Role of 5-HT2A receptors in the effects of ayahuasca on ethanol self-administration using a two-bottle choice paradigm in male mice

• Published in: Psychopharmacology Vol. 239; no. 6; pp. 1679 - 1687
• Main Authors: Serra, Yasmim A., Barros-Santos, Thaísa, Anjos-Santos, Alexia, Kisaki, Natali D., Jovita-Farias, Caio, Leite, João P. C., Santana, Maria C. E., Coimbra, João P. S. A., de Jesus, Nailton M. S., Sulima, Agnieszka, Barbosa, Paulo C. R., Malpezzi-Marinho, Elena L. A., Rice, Kenner C., Oliveira-Lima, Alexandre J., Berro, Laís F., Marinho, Eduardo A. V.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2022; Springer Nature B.V
• Subjects: Agonists; Alcohol; Biomedical and Life Sciences; Biomedicine; Drinking behavior; Drug self-administration; Ethanol; Neurosciences; Original Investigation; Pharmacology/Toxicology; Psychedelic drugs; Psychiatry; Psychotropic drugs; Receptor mechanisms; Serotonin S2 receptors; Self-administration; Mice; Ethanol; Serotonin; 5-HT; Ayahuasca
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-022-06104-w

Rationale Ayahuasca has been proposed as a potential treatment of alcohol (ethanol) use disorder (AUD). The serotonin 5-HT 2A receptor agonist N,N-dimethyltryptamine (DMT) is the main psychoactive component of ayahuasca, suggesting that its therapeutic effects may be mediated by 5-HT 2A receptors. Objectives 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 2A receptors in those effects. Methods 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 2A 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. Results 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. Conclusions Treatment with ayahuasca during alcohol abstinence blocked the expression of alcohol self-administration in mice, and 5-HT 2A receptor activation is critical for those effects to emerge. Our findings support a potential for ayahuasca and other 5-HT 2A receptor agonists as adjunctive pharmacotherapies for the treatment of AUD.