Profiling the effects of Naltrexone, Ketamine, and MDMA on behaviour and brain neurophysiology in alcohol- drinking rats

Abstract

Alcohol use disorder (AUD) is a highly prevalent and detrimental disorder, however the first
line of treatment is ineffective in preventing relapse. Recently, drug-assisted psychotherapy
trials using MDMA and ketamine have shown promise in treating adult patients with this
disorder, yet the brain mechanisms mediating these beneficial effects remains unknown.
This thesis aims to develop a multimodal framework through which to back-translate and
quantify the behavioural and neurophysiological consequences of drug action in a rat model
of AUD.
The effects of subcutaneous injections of saline, naltrexone (3 mg/kg), MDMA (5 mg/kg),
and ketamine (4 mg/kg) on alcohol consumption, social interaction, and in vivo
neurophysiology were tested in Sprague-Dawley rats (n=24; 12 female, 12 male) that had
previously been exposed to alcohol in both adolescence and adulthood.
Here, I show clear differences between female and male drinking and social behaviours.
Female rats consume more absolute alcohol in grams per kg of body weight in comparison
to their male counterparts (p=0.04) and spend more time alone than with a conspecific rat in
a three-chamber maze (p=0.01). I also show differences between drug induced spectral
signatures of the prefrontal cortex and nucleus accumbens local field potentials (LFP) of
freely moving rats, with ketamine elevating both gamma and high frequency oscillation
power and MDMA primarily inducing gamma oscillations.
These results demonstrate differences in female and male responses to alcohol
administration and highlight the need for representative research considering both sexes.
The differing trends seen in the LFP may reflect neural circuit biomarkers of drug action.
Given the role of these drugs in a psychotherapy setting, it is crucial to elucidate this
mechanism of their action. Consequently, I anticipate this to be the first of many in vivo
studies characterising the effects of these drugs, so that clinical trials can continue, and
patient benefit ensue.

Date of Award	23 Jan 2024
Original language	English
Awarding Institution	University of Bristol
Supervisor	Matt W Jones (Supervisor) & Daniel Titheradge (Supervisor)