Role of 5-HT<sub>2A</sub> receptors in the effects of ayahuasca on ethanol self-administration using a two-bottle choice paradigm in male mice.
Abstract
<h4>Rationale</h4>Ayahuasca has been proposed as a potential treatment of alcohol (ethanol) use disorder (AUD). The serotonin 5-HT<sub>2A</sub> receptor agonist N,N-dimethyltryptamine (DMT) is the main psychoactive component of ayahuasca, suggesting that its therapeutic effects may be mediated by 5-HT<sub>2A</sub> receptors.<h4>Objectives</h4>The aim of the present study was to investigate the effects of ayahuasca on the expression of ethanol self-administration using a two-bottle choice procedure and the role of 5-HT<sub>2A</sub> receptors in those effects.<h4>Methods</h4>Male mice had intermittent access to ethanol (10% v/v) in a two-bottle choice procedure for 30 days. Animals were then submitted to 3 treatment phases, each followed by ethanol re-exposure tests. During the treatment phase, every 3 days, animals received i.p. injections of either vehicle or the 5-HT<sub>2A</sub> receptor antagonist M100907 (M100, 1 mg/kg) followed by an i.g. (gavage) administration of vehicle or ayahuasca (100 mg/kg) and were exposed to the self-administration apparatus with no ethanol availability. During re-exposure tests, animals were submitted to the same conditions as during acquisition, with no treatments prior to those sessions.<h4>Results</h4>Treatment with ayahuasca blocked the expression of ethanol self-administration, decreasing ethanol intake and preference during re-exposure tests. Pretreatment with M100 blocked the effects of ayahuasca on ethanol drinking without significantly attenuating ethanol self-administration.<h4>Conclusions</h4>Treatment with ayahuasca during alcohol abstinence blocked the expression of alcohol self-administration in mice, and 5-HT<sub>2A</sub> receptor activation is critical for those effects to emerge. Our findings support a potential for ayahuasca and other 5-HT<sub>2A</sub> receptor agonists as adjunctive pharmacotherapies for the treatment of AUD.
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