hydrolase (FAAH), has been proposed as a therapeutic target for alcohol use disorder (AUD) and co-morbid psychiatric illnesses. Investigating this target in the living human brain and its relationship to clinical outcome is a critical step of informed drug development. Our objective was to establish whether brain FAAH levels are low in individuals with AUD and related to drinking behavior. In this pilot study, treatment-seeking patients with AUD completed two PET scans with the FAAH radiotracer [C-11]CURB after 3–7 days (n = 14) and 2–4 weeks (n = 9) of monitored abstinence. Healthy controls (n = 25) completed one scan. FAAH genetic polymorphism (rs324420) and blood concentrations of anandamide and other N-acylethanolamines metabolized by FAAH were determined and AUD symptoms assessed. In AUD, brain FAAH levels were globally lower than controls during early abstinence (F(1,36) = 5.447; p = 0.025)) and FAAH substrates (anandamide, oleoylethanolamide, and N-docosahexaenoylethanolamide) were significantly elevated (30–67%). No significant differences in FAAH or FAAH substrates were noted after 2–4 weeks abstinence. FAAH levels negatively correlated with drinks per week (r = −0.57, p = 0.032) and plasma concentrations of the three FAAH substrates (r > 0.57; p < 0.04)). Our findings suggest that early abstinence from alcohol in AUD is associated with transiently low brain FAAH levels, which are inversely related to heavier alcohol use and elevated plasma levels of FAAH substrates. Whether low FAAH is an adaptive beneficial response to chronic alcohol is unknown. Therapeutic strategies focusing on FAAH inhibition should consider the possibility that low FAAH during early abstinence may be related to drinking.

  • Effects of exposure to chronic uncertainty and a sensitizing regimen of amphetamine injections on locomotion, decision-making, and dopamine receptors in rats
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-06
    Victoria Fugariu; Martin H. Zack; José N. Nobrega; Paul J. Fletcher; Fiona D. Zeeb

    Gambling disorder (GD) is a behavioral addiction that may be linked to alterations in dopamine (DA) systems. Gambling involves chronic exposure to uncertain reward, which can sensitize the activity of DA systems. Here we explored how combinations of Pavlovian and instrumental uncertainty impact DA sensitization and risky decision-making. Experiment 1: 40 rats underwent 66 uncertainty exposure (UE) sessions during which they responded for saccharin. Animal responding was reinforced according to a fixed or variable (FR/VR) ratio schedule that turned on a conditioned stimulus (CS; light), which predicted saccharin on 50% or 100% of trials. Animals responded under one of the four conditions: FR-CS100% (no uncertainty), VR-CS100%, FR-CS50%, and VR-CS50% (maximal uncertainty). DA sensitization was inferred from an enhanced locomotor response to d-amphetamine (d-AMPH; 0.5 mg/kg) challenge. The rat gambling task (rGT) was used to assess decision-making. Experiment 2: 24 rats received 5 weeks of sensitizing d-AMPH or saline doses, followed by locomotor activity and rGT testing. Experiment 3: Effects of UE and a sensitizing d-AMPH regimen on DA D1, D2, and D3 receptor binding were assessed in 44 rats using autoradiography. Compared to FR-CS100%, VR-CS100% and VR-CS50% rats displayed a greater locomotor response to d-AMPH, and VR-CS50% rats demonstrated riskier decision-making. Chronic d-AMPH-treated rats mirrored the effects of VR-CS50% groups on these two indices. Both VR-CS50% and d-AMPH-treated groups had increased striatal DA D2 receptor binding. These results suggest that chronic uncertainty exposure, similar to exposure to a sensitizing d-AMPH regimen, sensitized the function of DA systems and increased risky decision-making.

  • Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-06
    Ida Fredriksson; Sarah V. Applebey; Angelica Minier-Toribio; Aniruddha Shekara; Jennifer M. Bossert; Yavin Shaham

    In the classical incubation of drug craving rat model, drug seeking is assessed after homecage forced abstinence. However, human abstinence is often voluntary because negative consequences of drug seeking outweigh the desire for the drug. Here, we developed a rat model of incubation of opioid craving after electric barrier-induced voluntary abstinence and determined whether the dopamine stabilizer (−)-OSU6162 would decrease this new form of incubation. We trained male and female rats to self-administer oxycodone (0.1 mg/kg/infusion, 6 h/day) for 14 days. We then exposed them to either homecage forced abstinence or voluntary abstinence induced by an electric barrier of increasing intensity near the drug-paired lever. On abstinence days 1, 15, or 30, we tested the rats for oxycodone seeking without shock and drug. We also examined the effect of (−)-OSU6162 (7.5 and 15 mg/kg) on oxycodone seeking on abstinence day 1 or after 15 days of either voluntary or forced abstinence. Independent of sex, the time-dependent increase in oxycodone seeking after cessation of opioid self-administration (incubation of opioid craving) was stronger after voluntary abstinence than after forced abstinence. In males, (−)-OSU6162 decreased incubated (day 15) but not non-incubated (day 1) oxycodone seeking after either voluntary or forced abstinence. In females, (−)-OSU6162 modestly decreased incubated oxycodone seeking after voluntary but not forced abstinence. Results suggest that voluntary abstinence induced by negative consequences of drug seeking can paradoxically potentiate opioid craving and relapse. We propose the dopamine stabilizer (−)-OSU6162 may serve as an adjunct pharmacological treatment to prevent relapse in male opioid users.

  • Addiction is driven by excessive goal-directed drug choice under negative affect: translational critique of habit and compulsion theory
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-06
    Lee Hogarth

    Drug addiction may be a goal-directed choice driven by excessive drug value in negative affective states, a habit driven by strong stimulus−response associations, or a compulsion driven by insensitivity to costs imposed on drug seeking. Laboratory animal and human evidence for these three theories is evaluated. Excessive goal theory is supported by dependence severity being associated with greater drug choice/economic demand. Drug choice is demonstrably goal-directed (driven by the expected value of the drug) and can be augmented by stress/negative mood induction and withdrawal—effects amplified in those with psychiatric symptoms and drug use coping motives. Furthermore, psychiatric symptoms confer risk of dependence, and coping motives mediate this risk. Habit theory of addiction has weaker support. Habitual behaviour seen in drug-exposed animals often does not occur in complex decision scenarios, or where responding is rewarded, so habit is unlikely to explain most human addictive behaviour where these conditions apply. Furthermore, most human studies have not found greater propensity to habitual behaviour in drug users or as a function of dependence severity, and the minority that have can be explained by task disengagement producing impaired explicit contingency knowledge. Compulsion theory of addiction also has weak support. The persistence of punished drug seeking in animals is better explained by greater drug value (evinced by the association with economic demand) than by insensitivity to costs. Furthermore, human studies have provided weak evidence that propensity discount cost imposed on drug seeking is associated with dependence severity. These data suggest that human addiction is primarily driven by excessive goal-directed drug choice under negative affect, and less by habit or compulsion. Addiction is pathological because negative states powerfully increase expected drug value acutely outweighing abstinence goals.

  • Contribution of D1R-expressing neurons of the dorsal dentate gyrus and Ca v 1.2 channels in extinction of cocaine conditioned place preference
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-06
    Caitlin E. Burgdorf; Charlotte C. Bavley; Delaney K. Fischer; Alexander P. Walsh; Arlene Martinez-Rivera; Jonathan E. Hackett; Lia J. Zallar; Kyle E. Ireton; Franz Hofmann; Johannes W. Hell; Richard L. Huganir; Anjali M. Rajadhyaksha

    Cocaine-associated contextual cues can trigger relapse behavior by recruiting the hippocampus. Extinction of cocaine-associated contextual memories can reduce cocaine-seeking behavior, however the molecular mechanisms within the hippocampus that underlie contextual extinction behavior and subsequent reinstatement remain poorly understood. Here, we extend our previous findings for a role of Cav1.2 L-type Ca2+ channels in dopamine 1 receptor (D1R)-expressing cells in extinction of cocaine conditioned place preference (CPP) in adult male mice. We report that attenuated cocaine CPP extinction in mice lacking Cav1.2 channels in D1R-expressing cells (D1cre, Cav1.2fl/fl) can be rescued through chemogenetic activation of D1R-expressing cells within the dorsal dentate gyrus (dDG), but not the dorsal CA1 (dCA1). This is supported by the finding that Cav1.2 channels are required in excitatory cells of the dDG, but not in the dCA1, for cocaine CPP extinction. Examination of the role of S1928 phosphorylation of Cav1.2, a protein kinase A (PKA) site using S1928A Cav1.2 phosphomutant mice revealed no extinction deficit, likely due to homeostatic scaling up of extinction-dependent S845 GluA1 phosphorylation in the dDG. However, phosphomutant mice failed to show cocaine-primed reinstatement which can be reversed by chemogenetic manipulation of excitatory cells in the dDG during extinction training. These findings outline an essential role for the interaction between D1R, Cav1.2, and GluA1 signaling in the dDG for extinction of cocaine-associated contextual memories.

  • ErbB4 knockdown in serotonergic neurons in the dorsal raphe induces anxiety-like behaviors
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-06
    Sheng-Rong Zhang; Jian-Lin Wu; Hao Chen; Rong Luo; Wen-Jun Chen; Li-Juan Tang; Xiao-Wen Li; Jian-Ming Yang; Tian-Ming Gao

    There is a close relationship between serotonergic (5-HT) activity and anxiety. ErbB4, a receptor tyrosine kinase, is expressed in 5-HT neurons. However, whether ErbB4 regulates 5-HT neuronal function and anxiety-related behaviors is unclear. Here, using transgenic and viral approaches, we show that mice with ErbB4 deficiency in 5-HT neurons exhibit heightened anxiety-like behavior and impaired fear extinction, possibly due to an increased excitability of 5-HT neurons in the dorsal raphe nucleus (DRN). Notably, the chemogenetic inhibition of 5-HT neurons in the DRN of ErbB4 mutant mice rescues anxiety-like behaviors. Altogether, our results unravel a previously unknown role of ErbB4 signaling in the regulation of DRN 5-HT neuronal function and anxiety-like behaviors, providing novel insights into the treatment of anxiety disorders.

  • Ketamine normalizes subgenual cingulate cortex hyper-activity in depression
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-02
    Laurel S. Morris; Sara Costi; Aaron Tan; Emily R. Stern; Dennis Charney; James W. Murrough

    Mounting evidence supports the rapid anti-depressant efficacy of the N-methyl-d-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful anti-depressant treatment. This study aimed to examine whether task-based sgACC activity was also higher in MDD patients compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol pre and post intravenous infusion of 40 min (0.5 mg/kg) ketamine treatment. Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD also had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its anti-depressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.

  • “Chasing the first high”: memory sampling in drug choice
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-02
    Aaron M. Bornstein; Hanna Pickard

    Although vivid memories of drug experiences are prevalent within clinical contexts and addiction folklore (“chasing the first high”), little is known about the relevance of cognitive processes governing memory retrieval to substance use disorder. Drawing on recent work that identifies episodic memory’s influence on decisions for reward, we propose a framework in which drug choices are biased by selective sampling of individual memories during two phases of addiction: (i) downward spiral into persistent use and (ii) relapse. Consideration of how memory retrieval influences the addiction process suggests novel treatment strategies. Rather than try to break learned associations between drug cues and drug rewards, treatment should aim to strengthen existing and/or create new associations between drug cues and drug-inconsistent rewards.

  • Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-02
    Nina Roth Mota; Geert Poelmans; Marieke Klein; Bàrbara Torrico; Noèlia Fernàndez-Castillo; Bru Cormand; Andreas Reif; Barbara Franke; Alejandro Arias Vásquez

    Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD–BMI and ADHD–obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD–BMI overlapping genes with brain volumes (primary GWAS data N = 10,720–10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the circadian rhythm was associated with BMI (P = 1.28 × 10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD–BMI and ADHD–obesity results. The ADHD–BMI overlapping genes were associated with putamen volume (P = 7.7 × 10−3; replication data P = 3.9 × 10−2)—a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD–obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.

  • Polygenic risk for Alzheimer's disease shapes hippocampal scene-selectivity
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-02
    Hannah L. Chandler; Carl J. Hodgetts; Xavier Caseras; Kevin Murphy; Thomas M. Lancaster

    Preclinical models of Alzheimer’s disease (AD) suggest APOE modulates brain function in structures vulnerable to AD pathophysiology. However, genome-wide association studies now demonstrate that AD risk is shaped by a broader polygenic architecture, estimated via polygenic risk scoring (AD-PRS). Despite this breakthrough, the effect of AD-PRS on brain function in young individuals remains unknown. In a large sample (N = 608) of young, asymptomatic individuals, we measure the impact of both (i) APOE and (ii) AD-PRS on a vulnerable cortico-limbic scene-processing network heavily implicated in AD pathophysiology. Integrity of this network, which includes the hippocampus (HC), is fundamental for maintaining cognitive function during ageing. We show that AD-PRS, not APOE, selectively influences activity within the HC in response to scenes, while other perceptual nodes remained intact. This work highlights the impact of polygenic contributions to brain function beyond APOE, which could aid potential therapeutic/interventional strategies in the detection and prevention of AD.

  • Effects of intranasal insulin as an enhancer of fear extinction: a randomized, double-blind, placebo-controlled experimental study
    Neuropsychopharmacology (IF 7.160) Pub Date : 2020-01-02
    Diana S. Ferreira de Sá; Sonja Römer; Alexandra H. Brückner; Tobias Issler; Alexander Hauck; Tanja Michael

    Fear-extinction based psychotherapy (exposure) is the most effective method for treating anxiety disorders. Notwithstanding, since some patients show impairments in the unlearning of fear and insufficient fear remission, there is a growing interest in using cognitive enhancers as adjuvants to exposure. As insulin plays a critical role in stress processes and acts as a memory enhancer, this study aimed to assess the capacity of intranasal insulin to augment fear extinction. A double-blind, placebo-controlled differential fear-conditioning paradigm was conducted in 123 healthy participants (63 females). Pictures of faces with neutral expressions were used as conditioned stimuli and electric shocks as unconditioned stimuli. The paradigm consisted of four phases presented on three consecutive days: acquisition (day 1), extinction (day 2), reinstatement and re-extinction (day 3). A single intranasal dose of insulin (160 IU) or placebo was applied on day 2, 45 min before fear extinction. Skin conductance response (SCR), fear-potentiated startle (FPS) and expectancy ratings were assessed. During extinction, the insulin group (independent of sex) showed a significantly stronger decrease in differential FPS in comparison with the placebo group. Furthermore, a sex-specific effect was found for SCR, with women in the insulin group showing a greater decrease of differential SCR both at early extinction and at late re-extinction. Our results provide first evidence that intranasal insulin facilitates fear extinction processes and is therefore a promising adjuvant for extinction-based therapies in anxiety and related disorders. Sex-specific effects should be taken into consideration in future studies.

  • A positron emission tomography occupancy study of brexpiprazole at dopamine D 2 and D 3 and serotonin 5-HT 1A and 5-HT 2A receptors, and serotonin reuptake transporters in subjects with schizophrenia
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-17
    Ragy R. Girgis; Andy Forbes; Anissa Abi-Dargham; Mark Slifstein

    The objective of this study (NCT01854944) was to assess D2/D3, 5-HT1A, 5-HT2A and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profile of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [11C]-(+)-PHNO to measure D2 and D3 receptor occupancy and [11C]CUMI101 to measure 5-HT1A occupancy; Cohort 2 received [11C]MDL100907 for 5-HT2A occupancy and [11C]DASB for SERT occupancy; Cohort 3 underwent scanning with [11C]-(+)-PHNO and [11C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28–55 years), participated in this study. Dose dependency was observed at D2 receptors, with occupancies reaching 64 ± 8% (mean +/− SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D3 receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT2A receptors. Negligible occupancy (<5%) was observed at 5-HT1A and SERT at 4 mg/day. In summary, brexpiprazole demonstrated in vivo binding to D2 receptors and 5-HT2A receptors at steady state after 10 days of daily administration in a dose dependent manner, while binding to D3, 5-HT1A receptors and SERT was not detectable with the radiotracers used for these targets. This pharmacologic profile is consistent with the observed antipsychotic and antidepressant effects.

  • Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-16
    Ryosuke Tarumi; Sakiko Tsugawa; Yoshihiro Noda; Eric Plitman; Shiori Honda; Karin Matsushita; Sofia Chavez; Kyosuke Sawada; Masataka Wada; Mie Matsui; Shinya Fujii; Takahiro Miyazaki; M. Mallar Chakravarty; Hiroyuki Uchida; Gary Remington; Ariel Graff-Guerrero; Masaru Mimura; Shinichiro Nakajima

    Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.

  • A time-dependent role for the transcription factor CREB in neuronal allocation to an engram underlying a fear memory revealed using a novel in vivo optogenetic tool to modulate CREB function
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-14
    Albert Park; Alexander D. Jacob; Brandon J. Walters; Sungmo Park; Asim J. Rashid; Jung Hoon Jung; Jocelyn Lau; G. Andrew Woolley; Paul W. Frankland; Sheena A. Josselyn

    The internal representation of an experience is thought to be encoded by long-lasting physical changes to the brain (“engrams”) (Josselyn et al. Nat Rev Neurosci 16:521–534, 2015; Josselyn et al. J Neurosci 37:4647–4657, 2017; Schacter. 2001; Tonegawa et al. Neuron 87:918–931, 2015). Previously, we (Han et al. Science 316:457–460, 2007) and others (Zhou et al. Nat Neurosci 12:1438–1443, 2009) showed within the lateral amygdala (LA), a region critical for auditory conditioned fear, eligible neurons compete against one other for allocation to an engram. Neurons with relatively higher function of the transcription factor CREB were more likely to be allocated to the engram. In these studies, though, CREB function was artificially increased for several days before training. Precisely when increased CREB function is important for allocation remains an unanswered question. Here, we took advantage of a novel optogenetic tool (opto-DN-CREB) (Ali et al. Chem Biol 22:1531–1539, 2015) to gain spatial and temporal control of CREB function in freely behaving mice. We found increasing CREB function in a small, random population of LA principal neurons in the minutes–hours, but not 24 h, before training was sufficient to enhance memory, likely because these neurons were preferentially allocated to the underlying engram. However, similarly increasing CREB activity in a small population of random LA neurons immediately after training disrupted subsequent memory retrieval, likely by disrupting the precise spatial and temporal patterns of offline post-training neuronal activity and/or function required for consolidation. These findings reveal the importance of the timing of CREB activity in regulating allocation and subsequent memory retrieval, and further, highlight the potential of optogenetic approaches to control protein function with temporal specificity in behaving animals.

  • Correction: Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-12
    Qian Li; Youjin Zhao; Ziqi Chen; Jingyi Long; Jing Dai; Xiaoqi Huang; Su Lui; Joaquim Radua; Eduard Vieta; Graham J. Kemp; John A. Sweeney; Fei Li; Qiyong Gong

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-07
    Antony D. Abraham, Edward J. Y. Leung, Brenden A. Wong, Zeena M. G. Rivera, Lauren C. Kruse, Jeremy J. Clark, Benjamin B. Land

    Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume ∆9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine. This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models.

  • Brain gray matter network organization in psychotic disorders
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-07
    Wenjing Zhang, Lei Du, Sarah K. Keedy, Elena I. Ivleva, Seenae Eum, Li Yao, Carol A. Tamminga, Brett A. Clementz, Matcheri S. Keshavan, Godfrey D. Pearlson, Elliot S. Gershon, Jeffrey R. Bishop, Qiyong Gong, Su Lui, John A. Sweeney

    Abnormal neuroanatomic brain networks have been reported in schizophrenia, but their characterization across patients with psychotic disorders, and their potential alterations in nonpsychotic relatives, remain to be clarified. Participants recruited by the Bipolar and Schizophrenia Network for Intermediate Phenotypes consortium included 326 probands with psychotic disorders (107 with schizophrenia (SZ), 87 with schizoaffective disorder (SAD), 132 with psychotic bipolar disorder (BD)), 315 of their nonpsychotic first-degree relatives and 202 healthy controls. Single-subject gray matter graphs were extracted from structural MRI scans, and whole-brain neuroanatomic organization was compared across the participant groups. Compared with healthy controls, psychotic probands showed decreased nodal efficiency mainly in bilateral superior temporal regions. These regions had altered morphological relationships primarily with frontal lobe regions, and their network-level alterations were associated with positive symptoms of psychosis. Nonpsychotic relatives showed lower nodal centrality metrics in the prefrontal cortex and subcortical regions, and higher nodal centrality metrics in the left cingulate cortex and left thalamus. Diagnosis-specific analysis indicated that individuals with SZ had lower nodal efficiency in bilateral superior temporal regions than controls, probands with SAD only exhibited lower nodal efficiency in the left superior and middle temporal gyrus, and individuals with psychotic BD did not show significant differences from healthy controls. Our findings provide novel evidence of clinically relevant disruptions in the anatomic association of the superior temporal lobe with other regions of whole-brain networks in patients with psychotic disorders, but not in their unaffected relatives, suggesting that it is a disease-related trait. Network disorganization primarily involving frontal lobe and subcortical regions in nonpsychotic relatives may be related to familial illness risk.

  • Correction: Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-04
    Peter Zhukovsky, Mickael Puaud, Bianca Jupp, Júlia Sala-Bayo, Johan Alsiö, Jing Xia, Lydia Searle, Zoe Morris, Aryan Sabir, Chiara Giuliano, Barry J. Everitt, David Belin, Trevor W. Robbins, Jeffrey W. Dalley

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

  • One-year clinical outcomes following theta burst stimulation for post-traumatic stress disorder
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-03
    Nicholas J. Petrosino, Mascha van’t Wout-Frank, Emily Aiken, Hannah R. Swearingen, Jennifer Barredo, Amin Zandvakili, Noah S. Philip

    Theta burst transcranial magnetic stimulation (TBS) is a potential new treatment for post-traumatic stress disorder (PTSD). We previously reported active intermittent TBS (iTBS) was associated with superior clinical outcomes for up to 1-month, in a sample of fifty veterans with PTSD, using a crossover design. In that study, participants randomized to the active group received a total of 4-weeks of active iTBS, or 2-weeks if randomized to sham. Results were superior with greater exposure to active iTBS, which raised the question of whether observed effects persisted over the longer-term. This study reviewed naturalistic outcomes up to 1-year from study endpoint, to test the hypothesis that greater exposure to active iTBS would be associated with superior outcomes. The primary outcome measure was clinical relapse, defined as any serious adverse event (e.g., suicide, psychiatric hospitalization, etc.,) or need for retreatment with repetitive transcranial magnetic stimulation (rTMS). Forty-six (92%) of the initial study’s intent-to-treat participants were included. Mean age was 51.0 ± 12.3 years and seven (15.2%) were female. The group originally randomized to active iTBS (4-weeks active iTBS) demonstrated superior outcomes at one year compared to those originally randomized to sham (2-weeks active iTBS); log-rank ChiSq = 5.871, df = 1, p = 0.015; OR = 3.50, 95% CI = 1.04–11.79. Mean days to relapse were 296.0 ± 22.1 in the 4-week group, and 182.0 ± 31.9 in the 2-week group. When used, TMS retreatment was generally effective. Exploratory neuroimaging revealed default mode network connectivity was predictive of 1-year outcomes (corrected p < 0.05). In summary, greater accumulated exposure to active iTBS demonstrated clinically meaningful improvements in the year following stimulation, and default mode connectivity could be used to predict longer-term outcomes.

  • Chronic opioid pretreatment potentiates the sensitization of fear learning by trauma
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-02
    Zachary T. Pennington, Jeremy M. Trott, Abha K. Rajbhandari, Kevin Li, Wendy M. Walwyn, Christopher J. Evans, Michael S. Fanselow
  • Mechanistic link between right prefrontal cortical activity and anxious arousal revealed using transcranial magnetic stimulation in healthy subjects
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-12-02
    Nicholas L. Balderston, Emily M. Beydler, Camille Roberts, Zhi-De Deng, Thomas Radman, Tiffany Lago, Bruce Luber, Sarah H. Lisanby, Monique Ernst, Christian Grillon

    Much of the mechanistic research on anxiety focuses on subcortical structures such as the amygdala; however, less is known about the distributed cortical circuit that also contributes to anxiety expression. One way to learn about this circuit is to probe candidate regions using transcranial magnetic stimulation (TMS). In this study, we tested the involvement of the dorsolateral prefrontal cortex (dlPFC), in anxiety expression using 10 Hz repetitive TMS (rTMS). In a within-subject, crossover experiment, the study measured anxiety in healthy subjects before and after a session of 10 Hz rTMS to the right dorsolateral prefrontal cortex (dlPFC). It used threat of predictable and unpredictable shock to induce anxiety and anxiety potentiated startle to assess anxiety. Counter to our hypotheses, results showed an increase in anxiety-potentiated startle following active but not sham rTMS. These results suggest a mechanistic link between right dlPFC activity and physiological anxiety expression. This result supports current models of prefrontal asymmetry in affect, and lays the groundwork for further exploration into the cortical mechanisms mediating anxiety, which may lead to novel anxiety treatments.

  • Kinetics of oxytocin effects on amygdala and striatal reactivity vary between women and men
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-30
    Jana Lieberz, Dirk Scheele, Franny B. Spengler, Tatjana Matheisen, Lìa Schneider, Birgit Stoffel-Wagner, Thomas Kinfe, René Hurlemann

    Accumulating evidence suggests that intranasal oxytocin (OXT; 24 IU) reduces amygdala responses to fear-related stimuli in men, while exerting inverse effects in women. However, OXT enhances activity of the brain reward system in both sexes. Importantly, a crucial and still open question is whether there are sex-specific dose-response relationships for the amygdala and striatal regions. To address this question, a total of 90 healthy women participated in a double-blind, placebo-controlled crossover functional magnetic resonance imaging (fMRI) study and the results were compared with our previous findings from men. Participants were randomly assigned to three doses of OXT (6 IU, 12 IU, and 24 IU) and completed an emotional face recognition task including fearful and happy faces of varying emotional intensities. Across doses, OXT enhanced amygdala reactivity to low fearful faces compared to placebo and increased responses to happy faces in the dorsal striatum in women. While treatment effects on amygdala reactivity were evident at each given dose, the OXT effect on striatal responses to social stimuli was more pronounced with higher doses, but this dose-dependent effect did not survive correction for multiple comparisons. Importantly, OXT effects on amygdala and striatal activation significantly differed between sexes and striatal baseline sexual-dimorphic response patterns were diminished after administration of OXT. Our findings suggest that OXT increases the salience of social signals by strengthening the sensitivity for these signals in the amygdala and in the striatum in women, while OXT may primarily induce anxiolysis by reducing amygdala responses in men.

  • Increased subjective and reinforcing effects of initial nicotine exposure in young adults with attention deficit hyperactivity disorder (ADHD) compared to matched peers: results from an experimental model of first-time tobacco use
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-30
    Scott H. Kollins, Maggie Sweitzer, F. Joseph McClernon, Kenneth A. Perkins

    Individuals with attention deficit hyperactivity disorder (ADHD) are at increased risk for adverse cigarette smoking outcomes, and little is known about factors underlying this risk. This study sought to evaluate the effects of initial nicotine exposure in young adults with and without ADHD using a novel paradigm of exposure to model initial smoking experiences. Participants were young adult nonsmokers (n = 61 ADHD, n = 75 Control) between the ages of 18–25 years (inclusive) who reported never having smoked a full cigarette, and no tobacco use in the prior 3 years. Participants were exposed to three different blinded doses of intranasally administered nicotine (0, 0.5, 1.0 mg) across three separate fixed dose experimental sessions. In subsequent sessions, participants were given the opportunity to self-administer nicotine under two different conditions—high and low cognitive demand. Physiological, subjective, and reinforcing effects of nicotine were the main outcomes. Nicotine plasma levels, and no group differences in effects of nicotine on heart rate or blood pressure, confirmed comparable dosing exposure across groups. ADHD participants reported significantly greater dizziness following nicotine, and greater pleasant subjective effects across all conditions, compared to non-ADHD non-smokers. There were no group differences on subjective reports of bad or unpleasant effects. Subsequent nicotine self-administration was significantly higher among non-smokers with ADHD, and their choices of nicotine were not influenced by cognitive condition. There are meaningful differences between young adults with and without ADHD with respect to the initial subjective and reinforcing effects of nicotine; and interventions to prevent use should start prior to typical age of experimentation among ADHD patients.

  • Prior cocaine self-administration impairs attention signals in anterior cingulate cortex
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-27
    Daniela Vázquez, Heather J. Pribut, Amanda C. Burton, Stephen S. Tennyson, Matthew R. Roesch

    Although maladaptive decision-making is a defining feature of drug abuse and addiction, we have yet to ascertain how cocaine self-administration disrupts neural signals in anterior cingulate cortex (ACC), a brain region thought to contribute to attentional control. To address this issue, rats were trained on a reward-guided decision-making task; reward value was manipulated by independently varying the size of or the delay to reward over several trial blocks. Subsequently, rats self-administered either a cocaine (experimental group) or sucrose (control) during 12 consecutive days, after which they underwent a 1-month withdrawal period. Upon completion of this period, rats performed the previously learned reward-guided decision-making task while we recorded from single neurons in ACC. We demonstrate that prior cocaine self-administration attenuates attention and attention-related ACC signals in an intake-dependent manner, and that changes in attention are decoupled from ACC firing. These effects likely contribute to the impaired decision-making—typified by chronic substance abuse and relapse—observed after drug use.

  • D3 dopamine receptors and a missense mutation of fatty acid amide hydrolase linked in mouse and men: implication for addiction
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-27
    Esmaeil Mansouri, José N. Nobrega, Matthew N. Hill, Rachel F. Tyndale, Francis S. Lee, Christian S. Hendershot, Laura M. Best, Patricia Di Ciano, Georgia Balsevich, Mathew E. Sloan, Stephen J. Kish, Junchao Tong, Bernard Le Foll, Isabelle Boileau

    The endocannabinoid and dopaminergic systems have independently been implicated in substance use disorder and obesity. We investigated a potential interaction between genetically inherited variation in fatty acid amide hydrolase (FAAH, C385A), which metabolizes the cannabis-like endocannabinoid anandamide, and dopaminergic system, measured by dopamine receptor levels and mRNA. Binding of the dopamine D3 preferring probe [C-11]-(+)-PHNO was measured with positron emission tomography (PET) in 79 human subjects genotyped for the FAAH C385A polymorphism (36/79 AC + AA). Autoradiography with [H-3]-(+)-PHNO and in situ hybridization with a D3-specific S-35 riboprobe were carried out in 30 knock-in mice with the FAAH C385A polymorphism (20/30 AC + AA). We found that the FAAH genetic variant C385A was associated with significantly higher (+)-PHNO binding in both humans and in knock-in mice, and this effect was restricted to D3 selective brain regions (limbic striatum, globus pallidus, and ventral pallidum (9–14%; p < 0.04) in humans and Islands of Calleja (28%; p = 0.036) in mice). In situ hybridization with a D3-specific S-35 riboprobe in FAAH knock-in C385A mice confirmed significantly increased D3 receptor mRNA across examined regions (7–44%; p < 0.02). The association of reduced FAAH function with higher dopamine D3 receptors in human and mouse brain provide a mechanistic link between two brain systems that have been implicated in addiction-risk. This may explain the greater vulnerability for addiction and obesity in individuals with C385A genetic variant and by extension, suggest that a D3 antagonism strategy in substance use disorders should consider FAAH C385A polymorphism.

  • Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-27
    Stephen K. Amoah, Brian A. Rodriguez, Constantine N. Logothetis, Praveen Chander, Carl M. Sellgren, Jason P. Weick, Steven D. Sheridan, Lauren L. Jantzie, Maree J. Webster, Nikolaos Mellios

    The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Last, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

  • Factors associated with successful antipsychotic dose reduction in schizophrenia: a systematic review of prospective clinical trials and meta-analysis of randomized controlled trials
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-26
    Hideaki Tani, Shotaro Takasu, Hiroyuki Uchida, Takefumi Suzuki, Masaru Mimura, Hiroyoshi Takeuchi

    This systematic review and meta-analysis examined predictors of successful antipsychotic dose reduction in schizophrenia. Prospective clinical trials and randomized controlled trials (RCTs) investigating antipsychotic dose reduction in schizophrenia were selected for systematic review and meta-analysis, respectively. In total, 37 trials were identified. Only eight studies focused on second-generation antipsychotics (SGAs); no studies investigated long-acting injectable SGAs. Of 24 studies evaluating relapse or symptom changes, 20 (83.3%) met the criteria for successful dose reduction. Factors associated with successful dose reduction were study duration <1 year, age >40 years, duration of illness >10 years, and post-reduction chlorpromazine equivalent (CPZE) dose >200 mg/day. Clinical deterioration was mostly re-stabilized by increasing the dose to the baseline level (N = 7/8, 87.5%). A meta-analysis of 18 RCTs revealed that relapse rate was significantly higher in the reduction group than the maintenance group (risk ratio [RR] = 1.96; 95% confidence interval [CI], 1.23–3.12), whereas neurocognition was significantly improved (standardized mean difference = 0.69; 95% CI, 0.25–1.12). Subgroup analysis indicated that only a post-reduction CPZE dose ≤200 mg/day was associated with an increased risk of relapse (RR = 2.79; 95% CI, 1.29–6.03). Thus, when reducing antipsychotic doses, clinicians should consider the long-term risk of relapse in younger patients with a relatively short illness duration and keep the final doses higher than CPZE 200 mg/day. Further studies, particularly those involving SGAs, are warranted to determine the optimal strategies for successful antipsychotic dose reduction in schizophrenia.

  • Heterogeneity and efficacy of antipsychotic treatment for schizophrenia with or without treatment resistance: a meta-analysis
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-25
    Yuya Mizuno, Robert A. McCutcheon, Stefan P. Brugger, Oliver D. Howes

    Two important clinical questions are whether there is a subtype of schizophrenia which responds differently to clozapine relative to other antipsychotics, and whether greater efficacy of clozapine is dependent on the degree of treatment-resistance. The authors address this by examining both variability and magnitude of response in patients treated with clozapine and other antipsychotics for both treatment-resistant schizophrenia (TRS) and non-resistant schizophrenia. Double-blind randomised controlled trials comparing clozapine with other antipsychotics in patients with schizophrenia were identified using five databases. Standard deviations and means of change in total, positive, and negative symptoms were extracted. Variability ratio (VR) and coefficient of variation ratio (CVR) were used to quantify relative variability in symptom change. Hedges’ g was used to quantify mean differences. Ten TRS studies (n = 822) and 29 non-TRS studies (n = 2566) were meta-analysed. Relative variability in change of total symptoms did not differ significantly between clozapine and other antipsychotics in TRS studies (VR = 1.84; 95%CI, 0.85–4.02). These findings were similar with CVR, and for positive and negative symptoms. Clozapine was superior to other antipsychotics in improving total symptoms in both TRS (g = 0.34; 95%CI, 0.13–0.56) and non-TRS (g = 0.20; 95%CI, 0.08–0.32) studies. Furthermore, clozapine was superior in improving positive symptoms in both study groups, but not for negative symptoms. Pooled effect sizes showed no significant difference between TRS and non-TRS studies. These findings do not support a subtype of schizophrenia which responds specifically to clozapine. Clozapine is more effective than other antipsychotics irrespective of treatment-resistance, arguing for its use more generally in schizophrenia. PROSPERO CRD42018086507

  • Single and repeated ketamine infusions for reduction of suicidal ideation in treatment-resistant depression
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-23
    Jennifer L. Phillips, Sandhaya Norris, Jeanne Talbot, Taylor Hatchard, Abigail Ortiz, Meagan Birmingham, Olabisi Owoeye, Lisa A. Batten, Pierre Blier

    Repeated administration of subanesthetic intravenous ketamine may prolong the rapid decrease in suicidal ideation (SI) elicited by single infusions. The purpose of this secondary analysis was to evaluate reduction in SI with a single ketamine infusion compared with an active control, and prolonged suppression of SI with repeated and maintenance infusions. Thirty-seven participants with treatment-resistant depression (TRD) and baseline SI first received a single ketamine infusion during a randomized, double-blind crossover with midazolam. Following relapse of depressive symptoms, participants received six open-label ketamine infusions administered thrice-weekly over 2 weeks. Antidepressant responders (≥50% decrease in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) received four further open-label infusions administered once-weekly. Changes in SI were assessed with the suicide items on the MADRS (item 10, MADRS-SI) and the Quick Inventory of Depressive Symptomatology-Self Report (item 12, QIDS-SI). Linear mixed models revealed that compared with midazolam, a single ketamine infusion elicited larger reduction in SI (P = 0.01), with maximal effects measured at 7 days postinfusion (P < 0.001, Cohen’s d = 0.83). Participants had cumulative reductions in MADRS-SI scores with repeated infusions (P < 0.001), and no further change with maintenance infusions (P = 0.94). QIDS-SI results were consistent with MADRS-SI. Overall, 69% of participants had a complete alleviation of SI following repeated infusions. In TRD, single and repeated ketamine infusions resulted in decreases in SI which were maintained with once-weekly maintenance infusions. This study adds to the growing body of research suggesting ketamine as a possible novel treatment strategy for SI in mood disorders.

  • Nucleus accumbens volume as a predictor of anxiety symptom improvement following CBT and SSRI treatment in two independent samples
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-22
    Katie L. Burkhouse, Jagan Jimmy, Nicholas Defelice, Heide Klumpp, Olusola Ajilore, Bobby Hosseini, Kate D. Fitzgerald, Christopher S. Monk, K. Luan Phan

    Structural variations of neural regions implicated in fear responses have been well documented in the pathophysiology of anxiety and may play an important role in treatment response. We examined whether gray matter volume of three neural regions supporting fear and avoidance responses [bilateral amygdala, nucleus accumbens (NAcc), and ventromedial prefrontal cortex (PFC)] predicted cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) treatment outcome in two independent samples of patients with anxiety disorders. Study 1 consisted of 81 adults with anxiety disorders and Study 2 included 55 children and adolescents with anxiety disorders. In both studies, patients completed baseline structural MRI scans and received either CBT or SSRI treatment. Clinician-rated interviews of anxiety symptoms were assessed at baseline and posttreatment. Among the adult sample, greater pre-treatment bilateral NAcc volume was associated with a greater reduction in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment. Greater left NAcc volume also predicted greater decreases in clinician-rated anxiety symptoms pre-to-post CBT and SSRI treatment among youth with current anxiety. Across studies, results were similar across treatments, and findings were maintained when adjusting for patient’s age, sex, and total intracranial brain volume. We found no evidence for baseline amygdala or ventromedial PFC volume serving as treatment predictors across the two samples. Together, these findings provide promising support for the role of NAcc volume as an objective marker of anxiety treatment improvement that spans across development. Future studies should clarify the specific mechanisms through which NAcc volume exerts its therapeutic effects.

  • Rats display empathic behavior independent of the opportunity for social interaction
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-21
    Stewart S. Cox, Carmela M. Reichel

    Empathy, the capacity for shared emotional valence with others, can allow for cooperativity and social bonding between individuals. However, clinical studies indicate it is dysregulated in neuropsychiatric disorders like autism and addiction, making a translationally relevant model of empathy extremely important. The evolutionary basis of the empathic behaviors observed across numerous species can be described using the Perception Action Model (PAM), in which shared affect can promote an action that eliminates the distress of both the “Target” and, by extension, the “Observer”. Increasing evidence suggests rodents will work to reduce the distress of a conspecific, but current models of helping behavior are unable to completely parse apart whether the reported behavior is driven by empathy or social reward. The current study demonstrates, using a novel behavioral model, rats learn to aid a distressed conspecific in the absence of social reward, retain the task over time, and previous experience increases the rate of task acquisition. Further, our model suggests that empathic behavior is subject to low effort as compared to a social reward. We next validated the specificity of this model to study empathic processes, characterized the importance of both the Target’s level of distress and the impact of the Observer’s familiarity with the target on empathic behavior. Overall, we believe this model adheres to the PAM of empathy by eliminating the influence of social interaction. Importantly, it can be used to directly evaluate the neurocircuitry of empathy and explore the interplay between blunted empathic behavior and neuropsychiatric disorders.

  • Cognitive rigidity and BDNF-mediated frontostriatal glutamate neuroadaptations during spontaneous nicotine withdrawal
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-21
    Robert D. Cole, Matty Zimmerman, Anastasia Matchanova, Munir Gunes Kutlu, Thomas J. Gould, Vinay Parikh

    Cognitive flexibility is the ability to switch strategic responses adaptively in changing environments. Cognitive rigidity imposed by neural circuit adaptations during nicotine abstinence may foster maladaptive nicotine taking in addicts. We systematically examined the effects of spontaneous withdrawal in mice exposed to either nicotine (6.3 or 18 mg/kg/day) or saline for 14 days on cognitive flexibility using an operant strategy set-shifting task. Because frontostriatal circuits are critical for cognitive flexibility and brain-derived neurotrophic factor (BDNF) modulates glutamate plasticity in these circuits, we also explored the effects of nicotine withdrawal on these neurochemical substrates. Mice undergoing nicotine withdrawal required more trials to attain strategy-switching criterion. Error analysis show that animals withdrawn from both nicotine doses committed higher perseverative errors, which correlated with measures of anxiety. However, animals treated with the higher nicotine dose also displayed more strategy maintenance errors that remained independent of negative affect. BDNF mRNA expression increased in the medial prefrontal cortex (mPFC) following nicotine withdrawal. Surprisingly, BDNF protein declined in mPFC but was elevated in dorsal striatum (DS). DS BDNF protein positively correlated with perseverative and maintenance errors, suggesting mPFC-DS overflow of BDNF during withdrawal. BDNF-evoked glutamate release and synapsin phosphorylation was attenuated within DS synapses, but enhanced in the nucleus accumbens, suggesting a dichotomous role of BDNF signaling in striatal regions. Taken together, these data suggest that spontaneous nicotine withdrawal impairs distinct components of cognitive set-shifting and these deficits may be linked to BDNF-mediated alterations in glutamate signaling dynamics in discrete frontostriatal circuits.

  • Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-20
    Timothy J. O’Neal, Marlaena N. Nooney, Katie Thien, Susan M. Ferguson

    Opioid addiction has been declared a public health emergency, with fatal overdoses following relapse reaching epidemic proportions and disease-associated costs continuing to escalate. Relapse is often triggered by re-exposure to drug-associated cues, and though the neural substrates responsible for relapse in vulnerable individuals remains ambiguous, the nucleus accumbens (NAc) has been shown to play a central role. NAc direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) can have oppositional control over reward-seeking and associative learning and are critically involved in reinstatement of psychostimulant-seeking. However, whether these pathways similarly regulate reinstatement of opioid-seeking remains unknown, as is their role in modulating motivation to take opioids. Here, we describe a method for classifying addiction severity in outbred rats following intermittent-access heroin self-administration that identifies subgroups as addiction-vulnerable (high-risk) or addiction-resistant (low-risk). Using dual viral-mediated gene transfer of DREADDs, we show that transient inactivation of dMSNs or activation of iMSNs is capable of suppressing cue-induced reinstatement of heroin-seeking in high- but not low-risk rats. Surprisingly, however, the motivation to self-administer heroin was unchanged, indicating a divergence in the encoding of heroin-taking and heroin-seeking in rats. We further show that transient activation of dMSNs or inactivation of iMSNs exacerbates cue-induced reinstatement of heroin-seeking in high- but not low-risk rats, again with no effect on motivation. These findings demonstrate a critical role for dMSNs and iMSNs in encoding vulnerability to reinstatement of heroin-seeking and provide much needed insight into the specific neurobiological changes that occur in vulnerable groups following heroin self-administration.

  • Distinct acute effects of LSD, MDMA, and d -amphetamine in healthy subjects
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-16
    Friederike Holze, Patrick Vizeli, Felix Müller, Laura Ley, Raoul Duerig, Nimmy Varghese, Anne Eckert, Stefan Borgwardt, Matthias E. Liechti

    Lysergic acid diethylamide (LSD) is a classic psychedelic, 3,4-methylenedioxymethamphetamine (MDMA) is an empathogen, and d-amphetamine is a classic stimulant. All three substances are used recreationally. LSD and MDMA are being investigated as medications to assist psychotherapy, and d-amphetamine is used for the treatment of attention-deficit/hyperactivity disorder. All three substances induce distinct acute subjective effects. However, differences in acute responses to these prototypical psychoactive substances have not been characterized in a controlled study. We investigated the acute autonomic, subjective, and endocrine effects of single doses of LSD (0.1 mg), MDMA (125 mg), d-amphetamine (40 mg), and placebo in a randomized, double-blind, cross-over study in 28 healthy subjects. All of the substances produced comparable increases in hemodynamic effects, body temperature, and pupil size, indicating equivalent autonomic responses at the doses used. LSD and MDMA increased heart rate more than d-amphetamine, and d-amphetamine increased blood pressure more than LSD and MDMA. LSD induced significantly higher ratings on the 5 Dimensions of Altered States of Consciousness scale and Mystical Experience Questionnaire than MDMA and d-amphetamine. LSD also produced greater subjective drug effects, ego dissolution, introversion, emotional excitation, anxiety, and inactivity than MDMA and d-amphetamine. LSD also induced greater impairments in subjective ratings of concentration, sense of time, and speed of thinking compared with MDMA and d-amphetamine. MDMA produced greater ratings of good drug effects, liking, high, and ego dissolution compared with d-amphetamine. d-Amphetamine increased ratings of activity and concentration compared with LSD. MDMA but not LSD or d-amphetamine increased plasma concentrations of oxytocin. None of the substances altered plasma concentrations of brain-derived neurotrophic factor. These results indicate clearly distinct acute effects of LSD, MDMA, and d-amphetamine and may assist the dose-finding in substance-assisted psychotherapy research.

  • The effect of chronic oxytocin treatment during abstinence from methamphetamine self-administration on incubation of craving, reinstatement, and anxiety
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-12
    Nicholas A. Everett, Sarah J. Baracz, Jennifer L. Cornish

    Methamphetamine (METH) abuse is characterised by chronic relapse and anxiety, for which there are no effective pharmacotherapies. Acute treatment with the neuropeptide oxytocin has shown therapeutic potential for METH addiction and has social and anxiolytic effects in METH-naïve rats. However, the effects of chronic oxytocin treatment in METH-experienced rats are unknown. This study investigated the effects of repeated oxytocin treatment during abstinence from METH self-administration on incubation of cue-induced relapse, yohimbine- and METH-induced reinstatement, trait anxiety, and social interaction. Male and female Sprague-Dawley rats self-administered intravenous METH for 2 h/day (12 days) and then on short-access (2 h/day; ShA) or long-access (6 h/day; LgA) sessions (10 days). Rats underwent 30 days of drug abstinence, during which they received 15 days of intraperitoneal oxytocin (1 mg/kg) or saline (days 6–20) injections. Anxiety and social interaction were tested on days 25–28, and incubation was assessed by testing cue-induced relapse on days 2 and 30. Rats underwent extinction after the final cue-relapse test, followed by yohimbine- and METH-primed reinstatement. LgA, but not ShA rats exhibited incubation of METH-craving and enhanced METH-primed reinstatement in both sexes, and enhanced yohimbine-induced reinstatement in females. Importantly, chronic oxytocin attenuated incubation and METH-primed reinstatement in both sexes, and yohimbine-induced reinstatement in females, although only in LgA rats. LgA produced a heightened anxiety phenotype, which was partially rescued by chronic oxytocin treatment. Using a translatable addiction model, these findings demonstrate the therapeutic efficacy of chronic oxytocin after METH self-administration and supports the clinical utility of oxytocin for METH addiction in both sexes.

  • Serotonin release measured in the human brain: a PET study with [ 11 C]CIMBI-36 and d-amphetamine challenge
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-12
    David Erritzoe, Abhishekh H. Ashok, Graham E. Searle, Alessandro Colasanti, Samuel Turton, Yvonne Lewis, Mickael Huiban, Sara Moz, Jan Passchier, Azeem Saleem, John Beaver, Anne Lingford-Hughes, David J. Nutt, Oliver D. Howes, Roger N. Gunn, Gitte M. Knudsen, Eugenii A. Rabiner

    Positron emission tomography (PET) enables non-invasive estimation of neurotransmitter fluctuations in the living human brain. While these methods have been applied to dopamine and some other transmitters, estimation of 5-hydroxytryptamine (5-HT; Serotonin) release has proved to be challenging. Here we demonstrate the utility of the novel 5-HT2A receptor agonist radioligand, [11C]CIMBI-36, and a d-amphetamine challenge to evaluate synaptic 5-HT changes in the living human brain. Seventeen healthy male volunteers received [11C]CIMBI-36 PET scans before and 3 h after an oral dose of d-amphetamine (0.5 mg/kg). Dynamic PET data were acquired over 90 min, and the total volume of distribution (VT) in the frontal cortex and the cerebellum derived from a kinetic analysis using MA1. The frontal cortex binding potential (BPNDfrontal) was calculated as (VTfrontal/VTcerebellum) − 1. ∆BPNDfrontal = 1 − (BPNDfrontal post-dose/BPNDfrontal baseline) was used as an index of 5-HT release. Statistical inference was tested by means of a paired Students t-test evaluating a reduction in post-amphetamine [11C]CIMBI-36 BPNDfrontal. Following d-amphetamine administration, [11C]CIMBI-36 BPNDfrontal was reduced by 14 ± 13% (p = 0.002). Similar effects were observed in other cortical regions examined in an exploratory analysis. [11C]CIMBI-36 binding is sensitive to synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge, the evaluation of the human brain serotonin system in neuropsychiatric disorders, such as major depression and Parkinson’s disease is enabled.

  • Repetitive transcranial magnetic stimulation targeting the insular cortex for reduction of heavy drinking in treatment-seeking alcohol-dependent subjects: a randomized controlled trial
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-11
    Irene Perini, Robin Kämpe, Theodor Arlestig, Hanna Karlsson, Andreas Löfberg, Michal Pietrzak, Abraham Zangen, Markus Heilig

    Insula responses to drug cues are correlated with cravings, and lesions in this area reduce nicotine seeking. Here, we investigated the potential efficacy of repetitive transcranial magnetic stimulation (rTMS) targeting the insula in alcohol addiction. Treatment-seeking alcohol-dependent patients (Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition; N = 56) participated in this double-blind, sham-controlled, randomized trial. Participants received 10 Hz rTMS or sham using an H8 coil, 5 days a week for 3 weeks. Stimulation targeted insular cortex and overlaying regions bilaterally, while excluding anterior prefrontal areas. Craving and self-reported as well as biomarker-based drinking measures were collected at baseline, during treatment, and through 12 weeks. Resting-state magnetic resonance imaging (rsMRI) data were collected before and after treatment. Task-based MRI was used to probe brain correlates of reward processing, affective responses, and alcohol following completion of treatment. A marked overall decrease in craving and drinking measures was observed during treatment, but did not differ between rTMS or sham stimulation. Both groups equally increased their alcohol use following completion of treatment and through the 12-week follow-up. Analysis using seeds in the insula identified differences in resting-state connectivity between active and sham groups at completion of treatment, potentially indicating an ability of treatment to modify insula function. However, while each task robustly replicated brain responses established in the literature, no effects of rTMS were found. Collectively, this study does not support efficacy of rTMS targeting the insula in alcohol addiction.

  • Amphetamine disrupts haemodynamic correlates of prediction errors in nucleus accumbens and orbitofrontal cortex
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-08
    Emilie Werlen, Soon-Lim Shin, Francois Gastambide, Jennifer Francois, Mark D. Tricklebank, Hugh M. Marston, John R. Huxter, Gary Gilmour, Mark E. Walton

    In an uncertain world, the ability to predict and update the relationships between environmental cues and outcomes is a fundamental element of adaptive behaviour. This type of learning is typically thought to depend on prediction error, the difference between expected and experienced events and in the reward domain that has been closely linked to mesolimbic dopamine. There is also increasing behavioural and neuroimaging evidence that disruption to this process may be a cross-diagnostic feature of several neuropsychiatric and neurological disorders in which dopamine is dysregulated. However, the precise relationship between haemodynamic measures, dopamine and reward-guided learning remains unclear. To help address this issue, we used a translational technique, oxygen amperometry, to record haemodynamic signals in the nucleus accumbens (NAc) and orbitofrontal cortex (OFC), while freely moving rats performed a probabilistic Pavlovian learning task. Using a model-based analysis approach to account for individual variations in learning, we found that the oxygen signal in the NAc correlated with a reward prediction error, whereas in the OFC it correlated with an unsigned prediction error or salience signal. Furthermore, an acute dose of amphetamine, creating a hyperdopaminergic state, disrupted rats’ ability to discriminate between cues associated with either a high or a low probability of reward and concomitantly corrupted prediction error signalling. These results demonstrate parallel but distinct prediction error signals in NAc and OFC during learning, both of which are affected by psychostimulant administration. Furthermore, they establish the viability of tracking and manipulating haemodynamic signatures of reward-guided learning observed in human fMRI studies by using a proxy signal for BOLD in a freely behaving rodent.

  • Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-07
    Annabel K. Short, Pamela M. Maras, Aidan L. Pham, Autumn S. Ivy, Tallie Z. Baram

    In humans, early-life adversity is associated with impairments in learning and memory that may emerge later in life. In rodent models, early-life adversity directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of early-life adversity on hippocampal dendritic arborization, synapse number and memory-function. Early-life adversity increases hippocampal CRH expression, and blocking hippocampal CRH receptor type-1 (CRHR1) immediately following early-life adversity prevented the consequent memory and LTP defects. Here, we tested if blocking CRHR1 in young adults ameliorates early-life adversity-provoked memory deficits later in life. A weeklong course of a CRHR1 antagonist in 2-month- old male rats prevented early-life adversity-induced deficits in object recognition memory that emerged by 12 months of age. Surprisingly, whereas the intervention did not mitigate early-life adversity-induced spatial memory losses at 4 and 8 months, it restored hippocampus-dependent location memory in 12-month-old rats that experienced early-life adversity. Neither early-life adversity nor CRHR1 blockade in the adult influenced anxiety- or depression-related behaviors. Altogether, these findings suggest that cognitive deficits attributable to adversity during early-life-sensitive periods are at least partially amenable to interventions later in life.

  • Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-06
    Qian Li, Youjin Zhao, Ziqi Chen, Jingyi Long, Jing Dai, Xiaoqi Huang, Su Lui, Joaquim Radua, Eduard Vieta, Graham J. Kemp, John A. Sweeney, Fei Li, Qiyong Gong

    Alterations in cortical thickness have been identified in major depressive disorder (MDD), but findings have been variable and inconsistent. To date, no reliable tools have been available for the meta-analysis of surface-based morphometric (SBM) studies to effectively characterize what has been learned in previous studies, and drug treatments may have differentially impacted findings. We conducted a comprehensive meta-analysis of magnetic resonance imaging (MRI) studies that explored cortical thickness in medication-free patients with MDD, using a newly developed meta-analytic mask compatible with seed-based d mapping (SDM) meta-analytic software. We performed the meta-regression to explore the effects of demographics and clinical characteristics on variation in cortical thickness in MDD. Fifteen studies describing 529 patients and 586 healthy controls (HCs) were included. Medication-free patients with MDD, relative to HCs, showed a complex pattern of increased cortical thickness in some areas (posterior cingulate cortex, ventromedial prefrontal cortex, and anterior cingulate cortex) and decreased cortical thickness in others (gyrus rectus, orbital segment of the superior frontal gyrus, and middle temporal gyrus). Most findings in the whole sample analysis were confirmed in a meta-analysis of studies recruiting medication-naive patients. Using the new mask specifically developed for SBM studies, this SDM meta-analysis provides evidence for regional cortical thickness alterations in MDD, mainly involving increased cortical thickness in the default mode network and decreased cortical thickness in the orbitofrontal and temporal cortex.

  • Replicating predictive serum correlates of greater translocator protein distribution volume in brain
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-11-04
    Sophia Attwells, Elaine Setiawan, Alan A. Wilson, Pablo M. Rusjan, Laura Miler, Cynthia Xu, Celeste Hutton, Muhammad I. Husain, Stephen Kish, Neil Vasdev, Sylvain Houle, Jeffrey H. Meyer

    Greater activation of glia, a key component of neuroinflammation, is an important process to target in neuropsychiatric illnesses. However, the magnitude of gliosis varies across cases so low-cost predictors are needed to stratify subjects for clinical trials. Here, several such blood serum measures were assessed in relation to TSPO VT, an index of translocator protein density, measured with positron emission tomography. Blood serum concentration of several products known to be synthesized by activated microglia (and to some extent astroglia) [prostaglandin E2 (PGE2), prostaglandin F2 alpha (PGF2α), and tumor necrosis factor alpha (TNFα)], controlled by an index of peripheral inflammation [C-reactive protein (CRP)] and TSPO VT were measured in 3 cohorts: prefrontal cortex TSPO VT of 20 subjects with major depressive episodes (MDEs) from major depressive disorder (MDD); and 56 subjects with treatment resistant MDEs from MDD; and dorsal caudate TSPO VT of 20 subjects with obsessive-compulsive disorder. Ln(PGE2/CRP) and ln(TNFα/CRP) consistently correlated with TSPO VT (R2 = 0.36 to 0.11, p = 0.0030 to p = 0.0076). Assessment of threshold serum values to predict highly elevated TSPO VT, demonstrated that a positive predictive value (PPV) of 80% was possible while retaining 40% of participant samples and that receiver operating curves (ROC) ranged from 75 to 81%. Post-hoc selection of ln(CRP) was more predictive (R2 = 0.23 to 0.39, p = 0.0058 to p = 0.00013; ROC > 80%). Systematic assessment of selected peripheral inflammatory markers is promising for developing low cost predictors of TSPO VT. Marker thresholds with high PPV will improve subject stratification for clinical trials of glial targeting therapeutics.

  • Alterations in functional brain networks in depressed patients with a suicide attempt history
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-31
    JeYoung Jung, Sunyoung Choi, Kyu-Man Han, Aram Kim, Wooyoung Kang, Jong-Woo Paik, Hae-Woo Lee, Byung-Joo Ham

    Suicide is a major challenge in public health and is strongly associated with major depressive disorder (MDD). Despite recent neuroimaging developments, the neural correlates of suicide behavior in patients with MDD remain unclear. Independent component analysis (ICA) for neuroimaging data allows the identification of functional brain networks without prior regions of interest and may help to identify neurobiological markers of specific disorders. Using ICA, we investigated the differences in resting-state brain networks in patients with MDD who had or did not have a history of suicide attempts and in healthy controls (HCs). Suicidal depressed (SD) patients, non-suicidal depressed (NSD) patients, and HCs significantly differed from each other in the pattern of connectivity of multiple functional networks, network synchronization, and functional network connectivity (FNC). The patient groups had a decreased network synchronization in the insular, cerebellum, basal ganglia, thalamus, operculum, frontoparietal cortices, and sensory cortices relative to the HCs. The decreased FNC between these networks (insular–default mode network and insular–cerebellum) was found in the SD group compared to the NSD and HC groups. These differences were not related to illness duration and medication status differences between SD and NSD. Furthermore, the degree of FNC in these networks was associated with the suicide ideation and stress level. Our results demonstrated that widespread but discrete network changes in brain networks and their interconnectivity was associated with suicide attempts in patients with MDD. Our results suggest that the neural basis underlying the psychopathology of attempted suicide in patients with MDD involves multiple brain networks and their interaction.

  • John W. Holaday, Ph.D.
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-28
    R. Adron Harris
  • Angiotensin involvement in trauma processing—exploring candidate neurocognitive mechanisms of preventing post-traumatic stress symptoms
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-26
    Lorika Shkreli, Marcella Lydia Woud, Roger Ramsbottom, Aleksandra Ewa Rupietta, Gerd Thomas Waldhauser, Robert Kumsta, Andrea Reinecke

    The angiotensin-II antagonist losartan is a promising candidate that has enhanced extinction in a post-traumatic stress disorder (PTSD) animal model and was related to reducing PTSD symptom development in humans. Here, we investigate the neurocognitive mechanisms underlying these results, testing the effect of losartan on data-driven and contextual processing of traumatic material, mechanisms proposed to be relevant for PTSD development. In a double-blind between-subject design, 40 healthy participants were randomised to a single oral dose of losartan (50 mg) or placebo, 1 h before being exposed to distressing films as a trauma analogue while heart rate (HR) was measured. Peritraumatic processing was investigated using blurry picture stimuli from the films, which transformed into clear images. Data-driven processing was measured by the level of blurriness at which contents were recognised. Contextual processing was measured as the amount of context information retrieved when describing the pictures’ contents. Negative-matched control images were used to test perceptual processing of peripheral trauma-cues. Post-traumatic stress symptoms were assessed via self-report questionnaires after analogue trauma and an intrusion diary completed over 4 days following the experiment. Compared to placebo, losartan facilitated contextual processing and enhanced detail perception in the negative-match pictures. During the films, the losartan group recorded lower HR and higher HR variability, reflecting lower autonomic stress responses. We discuss potential mechanisms of losartan in preventing PTSD symptomatology, including the role of reduced arousal and increased contextual processing during trauma exposure, as well as increased threat-safety differentiation when encountering peripheral trauma-cues in the aftermaths of traumatic events.

  • Exploring lithium’s transcriptional mechanisms of action in bipolar disorder: a multi-step study
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-25
    Ibrahim A. Akkouh, Silje Skrede, Asbjørn Holmgren, Kari M. Ersland, Lars Hansson, Shahram Bahrami, Ole A. Andreassen, Vidar M. Steen, Srdjan Djurovic, Timothy Hughes

    Lithium has been the first-line treatment for bipolar disorder (BD) for more than six decades. Although the molecular effects of lithium have been studied extensively and gene expression changes are generally believed to be involved, the specific mechanisms of action that mediate mood regulation are still not known. In this study, a multi-step approach was used to explore the transcriptional changes that may underlie lithium’s therapeutic efficacy. First, we identified genes that are associated both with lithium exposure and with BD, and second, we performed differential expression analysis of these genes in brain tissue samples from BD patients (n = 42) and healthy controls (n = 42). To identify genes that are regulated by lithium exposure, we used high-sensitivity RNA-sequencing of corpus callosum (CC) tissue samples from lithium-treated (n = 8) and non-treated (n = 9) rats. We found that lithium exposure significantly affected 1108 genes (FDR < 0.05), 702 upregulated and 406 downregulated. These genes were mostly enriched for molecular functions related to signal transduction, including well-established lithium-related pathways such as mTOR and Wnt signaling. To identify genes with differential expression in BD, we performed expression quantitative trait loci (eQTL) analysis on BD-associated genetic variants from the most recent genome-wide association study (GWAS) using three different gene expression databases. We found 307 unique eQTL genes regulated by BD-associated variants, of which 12 were also significantly modulated by lithium treatment in rats. Two of these showed differential expression in the CC of BD cases: RPS23 was significantly downregulated (p = 0.0036, fc = 0.80), while GRIN2A showed suggestive evidence of downregulation in BD (p = 0.056, fc = 0.65). Crucially, GRIN2A was also significantly upregulated by lithium in the rat brains (p = 2.2e-5, fc = 1.6), which suggests that modulation of GRIN2A expression may be a part of the therapeutic effect of the drug. These results indicate that the recent upsurge in research on this central component of the glutamatergic system, as a target of novel therapeutic agents for affective disorders, is warranted and should be intensified.

  • Dissociable roles for the ventral and dorsal medial prefrontal cortex in cue-guided risk/reward decision making
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-25
    Mieke van Holstein, Stan B. Floresco

    Converging evidence from studies with animals and humans have implicated separate regions of the medial prefrontal cortex (mPFC) corresponding to the anterior cingulate cortex (ACC), in mediating different aspects of reward-related decisions involving uncertainty or risk. However, the dissociable contributions of subregions of the ACC remain unclear, as discrepancies exist between human neuroimaging findings and preclinical rodent studies. To clarify how ventral vs. dorsal regions of the mPFC contribute to risk/reward decision making, the present study assessed the effects of inactivation of different subregions on performance of a “Blackjack task” that measured cue-guided decision making and shares similarities with paradigms used with humans. Male, Long-Evans rats were well-trained to choose between a Small/Certain reward vs a Large/Risky reward delivered with variable probabilities (i.e., good vs. poor-odds, 50% vs. 12.5%). The odds of obtaining the larger reward was signaled by auditory cues at the start of each trial. Inactivation of the ventral, infralimbic region of the mPFC increased risky choice selectively when the odds of winning were poor. By contrast, inactivation of the prelimbic and anterior cingulate regions of the dorsal mPFC led to suboptimal reductions in risky choice on good-odds trials. The effects of prelimbic vs anterior cingulate inactivations were associated with context-dependent alterations in reward vs negative feedback, respectively. These results further clarify the distinct yet complementary manners in which separate ACC regions promote optimal risk/reward decision making and complement neuroimaging findings that activity in human ventral vs dorsal ACC promotes risk aversion or risky choices.

  • Auditory sensory gating in young adolescents with early-onset psychosis: a comparison with attention deficit/hyperactivity disorder
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-24
    Cecilie Koldbæk Lemvigh, Jens Richardt Møllegaard Jepsen, Birgitte Fagerlund, Anne Katrine Pagsberg, Birte Yding Glenthøj, Jacob Rydkjær, Bob Oranje

    Numerous studies have demonstrated impaired sensory gating in schizophrenia and this impairment has been proposed as a candidate biomarker for the disorder. The typical age of onset for schizophrenia is early adulthood, however a sizable group of patients present with psychotic symptoms before the age of 18, commonly referred to as early-onset psychosis (EOP). How an earlier onset influences sensory gating is currently unknown. Impaired sensory gating may not be specific to psychosis, but rather a shared disturbance of neurodevelopmental disorders, such as attention deficit/hyperactivity disorder (ADHD). Therefore, the current study investigated P50 suppression in young adolescents (12–17 years old) with either EOP (N = 55) or ADHD (N = 28) and age and gender matched healthy controls (HC) (N = 71). In addition to P50 suppression, N100 and P200 suppression data were also analyzed. No significant group differences in either raw mean P50 amplitude or mean P50 gating ratios were observed between EOP, ADHD, and HC. Additionally, we observed no P50 suppression deficit in those EOP patients diagnosed with schizophrenia (N = 39). Similarly, we observed no differences in N100 or P200 between the three groups. Healthy levels of P50 suppression were found in both patient groups. The results are in line with some previous studies showing healthy levels of P50 suppression in the early phases of schizophrenia. Our findings do not support P50 sensory gating as a valid biomarker for EOP or ADHD.

  • Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-24
    Line Skute Bråten, Tore Haslemo, Marin M. Jukic, Magnus Ingelman-Sundberg, Espen Molden, Marianne Kristiansen Kringen

    Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into CYP2C19 genotype-predicted phenotype subgroups, i.e. normal (NMs), ultra rapid (UMs), intermediate (IMs), and poor metabolisers (PMs). The differences in dose-harmonized serum concentrations of sertraline and N-desmethylsertraline-to-sertraline metabolic ratio were compared between the subgroups, with CYP2C19 NMs set as reference. The patient proportions outside the therapeutic concentration range were also compared between the subgroups with NMs defined as reference. Compared with the CYP2C19 NMs, the sertraline serum concentration was increased 1.38-fold (95% CI 1.26–1.50) and 2.68-fold (95% CI 2.16–3.31) in CYP2C19 IMs and PMs, respectively (p < 0.001), while only a marginally lower serum concentration (−10%) was observed in CYP2C19 UMs (p = 0.012). The odds ratio for having a sertraline concentration above the therapeutic reference range was 1.97 (95% CI 1.21–3.21, p = 0.064) and 8.69 (95% CI 3.88–19.19, p < 0.001) higher for IMs and PMs vs. NMs, respectively. CYP2C19 IMs and PMs obtain significantly higher serum concentrations of sertraline than NMs. Based on the relative differences in serum concentrations compared to NMs, dose reductions of 60% and 25% should be considered in PMs and IMs, respectively, to reduce the risk of sertraline overexposure in these patients.

  • Augmenting extinction learning with d -cycloserine reduces return of fear: a randomized, placebo-controlled fMRI study
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-21
    Claudia Ebrahimi, Johanna Gechter, Ulrike Lueken, Florian Schlagenhauf, Hans-Ulrich Wittchen, Alfons O. Hamm, Andreas Ströhle

    d-cycloserine (DCS), a partial NMDA-receptor agonist, seems to be a promising enhancer for exposure therapy in anxiety disorders. It has been tested successfully in animal models of fear extinction, where DCS enhanced extinction learning. Applied in clinical studies, results of DCS-augmented exposure therapy remain ambiguous, calling for a deeper understanding of the underlying mechanisms of DCS and its exact effect on extinction learning and return of fear (ROF) in humans. In the present study, we investigated the effect of DCS-augmented extinction learning on behavioral, psychophysiological, and neural indices of ROF during a 24-h delayed recall test. Thirty-seven participants entered a randomized, placebo-controlled, double-blind, 3-day fear conditioning and delayed extinction fMRI design. One hour before extinction training, participants received an oral dose of 50 mg DCS or a placebo. Behavioral arousal ratings revealed a generalized ROF during extinction recall in the placebo but not DCS group. Furthermore, participants receiving DCS compared to placebo showed attenuated differential BOLD responses in left posterior hippocampus and amygdala from extinction learning to extinction recall, due to increased hippocampal recruitment in placebo and trendwise decreased amygdala responding in DCS subjects. Our finding that DCS reduces ROF in arousal ratings and neural structures subserving defensive reactions support a role for NMDA receptors in extinction memory consolidation and encourage further translational research.

  • A multipredictor model to predict the conversion of mild cognitive impairment to Alzheimer’s disease by using a predictive nomogram
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-21
    Kexin Huang, Yanyan Lin, Lifeng Yang, Yubo Wang, Suping Cai, Liaojun Pang, Xiaoming Wu, Liyu Huang

    Predicting the probability of converting from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) is still a challenging task. This study aims at providing a personalized MCI-to-AD conversion estimation by using a multipredictor nomogram that integrates neuroimaging features, cerebrospinal fluid (CSF) biomarker, and clinical assessments. To do so, 290 MCI patients were collected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), of whom 76 has converted to AD and 214 remained with MCI. All subjects were randomly divided into a primary and validation cohort. Radiomics signature (Rad-sig) was obtained based on 17 cerebral cortex features selected by using Least Absolute Shrinkage and Selection Operator (LASSO) algorithm. Clinical factors and amyloid-beta peptide (Aβ) concentration were selected by using Spearman correlation between the converted and not-converted patients. Then, a nomogram that combines image features, clinical factor, and Aβ concentration was constructed and validated. Furthermore, we explored the associations between various predictors from the macro- to the microperspective by assessing gene expression patterns. Our results showed that the multipredictor nomogram (C-index 0.978 and 0.956 in both cohorts, respectively) outperformed the nomogram using either Rad-sig or Aβ concentration as individual predictors. Significant associations were found between neuropsychological scores, cerebral cortex features, Aβ levels, and underlying gene pathways. Our study may have a clinical impact as a powerful predictive tool for predicting the conversion probability of MCI and providing associations between cognitive impairment, structural changes, Aβ levels, and underlying biological patterns from the macro- to the microperspective.

  • Reward sensitivity deficits in a rat model of compulsive eating behavior
    Neuropsychopharmacology (IF 7.160) Pub Date : 2019-10-17
    Catherine F. Moore, Michael Z. Leonard, Nicholas M. Micovic, Klaus A. Miczek, Valentina Sabino, Pietro Cottone

    Compulsive eating behavior is hypothesized to be driven in part by reward deficits likely due to neuroadaptations to the mesolimbic dopamine (DA) system. Therefore, the aim of this study was to assess deficits in reward system functioning and mesolimbic DA after alternating a standard chow with palatable diet, a model of compulsive eating. In this model, rats in the control group (Chow/Chow) are provided a standard chow diet 7 days a week, while the experimental group (Chow/Palatable) is provided chow for 5 days a week (“C Phase”), followed by 2 days of access to a highly palatable sucrose diet (“P Phase”). We first tested the sensitivity to d-Amphetamine’s stimulatory, reward-enhancing, and primary rewarding effects using a locomotor activity assay, an intracranial self-stimulation (ICSS) procedure, and a conditioned place preference test, respectively. We then quantified DA release in the nucleus accumbens (NAc) shell after treatment with d-Amphetamine using in vivo microdialysis, quantified levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT) mRNA using quantitative polymerase chain reaction (qPCR), and lastly, quantified baseline extracellular DA and function of DAT in vivo using quantitative “no-net-flux” microdialysis. Chow/Palatable rats displayed blunted d-Amphetamine-induced locomotor activity, insensitivity to d-Amphetamine potentiation of ICSS threshold, and decreased place preference for d-Amphetamine during the P Phase. We found that Chow/Palatable rats had blunted DA efflux following d-Amphetamine treatment. Furthermore, DAT mRNA was increased in Chow/Palatable rats during the P Phase. Finally, quantitative “no-net-flux” microdialysis revealed reduced extracellular baseline DA and DAT function in Chow/Palatable rats. Altogether, these results provide evidence of reduced reward system functioning and related neuroadaptations in the DA and DAT systems in this model of compulsive eating. Reward deficits, resulting from repeated overeating, may in turn contribute to the perpetuation of compulsive eating behavior.

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