BEHAVIORAL AND ELECTROPHYSIOLOGICAL EFFECTS OF LYSERGIC ACID DIETHYLAMIDE (LSD) IN A MOUSE MODEL OF ALCOHOL USE DISORDER (AUD)
Authors: De Gregorio *Danilo , Ferroni Carolina Giulia , Nicosia Noemi , Spadaccini Margherita 
Published: February 2025

Abstract

Introduction
Alcohol use disorder (AUD) is a major problem that causes significant health and social problem. Pharmacological treatments for AUD are limited in their effectiveness, and new drugs are required (ref). Recently, the potential use of psychedelics as novel therapies in treating mental diseases has come to the forefront in psychiatry. For instance, lysergic acid diethylamide (LSD) is a psychedelic acting as partial agonist of 5-HT2A receptors and exerts its mechanism of action through the modulation of the dopaminergic system in the ventral tegmental area (VTA). For instance, VTA plays a pivotal role in mediating the neurophysiology of AUD. Indeed, chronic alcohol consumption produces a disruption on the dopaminergic (DA) neurotransmission in the VTA. However, the mechanism of action and pre-clinical data about the effectiveness of psychedelic -based therapies for AUD remain limited.

Aims and Objectives
This translational study aims at determining whether the LSD can reduce alcohol consumption in an animal model of AUD as well as its ability to restore the impaired VTA DA neurotransmission induced by the AUD. To do so, we employed a mouse model of self-ethanol administration with a paradigm DID (Drinking in the dark) to mimic binge-like drinking in humans and we performed behavioral paradigms and in vivo single-unit extracellular recordings.

Method
C57BL6/J 8-week-old male mice underwent 6 cycles of DID. In each cycle, the water bottles were removed from all cages and replaced with bottles containing 20% ethanol solution for 2 hours per day, for 4 consecutive days in one experimental group (AUD mice). In another group of mice (control, CTL) the water bottles were not replaced with ethanol. After 6 cycles of DID, mice received a single intraperitoneal injection of vehicle or LSD (150 mcg/kg, a dose that has been demonstrated to exert antidepressant effects. The day after the injections, animals were assessed for the alcohol consumption with the 40 days two-bottle choice test. Twenty-four hours from the last drinking session in the two- bottle choice test, locomotion was assessed by using the open field test (OFT) and the rotarod test. Finally, in vivo single unit extracellular recordings of VTA DA neurons were performed.

Results
AUD mice did not show difference in locomotion in the OFT, compared to CTL (p=0.012). However, AUD mice displayed decreased latency to fall (p&lt;0.01) in the rotarod test. These effects were coupled to an increased DA VTA firing rate activity (p&lt;0.05) and reduced intra-burst frequency (p&lt;0.001) compared to CTL mice. LSD significantly reduced the alcohol intake (p&lt;0.05) and normalized the locomotor impairments in the AUD mice (p&lt;0.001). Moreover, LSD did not revert the enhanced DA VTA firing rate activity but it increased the intra-burst frequency (p&lt;0.001) which was reduced by the chronic alcohol consumption.

Discussion and Conclusion
This work show that 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.