Dysregulation of Brain Stress Systems Mediates Compulsive Alcohol Drinking

Abstract

The transition from moderate to compulsive alcohol drinking is driven by increasingly dysfunctional reward and stress systems. We review behavioral and pharmacological studies of alcohol self-administration in rats that were mainly conducted within the framework of the alcohol vapor model of dependence. We discuss neurotransmitter systems that are implicated in alcohol drinking, with a focus on contrasting those neurotransmitter systems that drive behavior in the dependent vs. nondependent states. We hypothesize that the identification of systems that become increasingly dysfunctional in alcohol dependence will reveal possible targets for successful interventions to reduce the motivation that drives compulsive alcohol drinking. In our opinion, drugs that (1) normalize, rather than block, a hypofunctional reward system via restoration of the function of hypothalamic stress systems, and (2) desensitize extrahypothalamic stress systems have the potential to selectively and effectively curb compulsive alcohol drinking.

Fig. 1

Effect of drugs reported to have acute effects in the alcohol-vapor dependence model of escalated alcohol drinking. To be included in this analysis, the studies had to include both dependent and nondependent rats and report a significant effect on alcohol drinking in either group. Studies were included that tested alcohol drinking during acute withdrawal (typically 2–8 h into withdrawal; memantine was tested at 24 h into withdrawal). The figure shows the difference in sensitivity between groups (i.e., percent change in drinking in the dependent group [drug relative to vehicle] minus the percent change in drinking in the nondependent group). We chose the highest dose of the drug that caused a group-specific effect. If not available (i.e., equally effective in both groups), we used the first effective dose to compare groups. Because none of the treatments caused large increases in alcohol drinking, the bars that are plotted can generally be interpreted as showing the relative effectiveness of each compound in reducing drinking in the two groups. Bars to the left of the “Equal Efficacy” line indicate compounds that are more effective in nondependent animals. Bars that are close to the “Equal Efficacy” line indicate that the treatment was similarly effective in both groups. Bars to the right of the “Equal Efficacy” line indicate compounds that are more effective in dependent animals. To collect numerical values for this analysis, figures from published reports were analyzed using a freely available tool for extracting raw data from scientific figures (Web Plot Digitizer, Version 3.9, http://arohatgi.info/WebPlotDigitizer).