Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-16 Michael J. McCarthy, Heather Wei, Caroline M. Nievergelt, Andrea Stautland, Adam X. Maihofer, David K. Welsh, Paul Shilling, Martin Alda, Ney Alliey-Rodriguez, Anit Anand, Ole A. Andreasson, Yokesh Balaraman, Wade H. Berrettini, Holli Bertram, Kristen J. Brennand, Joseph R. Calabrese, Cynthia V. Calkin, Ana Claasen, Clara Conroy, William H. Coryell, David Craig, Nicole D’Arcangelo, Anna Demodena, Srdjan Djurovic, Scott Feeder, Carrie Fisher, Nicole Frazier, Mark Frye, Fred Gage, Keming Gao, Julie Garnham, Elliot Gershon, Kara Glazer, Fernando Goes, Toyomi Goto, Gloria Harrington, Petter Jakobsen, Masoud Kamali, Elizabeth Karberg, Marisa Kelly, Susan G. Leckband, Falk Lohoff, Melvin G. McInnis, Francis Mondimore, Gunnar Morken, John Nurnberger, Sarah Obral, Ketil J. Oedegaard, Abigail Ortiz, Megan Ritchey, Kelly Ryan, Martha Schinagle, Helle Schoeyen, Candice Schwebel, Martha Shaw, Tatyana Shekhtman, Clare Slaney, Emma Stapp, Szabolcs Szelinger, Bruce Tarwater, Peter P. Zandi,..
Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patients, we measured circadian rhythms in fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-R patients were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.
Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-15 Tina Zimmermann, Julia C. Bartsch, Annika Beer, Ermelinda Lomazzo, Stephan Guggenhuber, Maren D. Lange, Laura Bindila, Hans-Christian Pape, Beat Lutz
Endocannabinoid signaling via anandamide (AEA) is implicated in a variety of neuronal functions and considered a promising therapeutic target for numerous emotion-related disorders. The major AEA degrading enzyme is fatty acid amide hydrolase (FAAH). Genetic deletion and pharmacological inhibition of FAAH reduces anxiety and improves emotional responses and memory in rodents and humans. Complementarily, the mechanisms and impact of decreased AEA signaling remain to be delineated in detail. In the present study, using the Cre/loxP system combined with an adeno-associated virus (AAV)-mediated delivery system, FAAH was selectively overexpressed in hippocampal CA1-CA3 glutamatergic neurons of adult mice. This approach led to specific FAAH overexpression at the postsynaptic site of CA1-CA3 neurons, to increased FAAH enzymatic activity, and, in consequence, to decreased hippocampal levels of AEA and palmitoylethanolamide (PEA), but the levels of the second major endocannabinoid 2-arachidonoyl glycerol (2-AG) and of oleoylethanolamide (OEA) were unchanged. Electrophysiological recordings revealed an enhancement of both excitatory and inhibitory synaptic activity and of long-term potentiation (LTP). In contrast, excitatory and inhibitory long-term depression (LTD) and short-term synaptic plasticity, apparent as depolarization-induced suppression of excitation (DSE) and inhibition (DSI), remained unaltered. These changes in hippocampal synaptic activity were associated with an increase in anxiety-like behavior, and a deficit in object recognition memory and in extinction of aversive memory. This study indicates that AEA is not involved in hippocampal short-term plasticity, or eLTD and iLTD, but modulates glutamatergic transmission most likely via presynaptic sites, and that disturbances in this process impair learning and emotional responses.
D2 receptors and cognitive flexibility in marmosets: Tri-phasic dose–response effects of intra-striatal quinpirole on serial reversal performance Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-15 Nicole K. Horst, Bianca Jupp, Angela C. Roberts, Trevor W. Robbins
Behavioral flexibility, which allows organisms to adapt their actions in response to environmental changes, is impaired in a number of neuropsychiatric conditions, including obsessive-compulsive disorder and addiction. Studies in human subjects and monkeys have reported correlations between individual differences in dopamine D2-type receptor (D2R) levels in the caudate nucleus and performance in a discrimination reversal task, in which established contingent relationships between abstract stimuli and rewards (or punishments) are reversed. Global genetic deletion of the D2R in mice disrupts reversal performance, indicating a likely causal role for this receptor in supporting flexible behaviors. To directly examine the specific role of caudate D2-type receptors in reversal performance, the D2/3/4R agonist quinpirole was infused via chronic indwelling cannulae into the medial caudate of male and female marmoset monkeys performing a touchscreen-based serial discrimination reversal task. Given prior evidence for dose-dependent effects of quinpirole and other dopaminergic drugs, a full-dose response curve was established. Individually, marmosets displayed marked differences in behavioral sensitivity to specific doses of intra-caudate quinpirole. Collectively, they exhibited a behaviorally specific bi-phasic deficit in reversal learning, being consistently impaired at both relatively low and high doses of quinpirole. However, intermediate doses of intra-caudate quinpirole produced significant improvement in reversal performance. These data support previous human and monkey neuroimaging studies by providing causal evidence of a U-shaped function describing how dopamine modulates cognitive flexibility in the primate striatum.
Dorsal raphe serotonin neurons inhibit operant responding for reward via inputs to the ventral tegmental area but not the nucleus accumbens: evidence from studies combining optogenetic stimulation and serotonin reuptake inhibition Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-12 Caleb J. Browne, Andrew R. Abela, Duong Chu, Zhaoxia Li, Xiaodong Ji, Evelyn K. Lambe, Paul J. Fletcher
The monoamine neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts an inhibitory influence over motivation, but the circuits mediating this are unknown. Here, we used an optogenetic approach to isolate the contribution of dorsal raphe nucleus (DRN) 5-HT neurons and 5-HT innervation of the mesolimbic dopamine (DA) system to motivated behavior in mice. We found that optogenetic stimulation of DRN 5-HT neurons enhanced downstream 5-HT release, but this was not sufficient to inhibit operant responding for saccharin, a measure of motivated behavior. However, combining optogenetic stimulation of DRN 5-HT neurons with a low dose of the selective serotonin reuptake inhibitor (SSRI) citalopram synergistically reduced operant responding. We then examined whether these effects could be recapitulated if optogenetic stimulation specifically targeted 5-HT terminals in the ventral tegmental area (VTA) or nucleus accumbens (NAc) of the mesolimbic DA system. Optogenetic stimulation of 5-HT input to the VTA combined with citalopram treatment produced a synergistic decrease in responding for saccharin, resembling the changes produced by targeting 5-HT neurons in the DRN. However, this effect was not observed when optogenetic stimulation targeted 5-HT input to the NAc. Taken together, these results suggest that DRN 5-HT neurons exert an inhibitory influence over operant responding for reward through a direct interaction with the mesolimbic DA system at the level of the VTA. These studies support an oppositional interaction between 5-HT and DA systems in controlling motivation and goal-directed behavior, and have important implications for the development and refinement of treatment strategies for psychiatric disorders such as depression and addiction.
Intrinsic functional connectivity correlates of person-level risk for bipolar disorder in offspring of affected parents Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-08 Danella M. Hafeman, Henry W. Chase, Kelly Monk, Lisa Bonar, Mary Beth Hickey, Alicia McCaffrey, Simona Graur, Anna Manelis, Cecile D. Ladouceur, John Merranko, David A. Axelson, Benjamin I. Goldstein, Tina R. Goldstein, Boris Birmaher, Mary L. Phillips
Offspring of parents with bipolar disorder (OBP) are at increased risk to develop bipolar disorder (BD). Alterations in resting-state functional connectivity (rsFC) have been identified in OBP; however, replication has been limited and correlation with person-level risk is unknown. A recent study found reduced rsFC between left inferior frontal gyrus (IFG) and clusters in the left insula (LINS), lentiform nucleus (LENT), and midcingulate cortex (MCING) in OBP (Roberts et al. 2017); here, we aim to extend these findings to at-risk youth. We scanned a subset of the Pittsburgh Bipolar Offspring Study, a longitudinal study of OBP and community controls. Twenty-four OBP, 20 offspring of control parents with non-bipolar psychopathology (OCP), and 27 healthy controls (HC) had acceptable rsFC data. After preprocessing steps, we assessed group differences in seed-based rsFC between the IFG and target clusters (LINS, LENT, MCING) using multivariate regression. Next, we tested whether rsFC correlated with person-level risk score and with other dimensional measures. We did not find group differences in rsFC between IFG and target regions. Within OBP, risk score negatively correlated with IFG-LINS rsFC (p = 0.002). Across groups, mood lability correlated negatively with rsFC between IFG and target regions (p = 0.0002), due to negative correlation with IFG-LINS (p = 0.0003) and IFG-MCING (p = 0.001) rsFC. While group-level differences were not replicated, IFG-LINS rsFC was negatively correlated with a person-level risk score in OBP and with mood lability (a predictor of BD) across the sample. Thus, IFG-LINS rsFC might constitute a risk marker, within OBP, for the development of BD.
Correction: Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-06 Mario de la Fuente Revenga, Daisuke Ibi, Travis Cuddy, Rudy Toneatti, Mitsumasa Kurita, Maryum K. Ijaz, Michael F. Miles, Jennifer T. Wolstenholme, Javier González-Maeso
Correction: Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity Correction: Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity, Published online: 06 November 2018; doi:10.1038/s41386-018-0255-x Correction: Chronic clozapine treatment restrains via HDAC2 the performance of mGlu2 receptor agonism in a rodent model of antipsychotic activity
Sex-dependent regulation of social reward by oxytocin receptors in the ventral tegmental area Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-06 Johnathan M. Borland, Lauren M. Aiani, Alisa Norvelle, Kymberly N. Grantham, Kylie O’Laughlin, Joseph I. Terranova, Kyle J. Frantz, H. Elliott Albers
Social reward is critical for social relationships, and yet we know little about the characteristics of social interactions that are rewarding or the neural mechanisms underlying that reward. Here, we investigate the sex-dependent role of oxytocin receptors within the ventral tegmental area (VTA) in mediating the magnitude and valence of social reward. Operant and classical conditioning tests were used to measure social reward associated with same-sex social interactions. The effects of oxytocin, selective oxytocin receptor agonists, antagonists, and vehicle injected into the VTA on social reward was determined in male and female Syrian hamsters. The colocalization of FOS and oxytocin in sites that project to the VTA following social interaction was also determined. Females find same-sex social interactions more rewarding than males and activation of oxytocin receptors in the VTA are critical for social reward in females, as well as males. These studies provide support for the hypothesis that there is an inverted U relationship between the duration of social interaction and social reward, mediated by oxytocin; and that in females the dose–response relationship is initiated at lower doses compared with males. Same-sex social interaction is more rewarding in females than in males, and an inverted U relationship mediated by oxytocin may have a critical role in assigning positive and negative valence to social stimuli. Understanding these sex differences in social reward processing may be essential for understanding the sex differences in the prevalence of many psychiatric disorders and the development of gender-specific treatments of neuropsychiatric disorders.
Moderators for depressed mood and systemic and transcriptional inflammatory responses: a randomized controlled trial of endotoxin Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-03 Michael R. Irwin, Steve Cole, Richard Olmstead, Elizabeth C. Breen, Hyong Jin Cho, Mona Moieni, Naomi I. Eisenberger
Activation of the innate immune system is thought to contribute to depression. Multiple social and behavioral factors are also known to instigate depression. Whether these socio-behavioral factors interact with inflammatory stimuli to alter proinflammatory responses and depressed mood is not known. In 115 healthy adults, social, emotional, and behavioral factors were assessed at baseline. A single infusion of endotoxin (Escherichia coli; 0.8 ng/kg of body weight) or placebo (0.9% saline) was administered with hourly assessment of depressed mood and proinflammatory cytokines (interleukin-6 (IL-6); tumor necrosis factor-α (TNF)). Inflammatory gene expression was examined at 30 min after infusion, prior to increase of inflammatory cytokines. As compared to placebo, endotoxin-induced increases of depressed mood were moderated by baseline levels of perceived stress, trait sensitivity to social disconnection, and severity of symptoms of anxiety and depression (all Ps < 0.05) but not early life stress, social status, social support, neuroticism, or sleep disturbance. Anxiety symptoms remained significant in multivariable analyses (P < 0.01). None of these socio-behavioral factors were related to increases in proinflammatory cytokines. Transcriptome profiling analyses indicated that perceived stress, sensitivity to social disconnection, and depressive symptoms were associated with increased activation of pro-inflammatory transcription control pathways (i.e., activator protein-1, nuclear factor-κB) in response to endotoxin (all Ps < 0.05). These results indicate that an array of socio-behavioral factors, which are associated with depression risk, modify vulnerability to inflammation-induced depressed mood. Together, these observations may be used to help target therapeutic interventions to mitigate occurrence of the inflammatory biotype of depression.
Neural modulation of social reinforcement learning by intranasal oxytocin in male adults with high-functioning autism spectrum disorder: a randomized trial Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-02 Jana A. Kruppa, Anna Gossen, Eileen Oberwelland Weiß, Gregor Kohls, Nicola Großheinrich, Hannah Cholemkery, Christine M. Freitag, Wolfram Karges, Elke Wölfle, Judith Sinzig, Gereon R. Fink, Beate Herpertz-Dahlmann, Kerstin Konrad, Martin Schulte-Rüther
Reduced social motivation is a hallmark of individuals with autism spectrum disorders (ASDs). Although the exact neural mechanisms are unclear, oxytocin has been shown to enhance motivation and attention to social stimuli, suggesting a potential to augment social reinforcement learning as the central mechanism of behavioral interventions in ASD. We tested how reinforcement learning in social contexts and associated reward prediction error (RPE) signals in the nucleus accumbens (NAcc) were modulated by intranasal oxytocin. Male adults with a childhood diagnosis of ASD (n = 15) and healthy controls (n = 24; aged 18–26 years) performed a probabilistic reinforcement learning task during functional magnetic resonance imaging in a single-center (research center in Germany), randomized double-blind, placebo-controlled cross-over trial. The interventions were intranasal oxytocin (Syntocinon®, Novartis; 10 puffs = 20 international units (IUs) per treatment) and placebo spray. Using computational modeling of behavioral data, trial-by-trial RPE signals were assessed and related to brain activation in NAcc during reinforcing feedback in social and non-social contexts. The order of oxytocin/placebo was randomized for 60 participants. Twenty-one participants were excluded from analyses, leaving 39 for the final analysis. Behaviorally, individuals with ASD showed enhanced learning under oxytocin when the learning target as well as feedback was social as compared to non-social (social vs. non-social target: 87.09% vs. 71.29%, 95% confidence interval (CI): 7.28–24.33, p = .003; social vs. non-social feedback: 81.00% vs. 71.29%, 95% CI: 2.81–16.61, p = .027). Correspondingly, oxytocin enhanced the correlation of the RPE signal with NAcc activation during social (vs. non-social) feedback in ASD (3.48 vs. −1.12, respectively, 95% CI: 2.98–6.22, p = .000), whereas in controls, this effect was found in the placebo condition (2.90 vs. −1.14, respectively, 95% CI: 1.07–7.01, p = 0.010). In ASD, a similar pattern emerged when the learning target was social (3.00 vs. −0.64, respectively, 95% CI: −0.13 to 7.41, p = 0.057), whereas controls showed a reduced correlation for social learning targets under oxytocin (−0.70 vs. 2.72, respectively, 95% CI: −5.86 to 0.98, p = 0.008). The current data suggest that intranasal oxytocin has the potential to enhance social reinforcement learning in ASD. Future studies are warranted that investigate whether oxytocin can potentiate social learning when combined with behavioral therapies, resulting in greater treatment benefits than traditional behavior-only approaches.
Laser capture microdissection–targeted mass spectrometry: a method for multiplexed protein quantification within individual layers of the cerebral cortex Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-02 Matthew L. MacDonald, Daley Favo, Megan Garver, Zhe Sun, Dominique Arion, Ying Ding, Nathan Yates, Robert A. Sweet, David A. Lewis
The mammalian neocortex is organized into layers distinguished by the size, packing density, and connectivity of their constituent neurons. Many neuropsychiatric illnesses are complex trait disorders with etiologic factors converging on neuronal protein networks. Cortical pathology of neuropsychiatric diseases, such as schizophrenia, is often restricted to, or more pronounced in, certain cortical layers, suggesting that genetic vulnerabilities manifest with laminar specificity. Thus, the ability to investigate cortical layer-specific protein levels in human postmortem brain is highly desirable. Here, we developed and validated a laser capture microdissection–mass spectrometry (LCM-MS) approach to quantify over 200 proteins in cortical layers 3 and 5 of two cohorts of human subjects as well as a monkey model of postmortem interval. LCM-MS was readily implementable and reliably identified protein patterns that differed between cortical layers 3 and 5. Our findings suggest that LCM-MS facilitates the precise quantification of proteins within individual cortical layers from human postmortem brain tissue, providing a powerful tool in the study of neuropsychiatric disease.
Endocannabinoid control of the insular-bed nucleus of the stria terminalis circuit regulates negative affective behavior associated with alcohol abstinence Neuropsychopharmacology (IF 6.544) Pub Date : 2018-11-02 Samuel W. Centanni, Bridget D. Morris, Joseph R. Luchsinger, Gaurav Bedse, Tracy L. Fetterly, Sachin Patel, Danny G. Winder
Negative affect is a core symptom domain associated with an array of neurological and psychiatric disorders and is only partially targeted by current therapies, highlighting the need for better, more targeted treatment options. This study focuses on negative affective symptoms associated with prolonged alcohol abstinence, one of the leading causes of relapse. Using a mouse model of chronic alcohol consumption followed by forced abstinence (CDFA), prolonged alcohol abstinence increased c-fos expression and spontaneous glutamatergic neurotransmission in the dorsal bed nucleus of the stria terminalis (dBNST), a region heavily implicated in negative affect in both humans and rodents. Further, pharmacologically enhancing eCBs with JZL184 prevents abstinence-induced increases in dBNST neuronal activity, underscoring the therapeutic potential of drugs targeting the brain’s eCB system. Next, we used a channelrhodopsin-assisted mapping strategy to identify excitatory inputs to the dBNST that could contribute to CDFA-induced negative affect. We identified the insular cortex (insula), a region involved in regulating interoception, as a dense, functional, endocannabinoid-sensitive input to the dBNST. Using a chemogenetic strategy to locally mimic eCB signaling, we demonstrate that the insula strongly influences CDFA behavioral and BNST neuronal activity. Lastly, we used viral anterograde transsynaptic expression in combination with a Gq-DREADD to selectively recruit dBNST neurons receiving insula projections. Chemogenetic recruitment of these neurons mimicked behavioral and c-fos responses observed in CDFA. Collectively, this study supports a role for the insula-BNST neural circuit in negative affective disturbances and highlights the therapeutic potential of the endocannabinoid system for treating negative affective disorders.
Manipulation of dorsal raphe serotonergic neurons modulates active coping to inescapable stress and anxiety-related behaviors in mice and rats Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-30 Naoya Nishitani, Kazuki Nagayasu, Nozomi Asaoka, Mayumi Yamashiro, Chihiro Andoh, Yuma Nagai, Haruko Kinoshita, Hiroyuki Kawai, Norihiro Shibui, Beihui Liu, James Hewinson, Hisashi Shirakawa, Takayuki Nakagawa, Hitoshi Hashimoto, Sergey Kasparov, Shuji Kaneko
Major depression and anxiety disorders are a social and economic burden worldwide. Serotonergic signaling has been implicated in the pathophysiology of these disorders and thus has been a crucial target for pharmacotherapy. However, the precise mechanisms underlying these disorders are still unclear. Here, we used species-optimized lentiviral vectors that were capable of efficient and specific transduction of serotonergic neurons in mice and rats for elucidation of serotonergic roles in anxiety-like behaviors and active coping behavior in both species. Immunohistochemical analyses revealed that lentiviral vectors with an upstream sequence of tryptophan hydroxylase 2 gene efficiently transduced serotonergic neurons with a specificity of approximately 95% in both mice and rats. Electrophysiological recordings showed that these lentiviral vectors induced sufficient expression of optogenetic tools for precise control of serotonergic neurons. Using these vectors, we demonstrate that acute activation of serotonergic neurons in the dorsal raphe nucleus increases active coping with inescapable stress in rats and mice in a time-locked manner, and that acute inhibition of these neurons increases anxiety-like behaviors specifically in rats. These findings further our understanding of the pathophysiological role of dorsal raphe serotonergic neurons in different species and the role of these neurons as therapeutic targets in major depression and anxiety disorders.
Neurophysiologic measures of target engagement predict response to auditory-based cognitive training in treatment refractory schizophrenia Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-30 William C. Hochberger, Yash B. Joshi, Michael L. Thomas, Wendy Zhang, Andrew W. Bismark, Emily B. H. Treichler, Melissa Tarasenko, John Nungaray, Joyce Sprock, Lauren Cardoso, Neal Swerdlow, Gregory A. Light
Cognitive impairment is a core feature of schizophrenia and a strong predictor of psychosocial disability. Auditory-based targeted cognitive training (TCT) aims to enhance verbal learning and other domains of cognitive functioning through “bottom-up” tuning of the neural systems underlying early auditory information processing (EAIP). Although TCT has demonstrated efficacy at the group level, individual response to TCT varies considerably, with nearly half of patients showing little-to-no benefit. EEG measures of EAIP, mismatch negativity (MMN) and P3a, are sensitive to the neural systems engaged by TCT exercises and might therefore predict clinical outcomes after a full course of treatment. This study aimed to determine whether initial malleability of MMN and P3a to 1-h of auditory-based TCT predicts improvements in verbal learning and clinical symptom reduction following a full (30-h) course of TCT. Treatment refractory patients diagnosed with schizophrenia were randomly assigned to receive treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 23). Results indicated that malleability (i.e., change from baseline after the initial 1-h dose of TCT) of MMN and P3a predicted improvements in verbal learning as well as decreases in the severity of positive symptoms. Examination of MMN and P3a malleability in patients after their first dose of TCT can be used to predict clinical response to a full course of treatment and shows promise for future biomarker-informed treatment assignment.
Prefrontal cortex Response to Drug cues, craving, and current depressive symptoms are associated with treatment outcomes in methadone-maintained patients Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-30 Andrew S. Huhn, Mary M. Sweeney, K. Brooner, Michael S. Kidorf, D. Andrew Tompkins, Hasan Ayaz, Kelly E. Dunn
Methadone maintenance is an effective treatment for opioid use disorder, yet many methadone-maintained patients (MMPs) continue to struggle with chronic relapse. The current study evaluated whether functional near-infrared spectroscopy (fNIRS) could identify prefrontal cortex (PFC) markers of ongoing opioid use in MMPs, and whether clinical measures of depression and self-report measures of craving would also be associated with opioid use. MMPs (n = 29) underwent a drug cue reactivity paradigm during fNIRS measurements of PFC reactivity. Self-reported opioid craving (measured by a visual analog scale; 0–100) was collected before and after drug cue reactivity, and depressive symptoms were assessed via the 17-item Hamilton Depression Rating Scale (HAM-D). Hierarchical regression and partial correlations were used to evaluate associations between weekly urine drug screens over a 90-day follow-up period and fNIRS, craving, and HAM-D assessments. Neural response to drug cues in the left lateral PFC, controlling for age, sex, and days in treatment was significantly associated with percent opioid-negative urine screens during follow-up (∆F1, 24 = 13.19, p = 0.001, ∆R2 = 0.30), and correctly classified 86% of MMPs as either using opioids, or abstaining from opioids (χ2(4) = 16.28, p = 0.003). Baseline craving (p < 0.001) and HAM-D assessment (p < 0.01) were also associated with percent opioid-negative urine screens. Combining fNIRS results, baseline craving scores, and HAM-D scores created a robust predictive model (∆F3, 22 = 16.75, p < 0.001, ∆R2 = 0.59). These data provide preliminary evidence that the fNIRS technology may have value as an objective measure of treatment outcomes within outpatient methadone clinics. Depressive symptoms and drug craving were also correlated with opioid use in MMPs.
Intermittent intake of rapid cocaine injections promotes the risk of relapse and increases mesocorticolimbic BDNF levels during abstinence Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-26 Aliou B. Gueye, Florence Allain, Anne-Noël Samaha
Cocaine is thought to be more addictive when it reaches the brain rapidly. We predicted that variation in the speed of cocaine delivery influences the likelihood of addiction in part by determining the risk of relapse after abstinence. Under an intermittent-access schedule, rats pressed a lever for rapid (injected over 5 s) or slower (90 s) intravenous cocaine injections (0.5 mg/kg/injection). Control rats self-administered food pellets. A tone-light cue accompanied each self-administered reward. The 5s- and 90s-rats took a similar average amount of cocaine. After 1 or 45 days of withdrawal/forced abstinence, lever-pressing behaviour was extinguished during a 6-h session. Immediately thereafter, cue- or cocaine (10 mg/kg, i.p.)-induced reinstatement was assessed for 1 h. After 1 or 45 days of withdrawal, only 5s-rats showed significant cocaine-induced reinstatement of reward-seeking behaviour. Both cocaine groups showed more cue-induced reinstatement behaviour on withdrawal day 45 than on withdrawal day 1, indicating incubation of conditioned drug craving. However, cue-induced reinstatement after extended abstinence was greatest in the 5s-rats. Brain-derived neurotrophic factor (BDNF) activity in the brain regulates reinstatement behaviour. Thus, 24 h after reinstatement tests, we measured BDNF protein concentrations in mesocorticolimbic regions. Only 5s-rats showed time-dependent increases in BDNF concentrations in the prelimbic cortex, nucleus accumbens core and ventral tegmental area after cocaine withdrawal (day 45 > day 1). Thus, rapidly rising brain cocaine levels might facilitate addiction by evoking changes in the brain that intensify drug craving after abstinence, and these changes persist long after the last bout of cocaine use.
Dopamine D2 receptor occupancy of lumateperone (ITI-007): a Positron Emission Tomography Study in patients with schizophrenia Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-26 Kimberly E. Vanover, Robert E. Davis, Yun Zhou, Weiguo Ye, James R. Brašić, Lorena Gapasin, Jelena Saillard, Michal Weingart, Robert E. Litman, Sharon Mates, Dean F. Wong
Dopamine D2 receptor occupancy (D2RO) is a key feature of all currently approved antipsychotic medications. However, antipsychotic efficacy associated with high D2RO is often limited by side effects such as motor disturbances and hyperprolactinemia. Lumateperone (ITI-007) is a first-in-class selective and simultaneous modulator of serotonin, dopamine and glutamate in development for the treatment of schizophrenia and other disorders. The primary objective of the present study was to determine D2RO at plasma steady state of 60 mg ITI-007, a dose that previously demonstrated antipsychotic efficacy in a controlled trial, administered orally open-label once daily in the morning for two weeks in patients with schizophrenia (N = 10) and after at least a two-week washout period from standard of care antipsychotics. D2RO was determined using positron emission tomography with 11C-raclopride as the radiotracer. Mean peak dorsal striatal D2RO was 39% at 60 mg ITI-007 occurring 1 h post-dose. Lumateperone was well-tolerated with a favorable safety profile in this study. There were no clinically significant changes in vital signs, ECGs, or clinical chemistry laboratory values, including prolactin levels. There were no adverse event reports of akathisia or other extrapyramidal motor side effects; mean scores on motor function scales indicated no motor disturbances with lumateperone treatment. This level of occupancy is lower than most other antipsychotic drugs at their efficacious doses and likely contributes to the favorable safety and tolerability profile of lumateperone with reduced risk for movement disorders and hyperprolactinemia. If approved, lumateperone may provide a new and safe treatment option for individuals living with schizophrenia.
In Memoriam: Arvid Carlsson—Pioneering Researcher and Nobel Laureate Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-26 Birte Glenthøj, H. Christian Fibiger
In Memoriam: Arvid Carlsson—Pioneering Researcher and Nobel Laureate In Memoriam: Arvid Carlsson—Pioneering Researcher and Nobel Laureate, Published online: 26 October 2018; doi:10.1038/s41386-018-0244-0 In Memoriam: Arvid Carlsson—Pioneering Researcher and Nobel Laureate
Effects of BDNF Val66Met genotype and schizophrenia familial risk on a neural functional network for cognitive control in humans Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-25 J. I. Schweiger, E. Bilek, A. Schäfer, U. Braun, C. Moessnang, A. Harneit, P. Post, K. Otto, N. Romanczcuk-Seiferth, S. Erk, C. Wackerhagen, M. Mattheisen, T. W. Mühleisen, S. Cichon, M. M. Nöthen, J. Frank, S. H. Witt, M. Rietschel, A. Heinz, H. Walter, A. Meyer-Lindenberg, H. Tost
Cognitive control represents an essential neuropsychological characteristic that allows for the rapid adaption of a changing environment by constant re-allocation of cognitive resources. This finely tuned mechanism is impaired in psychiatric disorders such as schizophrenia and contributes to cognitive deficits. Neuroimaging has highlighted the contribution of the anterior cingulate cortex (ACC) and prefrontal regions (PFC) on cognitive control and demonstrated the impact of genetic variation, as well as genetic liability for schizophrenia. In this study, we aimed to examine the influence of the functional single-nucleotide polymorphism (SNP) rs6265 of a plasticity-related neurotrophic factor gene, BDNF (Val66Met), on cognitive control. Strong evidence implicates BDNF Val66Met in neural plasticity in humans. Furthermore, several studies suggest that although the variant is not convincingly associated with schizophrenia risk, it seems to be a modifier of the clinical presentation and course of the disease. In order to clarify the underlying mechanisms using functional magnetic resonance imaging (fMRI), we studied the effects of this SNP on ACC and PFC activation, and the connectivity between these regions in a discovery sample of 85 healthy individuals and sought to replicate this effect in an independent sample of 253 individuals. Additionally, we tested the identified imaging phenotype in relation to schizophrenia familial risk in a sample of 58 unaffected first-degree relatives of schizophrenia patients. We found a significant increase in interregional connectivity between ACC and PFC in the risk-associated BDNF 66Met allele carriers. Furthermore, we replicated this effect in an independent sample and demonstrated its independence of structural confounds, as well as task specificity. A similar coupling increase was detectable in individuals with increased familial risk for schizophrenia. Our results show that a key neural circuit for cognitive control is influenced by a plasticity-related genetic variant, which may render this circuit particular susceptible to genetic and environmental risk factors for schizophrenia.
Dopamine is a double-edged sword: dopaminergic modulation enhances memory retrieval performance but impairs metacognition Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-25 Mareike Clos, Nico Bunzeck, Tobias Sommer
While memory encoding and consolidation processes have been linked with dopaminergic signaling for a long time, the role of dopamine in episodic memory retrieval remained mostly unexplored. Based on previous observations of striatal activity during memory retrieval, we used pharmacological functional magnetic resonance imaging to investigate the effects of dopamine on retrieval performance and metacognitive memory confidence in healthy humans. Dopaminergic modulation by the D2 antagonist haloperidol administered acutely during the retrieval phase improved recognition accuracy of previously learned pictures significantly and was associated with increased activity in the substantia nigra/ventral tegmental area, locus coeruleus, hippocampus, and amygdala during retrieval. In contrast, confidence for new decisions was impaired by unsystematically increased activity of the striatum across confidence levels and restricted range of responsiveness in frontostriatal networks under haloperidol. These findings offer new insights into the mechanisms underlying memory retrieval and metacognition and provide a broader perspective on the presence of memory problems in dopamine-related diseases and the treatment of memory disorders.
Identifying substance use risk based on deep neural networks and Instagram social media data Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-24 Saeed Hassanpour, Naofumi Tomita, Timothy Delise, Benjamin Crosier, Lisa A. Marsch
Social media may provide new insight into our understanding of substance use and addiction. In this study, we developed a deep-learning method to automatically classify individuals’ risk for alcohol, tobacco, and drug use based on the content from their Instagram profiles. In total, 2287 active Instagram users participated in the study. Deep convolutional neural networks for images and long short-term memory (LSTM) for text were used to extract predictive features from these data for risk assessment. The evaluation of our approach on a held-out test set of 228 individuals showed that among the substances we evaluated, our method could estimate the risk of alcohol abuse with statistical significance. These results are the first to suggest that deep-learning approaches applied to social media data can be used to identify potential substance use risk behavior, such as alcohol use. Utilization of automated estimation techniques can provide new insights for the next generation of population-level risk assessment and intervention delivery.
Break the net, break the cycle: removal of perineuronal nets in the lateral hypothalamus decreases cocaine relapse Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-24 Nathan J. Marchant
Break the net, break the cycle: removal of perineuronal nets in the lateral hypothalamus decreases cocaine relapse Break the net, break the cycle: removal of perineuronal nets in the lateral hypothalamus decreases cocaine relapse, Published online: 24 October 2018; doi:10.1038/s41386-018-0245-z Break the net, break the cycle: removal of perineuronal nets in the lateral hypothalamus decreases cocaine relapse
Impaired cognitive behavioral flexibility following methamphetamine or high caloric diet consumption: a common 5-HT2C mechanism? Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-24 Matthew L. Banks
Impaired cognitive behavioral flexibility following methamphetamine or high caloric diet consumption: a common 5-HT2C mechanism? Impaired cognitive behavioral flexibility following methamphetamine or high caloric diet consumption: a common 5-HT2C mechanism?, Published online: 24 October 2018; doi:10.1038/s41386-018-0243-1 Impaired cognitive behavioral flexibility following methamphetamine or high caloric diet consumption: a common 5-HT2C mechanism?
Decoding the role of the microbiome on amygdala function and social behaviour Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-19 John F. Cryan, Timothy G. Dinan
Decoding the role of the microbiome on amygdala function and social behaviour Decoding the role of the microbiome on amygdala function and social behaviour, Published online: 19 October 2018; doi:10.1038/s41386-018-0233-3 Decoding the role of the microbiome on amygdala function and social behaviour
Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic imaging and resonance study Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-17 Kristina M. Deligiannidis, Christina L. Fales, Aimee R. Kroll-Desrosiers, Scott A. Shaffer, Vanessa Villamarin, Yanglan Tan, Janet E. Hall, Blaise B. Frederick, Elif M. Sikoglu, Richard A. Edden, Anthony J. Rothschild, Constance M. Moore
Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy (1H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.
Low-dose intranasal oxytocin delivered with Breath Powered device modulates pupil diameter and amygdala activity: a randomized controlled pupillometry and fMRI study Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-16 Daniel S. Quintana, Lars T. Westlye, Dag Alnæs, Tobias Kaufmann, Ramy A. Mahmoud, Knut T. Smerud, Per G. Djupesland, Ole A. Andreassen
Little is known about how intranasally administered oxytocin reaches the brain and modulates social behavior and cognition. Pupil dilation is a sensitive index of attentional allocation and effort, and inter-individual variability in pupil diameter during performance of social-cognitive tasks may provide a better assessment of pharmacological effects on the brain than behavioral measures. Here, we leverage the close relationship between pupil and neural activity to inform our understanding of nose-to-brain oxytocin routes and possible dose–response relationships. To this end, we assessed pupil diameter data from a previously reported functional magnetic resonance imaging (fMRI) study under four treatment conditions—including two different doses of intranasal oxytocin using a novel Breath Powered nasal device, intravenous (IV) oxytocin, and placebo—and investigated the association with amygdala activation in response to emotional stimuli. The study used a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults administering a single-dose of these four treatments. A significant main effect of treatment condition on pupil diameter was observed. Posthoc tests revealed reduced pupil diameter after 8IU intranasal oxytocin compared to placebo, but no significant difference between 8IU intranasal oxytocin and either 24IU intranasal oxytocin or IV oxytocin treatment conditions. Analysis also showed a significant relationship between pupil diameter and right amygdala activation after 8IU intranasal oxytocin. Although there was no significant difference between 8IU intranasal oxytocin and IV oxytocin on right amygdala activity and pupil diameter, the significant difference between 8IU intranasal oxytocin and placebo is consistent with the hypothesis that oxytocin can travel to the brain via a nose-to-brain route.
Homeostatic cAMP regulation by the RGS7 complex controls depression-related behaviors Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-11 Cesare Orlandi, Laurie P. Sutton, Brian S. Muntean, Chenghui Song, Kirill A. Martemyanov
Affective disorders arise from abnormal responses of the brain to prolonged exposure to challenging environmental stimuli. Recent work identified the orphan receptor GPR158 as a molecular link between chronic stress and depression. Here we reveal a non-canonical mechanism by which GPR158 exerts its effects on stress-induced depression by the complex formation with Regulator of G protein Signaling 7 (RGS7). Chronic stress promotes membrane recruitment of RGS7 via GPR158 in the medial prefrontal cortex (mPFC). The resultant complex suppresses homeostatic regulation of cAMP by inhibitory GPCRs in the region. Accordingly, RGS7 loss in mice induces an antidepressant-like phenotype and resiliency to stress, whereas its restoration within the mPFC is sufficient to rescue this phenotype in a GPR158-dependent way. These findings mechanistically link the unusual orphan receptor-RGS complex to a major stress mediator, the cAMP system and suggest new avenues for pharmacological interventions in affective disorders.
GSK3β in the prefrontal cortex: a molecular handle specific to addiction pathology? Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-11 Andrew L. Eagle, A. J. Robison
GSK3β in the prefrontal cortex: a molecular handle specific to addiction pathology? GSK3β in the prefrontal cortex: a molecular handle specific to addiction pathology?, Published online: 11 October 2018; doi:10.1038/s41386-018-0224-4 GSK3β in the prefrontal cortex: a molecular handle specific to addiction pathology?
Urinary tetrahydrocannabinol is associated with poorer working memory performance and alterations in associated brain activity Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-10 Max M. Owens, Shannon McNally, Tashia Petker, Michael Amlung, Iris Balodis, Lawrence H. Sweet, James MacKillop
Worldwide, cannabis is one of the most widely used psychoactive substances and cannabis use has been implicated in poorer performance in several cognitive domains, including working memory (WM). However, the neural mechanisms underlying these WM decrements are not well understood and the current study investigated the association of cannabis involvement with WM performance and associated neural activation in the Human Connectome Project (N = 1038). Multiple indicators of cannabis involvement were examined in relation to behavioral performance and brain activity in a visual N-back task using functional magnetic resonance imaging. A positive urine drug screen for tetrahydocannabinol (THC+ status), the principal psychoactive constituent in cannabis, was associated with worse WM performance and differential brain response in areas previously linked to WM performance. Furthermore, decreases in blood-activation-level-dependent (BOLD) signal in WM task-positive brain regions and increases in task-negative regions mediated the relationship between THC+ status and WM performance. In contrast, WM performance and BOLD response during the N-back task were not associated with total lifetime cannabis use, age of first use, or other indicators of involvement, suggesting that the effects of cannabis on WM were short-term residual effects, rather than long-term persistent effects. These findings elucidate differential influences of cannabis involvement on neurocognition and have significant potential implications for occupational performance in diverse settings.
Heritability of cerebral glutamate levels and their association with schizophrenia spectrum disorders: a 1[H]-spectroscopy twin study Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-09 Christian Stefan Legind, Brian Villumsen Broberg, René Christiaan William Mandl, Rachel Brouwer, Simon Jesper Anhøj, Rikke Hilker, Maria Høj Jensen, Philip McGuire, Hilleke Hulshoff Pol, Birgitte Fagerlund, Egill Rostrup, Birte Yding Glenthøj
Research findings implicate cerebral glutamate in the pathophysiology of schizophrenia, including genetic studies reporting associations with glutamatergic neurotransmission. The extent to which aberrant glutamate levels can be explained by genetic factors is unknown, and if glutamate can serve as a marker of genetic susceptibility for schizophrenia remains to be established. We investigated the heritability of cerebral glutamate levels and whether a potential association with schizophrenia spectrum disorders could be explained by genetic factors. Twenty-three monozygotic (MZ) and 20 dizygotic (DZ) proband pairs con- or discordant for schizophrenia spectrum disorders, along with healthy control pairs (MZ = 28, DZ = 18) were recruited via the National Danish Twin Register and the Psychiatric Central Register (17 additional twins were scanned without their siblings). Glutamate levels in the left thalamus and the anterior cingulate cortex (ACC) were measured using 1[H]-magnetic resonance spectroscopy at 3 Tesla and analyzed by structural equation modeling. Glutamate levels in the left thalamus were heritable and positively correlated with liability for schizophrenia spectrum disorders (phenotypic correlation, 0.16, [0.02–0.29]; p = 0.010). The correlation was explained by common genes influencing both the levels of glutamate and liability for schizophrenia spectrum disorders. In the ACC, glutamate and glx levels were heritable, but not correlated to disease liability. Increases in thalamic glutamate levels found in schizophrenia spectrum disorders are explained by genetic influences related to the disease, and as such the measure could be a potential marker of genetic susceptibility, useful in early detection and stratification of patients with psychosis.
Sex differences in schizophrenia: estrogen and mitochondria Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-07 Vanessa F. Gonçalves, Ari B. Cuperfain, James L. Kennedy
Sex differences in schizophrenia: estrogen and mitochondria Sex differences in schizophrenia: estrogen and mitochondria, Published online: 07 October 2018; doi:10.1038/s41386-018-0228-0 Sex differences in schizophrenia: estrogen and mitochondria
An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-07 Carla Nasca, Natalie Rasgon, Bruce McEwen
An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders, Published online: 07 October 2018; doi:10.1038/s41386-018-0227-1 An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders
Treating cue-reactivity with brain stimulation: a new (transdiagnostic) approach Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-07 Colleen A. Hanlon
Treating cue-reactivity with brain stimulation: a new (transdiagnostic) approach Treating cue-reactivity with brain stimulation: a new (transdiagnostic) approach, Published online: 07 October 2018; doi:10.1038/s41386-018-0215-5 Treating cue-reactivity with brain stimulation: a new (transdiagnostic) approach
Drug-taking in a socio-sexual context enhances vulnerability for addiction in male rats Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-06 Lindsey B. Kuiper, Lauren N. Beloate, Braxton M. Dupuy, Lique M. Coolen
Vulnerability to develop addiction is influenced by numerous factors, including social behavior. Specifically, in human users, drug taking in a socio-sexual context appears to enhance further drug-seeking behavior. Users report heightened sexual pleasure as a motivation for further drug use and display risk behaviors even when tested in drug-free state. Here, using a preclinical model of limited voluntary drug use in rats, the hypothesis was tested that methamphetamine (Meth)-taking concurrently with socio-sexual experience increases vulnerability to addiction. Male Sprague Dawley rats were socially housed and underwent limited-access Meth self-administration (maximum 1 mg/kg/session). Meth-taking was either concurrent or non-concurrent with sexual behavior: concurrent animals were mated with a receptive female immediately after each session, while non-concurrent animals gained equivalent sexual experience the week prior. Next, drug-seeking behaviors were measured during cue reactivity, extinction, and reinstatement sessions using different extinction and reinstatement protocols in 4 separate studies. Both groups equally acquired Meth self-administration and did not differ in total Meth intake. However, drug-seeking behavior was significantly higher in concurrent animals during cue reactivity tasks, extinction sessions, and cue- or Meth-induced reinstatement tests. In addition, sexual behavior in the absence of Meth triggered reinstatement of drug-seeking in concurrent animals. These results indicate that Meth-taking in a socio-sexual context significantly enhances vulnerability for drug addiction in male rats. This preclinical paradigm of drug self-administration concurrent with socio-sexual behavior provides a useful model for studying the underlying neurobiology of socially driven vulnerability to drug addiction.
Relapse to opioid seeking in rat models: behavior, pharmacology and circuits Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-06 David J. Reiner, Ida Fredriksson, Olivia M. Lofaro, Jennifer M. Bossert, Yavin Shaham
Lifetime relapse rates remain a major obstacle in addressing the current opioid crisis. Relapse to opioid use can be modeled in rodent studies where drug self-administration is followed by a period of abstinence and a subsequent test for drug seeking. Abstinence can be achieved through extinction training, forced abstinence, or voluntary abstinence. Voluntary abstinence can be accomplished by introducing adverse consequences of continued drug self-administration (e.g., punishment or electric barrier) or by introducing an alternative nondrug reward in a discrete choice procedure (drug versus palatable food or social interaction). In this review, we first discuss pharmacological and circuit mechanisms of opioid seeking, as assessed in the classical extinction-reinstatement model, where reinstatement is induced by reexposure to the self-administered drug (drug priming), discrete cues, discriminative cues, drug-associated contexts, different forms of stress, or withdrawal states. Next, we discuss pharmacological and circuit mechanisms of relapse after forced or voluntary abstinence, including the phenomenon of “incubation of heroin craving” (the time-dependent increases in heroin seeking during abstinence). We conclude by discussing the clinical implications of these preclinical relapse models.
Ovarian hormones, genes, and the brain: the case of estradiol and the brain-derived neurotrophic factor (BDNF) gene Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-04 Shau-Ming Wei, Karen F. Berman
Ovarian hormones, genes, and the brain: the case of estradiol and the brain-derived neurotrophic factor (BDNF) gene Ovarian hormones, genes, and the brain: the case of estradiol and the brain-derived neurotrophic factor (BDNF) gene, Published online: 04 October 2018; doi:10.1038/s41386-018-0223-5 Ovarian hormones, genes, and the brain: the case of estradiol and the brain-derived neurotrophic factor (BDNF) gene
Deletion of the type 2 metabotropic glutamate receptor increases heroin abuse vulnerability in transgenic rats Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-03 Jun-Tao Gao, Chloe Jordan, Guo-Hua Bi, Yi He, Hong-Ju Yang, Eliot L. Gardner, Zheng-Xiong Xi
Opioid abuse is a rapidly growing public health crisis in the USA. Despite extensive research in the past decades, little is known about the etiology of opioid addiction or the neurobiological risk factors that increase vulnerability to opioid use and abuse. Recent studies suggest that the type 2 metabotropic glutamate receptor (mGluR2) is critically involved in substance abuse and addiction. In the present study, we evaluated whether low-mGluR2 expression may represent a risk factor for the development of opioid abuse and addiction using transgenic mGluR2-knockout (mGluR2-KO) rats. Compared to wild-type controls, mGluR2-KO rats exhibited higher nucleus accumbens (NAc) dopamine (DA) and locomotor responses to heroin, higher heroin self-administration and heroin intake, more potent morphine-induced analgesia and more severe naloxone-precipitated withdrawal symptoms. In contrast, mGluR2-KO rats displayed lower motivation for heroin self-administration under high price progressive-ratio (PR) reinforcement conditions. Taken together, these findings suggest that mGluR2 may play an inhibitory role in opioid action, such that deletion of this receptor results in an increase in brain DA responses to heroin and in acute opioid reward and analgesia. Low-mGluR2 expression in the brain may therefore be a risk factor for the initial development of opioid abuse and addiction.
Can neuroimaging help combat the opioid epidemic? A systematic review of clinical and pharmacological challenge fMRI studies with recommendations for future research Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-03 Hestia Moningka, Sarah Lichenstein, Patrick D. Worhunsky, Elise E. DeVito, Dustin Scheinost, Sarah W. Yip
The current opioid epidemic is an urgent public health problem, with enormous individual, societal, and healthcare costs. Despite effective, evidence-based treatments, there is significant individual variability in treatment responses and relapse rates are high. In addition, the neurobiology of opioid-use disorder (OUD) and its treatment is not well understood. This review synthesizes published fMRI literature relevant to OUD, with an emphasis on findings related to opioid medications and treatment, and proposes areas for further research. We conducted a systematic literature review of Medline and Psychinfo to identify (i) fMRI studies comparing OUD and control participants; (ii) studies related to medication, treatment, abstinence or withdrawal effects in OUD; and (ii) studies involving manipulation of the opioid system in healthy individuals. Following application of exclusionary criteria (e.g., insufficient sample size), 45 studies were retained comprising data from ~1400 individuals. We found convergent evidence that individuals with OUD display widespread heightened neural activation to heroin cues. This pattern is potentiated by heroin, attenuated by medication-assisted treatments for opioids, predicts treatment response, and is reduced following extended abstinence. Nonetheless, there is a paucity of literature examining neural characteristics of OUD and its treatment. We discuss limitations of extant research and identify critical areas for future neuroimaging studies, including the urgent need for studies examining prescription opioid users, assessing sex differences and utilizing a wider range of clinically relevant task-based fMRI paradigms across different stages of addiction.
Neuropeptide Y and representation of salience in human nucleus accumbens Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-02 Katherine G. Warthen, Benjamin Sanford, Kendal Walker, Keith G. Jones, Mike Angstadt, Chandra Sripada, David Goldman, Jon-Kar Zubieta, Robert C. Welsh, Margit Burmeister, Brian J. Mickey
Neuropeptide Y (NPY) produces anxiolytic effects in rodent models, and naturally occurring Low-NPY expression in humans has been associated with negative emotional phenotypes. Studies in rodent models have also demonstrated that NPY elicits reward behaviors through its action in the nucleus accumbens (NAc), but the impact of NPY on the human NAc is largely unexplored. We recruited 222 healthy young adults of either sex and genetically selected 53 of these subjects at the extremes of NPY expression (Low-NPY and High-NPY) to participate in functional magnetic resonance imaging. Responses of the NAc and surrounding ventral striatum were quantified during a monetary incentive delay task in which stimuli varied by salience (high versus low) and valence (win versus loss). We found that bilateral NAc responses to high-salience versus low-salience stimuli were greater for Low-NPY subjects relative to High-NPY subjects, regardless of stimulus valence. To our knowledge, these results provide the first evidence in humans linking NPY with salience sensitivity of the NAc, raising the possibility that individual differences in NPY expression moderate the risk for disorders of mesoaccumbal function such as addictions and mood disorders. Additionally, we found that head motion was greater among High-NPY subjects, consistent with previous reports linking NPY with hyperactivity. Future studies in animal models are warranted to elucidate the neural mechanisms through which NPY influences NAc function and related behaviors.
Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-02 Gemma Modinos, Fatma Şimşek, Matilda Azis, Matthijs Bossong, Ilaria Bonoldi, Carly Samson, Beverly Quinn, Jesus Perez, Matthew R. Broome, Fernando Zelaya, David J. Lythgoe, Oliver D. Howes, James M. Stone, Anthony A. Grace, Paul Allen, Philip McGuire
Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis, Published online: 02 October 2018; doi:10.1038/s41386-018-0118-5 Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis
Guidance cues: linking drug use in adolescence with psychiatric disorders Neuropsychopharmacology (IF 6.544) Pub Date : 2018-10-01 Lauren M. Reynolds, Cecilia Flores
Guidance cues: linking drug use in adolescence with psychiatric disorders Guidance cues: linking drug use in adolescence with psychiatric disorders, Published online: 01 October 2018; doi:10.1038/s41386-018-0221-7 Guidance cues: linking drug use in adolescence with psychiatric disorders
Sex differences in the incidence of antidepressant-induced mania (AIM) in bipolar disorders Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-28 Aislinn Williams, Melvin G. McInnis
Sex differences in the incidence of antidepressant-induced mania (AIM) in bipolar disorders Sex differences in the incidence of antidepressant-induced mania (AIM) in bipolar disorders, Published online: 28 September 2018; doi:10.1038/s41386-018-0216-4 Sex differences in the incidence of antidepressant-induced mania (AIM) in bipolar disorders
Dissociable effects of acute SSRI (escitalopram) on executive, learning and emotional functions in healthy humans Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-26 Nikolina Skandali, James B. Rowe, Valerie Voon, Julia B. Deakin, Rudolf N. Cardinal, Francesca Cormack, Luca Passamonti, William R. Bevan-Jones, Ralf Regenthal, Samuel R. Chamberlain, Trevor W. Robbins, Barbara J. Sahakian
Serotonin is implicated in multiple executive functions including goal-directed learning, cognitive flexibility, response inhibition and emotional regulation. These functions are impaired in several psychiatric disorders, such as depression and obsessive–compulsive disorder. We tested the cognitive effects of the selective serotonin reuptake inhibitor escitalopram, using an acute and clinically relevant dose (20 mg), in 66 healthy male and female volunteers in a double-blind, placebo-controlled study. Participants performed a cognitive test battery including a probabilistic and reversal learning task, the CANTAB intra-dimensional/extra-dimensional shift test of cognitive flexibility, a response inhibition task with interleaved stop-signal and No-Go trials and tasks measuring emotional processing. We showed that acute escitalopram administration impaired learning and cognitive flexibility, but improved the ability to inhibit responses in stop-signal trials while leaving unaffected acute emotional processing. Our findings suggest a dissociation of effects of acute escitalopram on cognitive functions, possibly mediated by differential modulation of brain serotonin levels in distinct functional neural circuits.
Regulation of raphe serotonin neurons by serotonin 1A and 2B receptors Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-25 Arnauld Belmer, Luc Maroteaux
Regulation of raphe serotonin neurons by serotonin 1A and 2B receptors Regulation of raphe serotonin neurons by serotonin 1A and 2B receptors, Published online: 25 September 2018; doi:10.1038/s41386-018-0214-6 Regulation of raphe serotonin neurons by serotonin 1A and 2B receptors
Unique treatment potential of cannabidiol for the prevention of relapse to drug use Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-25 Friedbert Weiss, Gustavo Gonzalez-Cuevas
Unique treatment potential of cannabidiol for the prevention of relapse to drug use Unique treatment potential of cannabidiol for the prevention of relapse to drug use, Published online: 25 September 2018; doi:10.1038/s41386-018-0218-2 Unique treatment potential of cannabidiol for the prevention of relapse to drug use
Untangling the complexity of opioid receptor function Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-24 Rita J. Valentino, Nora Volkow
Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970’s, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.
Recent advances in the study of aggression Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-21 Meghan E. Flanigan, Scott J. Russo
Recent advances in the study of aggression Recent advances in the study of aggression, Published online: 21 September 2018; doi:10.1038/s41386-018-0226-2 Recent advances in the study of aggression
Tinkering with THC-to-CBD ratios in Marijuana Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-19 Bertha K. Madras
Tinkering with THC-to-CBD ratios in Marijuana Tinkering with THC-to-CBD ratios in Marijuana, Published online: 19 September 2018; doi:10.1038/s41386-018-0217-3 Tinkering with THC-to-CBD ratios in Marijuana
Effect of exogenous testosterone on cooperation depends on personality and time pressure Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-19 Brian M. Bird, Shawn N. Geniole, Tanya L. Procyshyn, Triana L. Ortiz, Justin M. Carré, Neil V. Watson
The social heuristic hypothesis posits that human cooperation is an intuitive response that is expressed especially under conditions of time-constraint. Conversely, it proposes that for individuals given an opportunity for reflection, cooperation is more likely to be curtailed by an optimizing process calibrated to maximize individual benefit in a given situation. Notably, the steroid hormone testosterone has also been implicated in intuitive decision-making, including both prosocial and anti-social behaviors, with effects strongest in men with particular dispositional characteristics. This raises the possibility that increased testosterone may augment the effects predicted by the social heuristic hypothesis, particularly among men higher in specific dispositional characteristics (dominance, impulsivity, independent self-construal: high risk for testosterone-induced antisocial behavior). Here, in a testosterone administration study with a relatively large sample of men (N = 400), we test this possibility in a double-blind, placebo-controlled paradigm, with men randomly assigned to play a one-shot public goods game either under time-pressure (forced intuition) or with a time delay (forced reflection). Results revealed that within the placebo group, time-pressure (versus forced delay) increased cooperation among low risk men, but decreased cooperation among high risk men. Testosterone further moderated this pattern by abolishing the time-pressure effect in low risk men and—in high risk men—reversing the effect by selectively reducing offers (compared to placebo) under forced delay. This is the first evidence that testosterone and personality can interact with time-pressure and delay to predict human cooperation.
State-dependent effects of the D2 partial agonist aripiprazole on dopamine neuron activity in the MAM neurodevelopmental model of schizophrenia Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-18 Susan F. Sonnenschein, Kathryn M. Gill, Anthony A. Grace
Aripiprazole is an antipsychotic drug characterized by partial agonist activity at D2 receptors to normalize both hyperdopaminergic and hypodopaminergic states. Traditional D2 antagonist antipsychotic drugs have been shown previously to reduce dopamine neuron activity through action on D2 autoreceptors to produce an overexcitation-induced cessation of cell firing, referred to as depolarization block. It is unclear whether aripiprazole reduces dopamine neuron activity via inhibition or, as seen following D2 antagonist administration, depolarization block. The impact of acute and repeated aripiprazole treatment was examined in the methylazoxymethanol acetate (MAM) rodent model to observe its effects on a hyperdopaminergic system, compared to normal rats. We found that administration of aripiprazole acutely or after 1 or 7 days of withdrawal from 21-day repeated treatment led to a decrease in the number of spontaneously active dopamine neurons in MAM rats but not in controls. This reduction was not reversed by apomorphine (100–200 µg/kg i.p. or 20 µg/kg i.v.) administration, suggesting that it was not due to depolarization block. In contrast, 1 h after induction of depolarization block of dopamine neurons by acute haloperidol treatment (0.6 mg/kg i.p.), aripiprazole (1 mg/kg, i.p.) reversed the depolarization block state. Therefore, aripiprazole rapidly reduced the hyperdopaminergic activity selectively in MAM rats. The reduction is unlikely due to depolarization block and persists following 7-day withdrawal from repeated treatment. Aripiprazole also removes haloperidol-induced depolarization block in MAM rats, which may underlie the acute psychotic state often observed with switching to this treatment.
Dynamic network targeting for closed-loop deep brain stimulation Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-18 Alexander B. Herman, Alik S. Widge
Dynamic network targeting for closed-loop deep brain stimulation Dynamic network targeting for closed-loop deep brain stimulation, Published online: 18 September 2018; doi:10.1038/s41386-018-0210-x Dynamic network targeting for closed-loop deep brain stimulation
Digital phenotyping approaches and mobile devices enhance CNS biopharmaceutical research and development Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-18 Daniel G. Smith
Digital phenotyping approaches and mobile devices enhance CNS biopharmaceutical research and development Digital phenotyping approaches and mobile devices enhance CNS biopharmaceutical research and development, Published online: 18 September 2018; doi:10.1038/s41386-018-0222-6 Digital phenotyping approaches and mobile devices enhance CNS biopharmaceutical research and development
NMDA-receptor independent actions of ketamine: a new chapter in a story that’s not so old Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-13 Nathan H. Wray, Mark M. Rasenick
NMDA-receptor independent actions of ketamine: a new chapter in a story that’s not so old NMDA-receptor independent actions of ketamine: a new chapter in a story that’s not so old, Published online: 13 September 2018; doi:10.1038/s41386-018-0201-y NMDA-receptor independent actions of ketamine: a new chapter in a story that’s not so old
Motion mapping in humans as a biomarker for psychiatric disorders Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-13 Ipsit V. Vahia, Brent P. Forester
Motion mapping in humans as a biomarker for psychiatric disorders Motion mapping in humans as a biomarker for psychiatric disorders, Published online: 13 September 2018; doi:10.1038/s41386-018-0205-7 Motion mapping in humans as a biomarker for psychiatric disorders
TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-12 Akiyoshi Kunugi, Maiko Tanaka, Atsushi Suzuki, Yasukazu Tajima, Noriko Suzuki, Motohisa Suzuki, Shinji Nakamura, Haruhiko Kuno, Akihiro Yokota, Satoshi Sogabe, Yohei Kosugi, Yasuyuki Awasaki, Tomohiro Kaku, Haruhide Kimura
Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPA-R) is a promising strategy to treat psychiatric and neurological diseases if issues of bell-shaped response and narrow safety margin against seizure can be overcome. Here, we show that structural interference at Ser743 in AMPA-R is a key to lower the agonistic effect of AMPA-R potentiators containing dihydropyridothiadiazine 2,2-dioxides skeleton. With this structural insight, TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide, was discovered as a novel AMPA-R potentiator with a lower agonistic effect than an AMPA-R potentiator LY451646 ((R)-N-(2-(4′-cyanobiphenyl-4-yl)propyl)propane-2-sulfonamide) in rat primary neurons. TAK-137 induced brain-derived neurotrophic factor in neurons in rodents and potently improved cognition in both rats and monkeys. Compared to LY451646, TAK-137 had a wider safety margin against seizure in rats. TAK-137 enhanced neural progenitor proliferation over a broader range of doses in rodents. Thus, TAK-137 is a promising AMPA-R potentiator with potent procognitive effects and lower risks of bell-shaped response and seizure. These data may open the door for the development of AMPA-R potentiators as therapeutic drugs for psychiatric and neurological diseases.
Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-12 Karen Curtin, Annette E. Fleckenstein, Brooks R. Keeshin, Deborah A. Yurgelun-Todd, Perry F. Renshaw, Ken R. Smith, Glen R. Hanson
Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson’s disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th version (ICD-9) diagnosis codes 314.0–314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson’s disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0–3.0; P < 0.0001) compared with 158,790 non-ADHD persons, after controlling for sex and age and adjusting for tobacco use and psychotic conditions. In 4960 ADHD patients prescribed psychostimulants, risk of basal ganglia and cerebellum diseases between ages 21 and 49 years was especially pronounced, at 8.6-fold (95% CI: 4.8–15.6; P < 0001). The association of ADHD patients prescribed psychostimulants with higher risk of diseases of the basal ganglia and cerebellum may reflect a more severe ADHD phenotype rather than a direct association between prescribed stimulant use and basal ganglia or cerebellum disorders. Future studies to assess and stratify patient risk so as to inform treatment are warranted.
Vaccines to treat opioid use disorders and to reduce opioid overdoses Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-12 Carly Baehr, Marco Pravetoni
Vaccines to treat opioid use disorders and to reduce opioid overdoses Vaccines to treat opioid use disorders and to reduce opioid overdoses, Published online: 12 September 2018; doi:10.1038/s41386-018-0197-3 Vaccines to treat opioid use disorders and to reduce opioid overdoses
Novel models of drug relapse and craving after voluntary abstinence Neuropsychopharmacology (IF 6.544) Pub Date : 2018-09-11 Marco Venniro, Daniele Caprioli, Yavin Shaham
Novel models of drug relapse and craving after voluntary abstinence Novel models of drug relapse and craving after voluntary abstinence, Published online: 11 September 2018; doi:10.1038/s41386-018-0196-4 Novel models of drug relapse and craving after voluntary abstinence
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