Ayahuasca, a psychedelic beverage, modulates neuroplasticity induced by ethanol in mice
Introduction
Although ethanol is a licit drug, it is associated with high morbidity and mortality. Ethanol abuse is responsible for about 3 million deaths per year worldwide, being associated with more than 200 diseases, such as cancer, cardiovascular and liver diseases, and traffic injuries, aggression, and homicides [1]. The prevalence of current drinkers differs among regions, reaching 54.1 % in the Americas and 59.9 % in Europe. Therefore, alcohol use disorder (AUD) is most prevalent in these regions (Americas – 4.1 %; Europe – 3.7 %) [1]. AUD is the uncontrolled use of ethanol despite the absence or reduction of pleasant effects and the awareness of the harm caused by its repeated administration [2]. Ethanol withdrawal may lead to symptoms of anxiety, depression, and irritability that act as a negative reinforcement for the continued use of the drug [3], whose mechanism involves “drinking-to-cope”, a process related to negative effect. Treatments available to AUD are based on psychosocial and pharmacological therapies. The psychosocial tools include individual, group and family therapies, and the pharmacological therapies include treatment of the alcohol withdrawal symptoms (anxiolytics and antidepressants) and specific therapies that cause aversion to ethanol (disulfiram) or craving reduction (naltrexone). Thus, treatments are scarce, and relapse occurs in more than half of the patients with AUD [4], being even higher for patients with co-occurring anxiety disorder [5].
In this context, psychedelic substances have been widely studied as possible therapeutic strategies for addiction treatment. Ayahuasca (AYA) is a psychoactive beverage originally from the Amazon Indians used in religious rituals such as Santo Daime and Barquinha [6]. AYA is prepared by the decoction of the leaves of Psychotria viridis, which contain the hallucinogenic substance N,N-dimethyltryptamine (DMT), and Banisteriopsis caapi vines, whose main constituents are β-carbolines alkaloids, such as harmine (HRM), harmaline (HRL), and tetrahydroharmine (THH). The synergistic effect of both plants is explained by the monoamine oxidase type A inhibition of the β-carbolines alkaloids, which allows DMT absorption by oral administration [7,8]. Clinical studies have shown the beneficial effects of AYA in the treatment of depression, anxiety, and addiction [[9], [10], [11], [12], [13], [14]]. Preclinical studies also showed that AYA compounds, such as harmine and others β-carbolines, induced anxiolytic and antidepressant-like effects; however, chronic exposure to AYA tea did not affect anxiety and memory in mice [[15], [16], [17]].
DMT has a similar chemical structure to serotonin and is a partial agonist at 5-HT1a, 5-HT1b, 5-HT2a, and 5-HT2c receptors [18], whereas THH blocks serotonin reuptake, increasing serotonin levels in the brain [19]. Ethanol interferes in the dopaminergic, serotonergic, and opioid systems [20,21] leading to high dopamine levels in the nucleus accumbens, mainly mediated by D1 receptor, and increasing serotonin receptor expression [[22], [23], [24]]. Dynorphin, whose precursor is prodynorphin, is a potent endogenous opioid that acts preferentially on κ-opioid receptors. Studies indicate that dynorphin and κ receptors are involved in several psychiatric disorders, including anxiety, depression and addiction [[25], [26], [27], [28]]. Both chronic and acute exposure to ethanol produce neuroplasticity in the opioid system that reflect changes in the levels, expression and activity of dynorphin and κ receptors [[29], [30], [31]].
The ethanol-induced behavioral sensitization (EIBS) is a phenomenon associated with neuroadaptation induced by ethanol [20]. It can be measured by the enhancement of locomotor activity following chronic or intermittent ethanol exposure and is divided in two phases: acquisition or development and expression. Acquisition phase is characterized by immediate molecular and cellular changes mainly in the prefrontal cortex and in the ventral tegmental area [32,33]. The expression phase is related to the long-lasting consequences of these effects and the main substrate is the nucleus accumbens In general, the sensitization expression is revealed after a period of drug withdrawal upon a challenge administration [32]. Thus, this study aimed to evaluate the effects of AYA on EIBS and in anxiety, one of the main symptoms of the ethanol withdrawal, and to investigate if AYA modulates dopamine (D1, D2) and serotonin (5-HT1a, 5-HT2a) receptors, and dynorphin and prodynorphin levels.
Section snippets
Animals
Seventy-two adult male Swiss mice (6–7 weeks-old) were housed in polypropylene cages (26 × 36 × 19 cm) with free access to food and water. They were housed in a room with constant temperature (22 ± 1 °C) on a 12:12 h light/dark cycle (lights on at 7:00 am). All experiments were performed during the light period and the behavioral experiments were conducted between 7:30 am and 12 pm. One animal died during the experiments (SAL/AYA/ET group). The experimental procedures were approved by the
Alkaloid levels in AYA
Table 1 shows values of HRL, HRM, THH, and DMT concentration in lyophilized AYA.
Effect of AYA on EIBS
Locomotor activity during habituation showed no significant differences among the groups (data not shown). ANOVA repeated measures revealed a significant time effect (F4,236 = 5.60, p < 0.001) and treatment × time interaction (F4,236 = 3.69; p < 0.001; Fig. 2A) during the acquisition phase. Animals from the ethanol group showed significantly increased locomotor activity when compared with saline group on all days
Discussion
A clinical study has indicated that AYA, in a religious context, has been effective as a treatment for drug addiction [46]. However, more preclinical studies are required for a better understanding of the effects of AYA. We found that oral administration of AYA during eight consecutive days at a dose of 1.76 mg DMT/kg was effective to attenuate the expression of ethanol-induced behavioral sensitization in mice. We also observed that AYA caused an anxiolytic effect during ethanol withdrawal,
CRediT authorship contribution statement
Carolina Aparecida Faria Almeida: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing - original draft, Writing - review & editing, Investigation, Visualization. Antonio Alves Pereira-Junior: Investigation. Jéssica Gonçalves Rangel: Investigation. Bruna Pinheiro Pereira: Investigation. Karla Cristinne Mancini Costa: Investigation. Vitor Bruno: Investigation, Writing - review & editing. Gabriela Oliveira Silveira: Investigation, Writing - original draft, Writing -
Declaration of Competing Interest
None.
Acknowledgments
The authors gratefully acknowledge the technical support of Marcos Vinícios Salles Dias, Lidia Emmanuela Wiazowski Spelta, and Camila Martins Chaves. This study received funding by the Fundação de Amparo à Pesquisa do Estado de Minas Gerais, Brazil (FAPEMIG, grant number APQ-01145-16), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior- Brasil (CAPES, Finance Code 001); Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grant numbers 405353/2016-2 and 141878/2020-7);
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2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The mechanism(s) of action entrained by psychedelics to elicit fast-onset and sustained therapeutic improvement from psychiatric states is still under scrutiny and poorly understood (Inserra et al., 2021; Vollenweider and Preller, 2020). Preliminary preclinical evidence suggests that a modulation of gene expression (González-Maeso et al., 2003; Martin et al., 2014; Nichols and Sanders-Bush, 2002) leading to an enhancement of neurogenesis (Catlow et al., 2013; Lima da Cruz et al., 2018; Morales-Garcia et al., 2020), and neuronal and synaptic plasticity (Almeida et al., 2022; Ly et al., 2018; Raval et al., 2021) might mediate the therapeutic effects of psychedelics. In rodents, a single administration of LSD elicits antidepressant-like effects detectable 1 month after administration (Hibicke et al., 2020), while chronic administration alters gene expression in the prefrontal cortex (PFC) (Martin et al., 2014), a key node of the corticolimbic system linked to cognition and psychiatric disorders (Gawryluk et al., 2011; Goto et al., 2010; Miller and Cohen, 2001; Numata et al., 2012).