Continued seeking and drinking of alcohol despite adverse legal, health, economic, and societal consequences is a central hallmark of human alcohol use disorders. This compulsive drive for alcohol, defined by resistance to adverse and deleterious consequences, represents a major challenge when attempting to treat alcoholism clinically. Thus, there has long been interest in developing pre-clinical rodent models for the compulsive drug use that characterizes drug addiction. Here, we review recent studies that have attempted to model compulsive aspects of alcohol and cocaine intake in rodents, and consider technical and conceptual issues that need to be addressed when trying to recapitulate compulsive aspects of human addiction. Aversion-resistant alcohol intake has been examined by pairing intake or seeking with the bitter tastant quinine or with footshock, and exciting recent work has used these models to identify neuroadaptations in the amygdala, cortex, and striatal regions that promote compulsive intake. Thus, rodent models do seem to reflect important aspects of compulsive drives that sustain human addiction, and will likely provide critical insights into the molecular and circuit underpinnings of aversion-resistant intake as well as novel therapeutic interventions for compulsive aspects of addiction.

No abstract

Ethanol alters the distribution and abundance of PKC␦ in neural cell lines. Here we investigated whether PKC␦ also regulates behavioral responses to ethanol. PKC␦ Ϫ/Ϫ mice showed reduced intoxication when administered ethanol and reduced ataxia when administered the nonselective GABA A receptor agonists pentobarbital and pregnanolone. However, their response to flunitrazepam was not altered, suggesting that PKC␦ regulates benzodiazepine-insensitive GABA A receptors, most of which contain ␦ subunits and mediate tonic inhibitory currents in neurons. Indeed, the distribution of PKC␦ overlapped with GABA A ␦ subunits in thalamus and hippocampus, and ethanol failed to enhance tonic GABA currents in PKC␦ Ϫ/Ϫ thalamic and hippocampal neurons. Moreover, using an ATP analog-sensitive PKC␦ mutant in mouse L(tk Ϫ ) fibroblasts that express ␣4␤3␦ GABA A receptors, we found that ethanol enhancement of GABA currents was PKC␦-dependent. Thus, PKC␦ enhances ethanol intoxication partly through regulation of GABA A receptors that contain ␦ subunits and mediate tonic inhibitory currents. These findings indicate that PKC␦ contributes to a high level of behavioral response to ethanol, which is negatively associated with risk of developing an alcohol use disorder in humans.

These findings demonstrate the staged occurrence in mice of 2 distinct behavioral characteristics of alcoholism, i.e., inflexible and indifferent alcohol drinking.

These profound individual differences in alcohol intake, reinforcement, motivation, and AUD-like behavior provide a promising tool to unravel the neurobehavioral underpinnings of individual vulnerability for AUD.