661. A SINGLE DOSE OF LYSERGIC ACID DIETHYLAMIDE (LSD) REDUCES ALCOHOL CONSUMPTION AND REVERTS DOPAMINERGIC (DA) DISFUNCTION IN MALE MICE

Abstract Background Alcohol use disorder (AUD) presents significant health and societal issues. The disorder is characterized by locomotor impairments and disruption of the dopaminergic neurotransmission in the ventral tegmental area (VTA). Current AUD treatments are limited, necessitating the exploration of novel drugs. The potential therapeutic use of psychedelics, particularly lysergic acid diethylamide (LSD), has gained attention in psychiatry and addiction. However, our understanding of their mechanism of action and the demonstration of their pre-clinical effectiveness for AUD remain incomplete. Aims & Objectives This translational study employs a mouse model of binge-like drinking to investigate whether LSD can reduce alcohol consumption and restore impaired VTA DA neurotransmission. Method C57BL6/J 8-week-old male mice underwent 6 cycles of DID. In each cycle, water was replaced with a 20% ethanol solution for 2 hours per day for 4 consecutive days in the AUD group, while the control group (CTL) received no ethanol. After 6 cycles, mice received a single intraperitoneal injection of vehicle or LSD (150 mg/kg). Spontaneous alcohol intake was evaluated starting on the next day using a 40-day two-bottle choice test. Locomotor activity was assessed by using the open field (OFT) and the rotarod tests 24 hours after the last drinking session. Finally, in vivo single-unit extracellular recordings of VTA DA neurons were performed. Results AUD mice did not show differences in locomotion in the OFT compared to CTL (p = 0.012). However, AUD mice displayed decreased latency to fall (p<0.01) in the rotarod test. These effects were coupled to an increased DA VTA firing rate activity (p<0.05) and reduced intra-burst frequency (f=6,724, p<0.001) compared to CTL mice. LSD significantly reduced the alcohol intake (f(interaction)=2,690, f(treatment)=2,782, f(ethanol concentration)=11,30, p<0.05, two-way ANOVA followed by Bonferroni post hoc comparisons) and normalized the locomotor impairments in the AUD mice (p<0.001). LSD did not revert the enhanced DA VTA firing rate activity, however it increased the intra-burst frequency (f=3.811, p<0.001, one-way ANOVA followed by Bonferroni post-hoc comparisons), which was reduced by chronic alcohol consumption. Discussion & Conclusions This work shows that a single administration of LSD reduces alcohol consumption and reverts locomotor impairment. Moreover, LSD partially restores the VTA DA deficits induced by chronic alcohol consumption. Overall, this study will broaden our understanding of the potential therapeutic effects of psychedelics in treating AUD.