The neural circuitry that mediates prepulse inhibition of the startle reflex (PPI) overlaps considerably with the neural mechanisms (e.g., mesolimbic structures and dopamine activity) that mediate alcohol- induced and alcohol cue-induced changes in mesolimbic dopamine activity. Given this congruence in neural circuitry, PPI has considerable promise as a centrally mediated and biologically based measure of the mesolimbic activating effects of alcohol and alcohol cues. The long-term objective of this research is to develop PPI as an integral component of a paradigm that will be used to test current assumptions about the biological (e.g., dopamine activity) and cognitive processes (e.g., subjective stimulation, reinforcement, and craving) that underlie the acquisition and expression of addictive behavior. Specifically, this research will test the following primary hypotheses: 1) Intravenous administration of a low dose of alcohol in moderate to heavy social drinkers decrease prepulse inhibition of the startle response and increases self-reported stimulation; 2) These effects are mediated in part by mesolimbic dopamine activity and therefore should be blocked by a drug that is known to reduce dopamine activity in these structures (e.g., haloperidol); 3) Exposure to alcohol cues in alcohol dependent patients results in decreases prepulse inhibition of the startle response and increases urge to drink; 4) These effects are also mediated in part by mesolimbic dopamine and can be blocked with a drug that reduces dopamine activity (e.g., haloperidol). Hypotheses 1 and 2 will be tested in a 2 x 2 factorial design, in which intravenous infusion of alcohol will be compared with saline infusion and crossed with haloperidol and placebo using the startle reflex and self-report measures of stimulation and affect as dependent variables. Hypotheses 3 and 4 test will be tested in a 2 x 2 factorial design, in which control cues will be compared with alcohol cues and crossed with haloperidol and placebo. The findings of these studies are expected to lead to a more detailed conceptualization of the biological and cognitive underpinnings of alcohol dependence and guide the development of new interventions for alcohol dependence.
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