Alcohol addiction (hereafter equated to alcohol dependence according to the WHO ICD 10 classification, or moderate-to-severe alcohol use disorder, AUD, according to the DSM classification of the American Psychiatric Association), is a complex psychiatric illness with an approximate global lifetime prevelance (of AUD) of 14.1 % and 3.4 % for men and women respectively. Only a subset of alcohol users develop addiction, suggesting that research to discover novel treatments should consider individual differences in susceptibility for clinically relevant behaviors. Continued use of alcohol despite negative consequences, commonly referred to as “compulsive use”, is a hallmark of the transition from recreational to addictive use of alcohol. Research in animal models has begun to identify mechanisms behind compulsive alcohol taking, but the neural basis of individual differences in this behavior remains poorly understood.

The main aim of this thesis is to investigate the neural mechanisms of individual susceptibility to compulsive alcohol use, a key feature of alcohol addiction, and the potential role of sex as a biological variable.

In paper I, we characterized susceptibility to developing compulsive alcohol self-administration in rats. We identified an ensemble of neurons in the central nucleus of the amygdala (CeA) that promoted compulsive self-administration. We identified these neurons as PKCδ neurons, one of two major subpopulations in the central nucleus. Lastly, we investigated the causal role of PKCδ itself in compulsive self-administration by knocking down its expression and found that this reduced compulsive self-administration. In paper II, we studied the role of the GABA_B receptor agonist, baclofen, in compulsive alcohol self-administration, and on activity of neurons in the centrolateral amygdala (CeL). This study provides a mechanistic rationale for developing improved alcohol addiction medications that target GABA_B receptors and PKCδ⁺ neurons in the CeL. In paper III we characterized sex differences in animal models of alcohol addiction, including compulsive alcohol self-administration. We found that female rats consumed equal amount of alcohol as males in unpunished conditions, but that they were more resistant to aversive consequences when alcohol rewards were paired with either footshock or quinine adulteration. We investigated potential predictors of compulsive self-administration in both sexes and found that for male rats, compulsivity was predicted by motivation to obtain alcohol, whereas for females, compulsivity was promoted by stress-pain factors. Lastly, in paper IV, we characterize a novel tool for studying the role of PKCδ⁺ neurons, a transgenic rat line that expresses Cre-recombinase under the control of the PKCδ⁺ promoter, allowing selective access to, and control of PKCδ+ neurons.

Collectively, these studies highlight PKCδ-expressing neurons in the CeA as critical players in punishment-resistant alcohol self-administration, pointing to a new avenue for developing targeted treatments. The findings also emphasize the need for sex-specific approaches in both preclinical models and clinical interventions.