COGNITIVE FLEXIBILITY AS A TARGET FOR RELAPSE PREVENTION

Recovery involves replacing drinking with more adaptive behavior. Once the more adaptive behaviorbecomes habitual, recovery is more resistant to relapse produced by stimuli previously occasioningdrinking. However, until this transition occurs, the new adaptive behavior is easily displaced. Thistransition requires cognitive flexibility in order to attend to the stimuli and contingencies associatedwith the new behavior. Unfortunately, heavy drinking reduces cognitive flexibility, especially infemales. This reduced cognitive flexibility appears to result from reduced cholinergic activity at ?4?2and ?7 nicotinic receptors, particularly those in the hippocampus and anterior cingulate innervated bycholinergic neurons originating in the medial septum. Restoring cholinergic function may restorecognitive flexibility during the new learning involved in transitioning from habitual drinking to moreadaptive habits; and thus, speed this transition. Speeding this transition minimizes the most fragileperiod of recovery, the early stages before new habits have developed. However, increasingcholinergic function above an optimal level impairs new learning. Thus, enhancing cholinergicfunction may only speed recovery when chronic drinking has reduced cognitive flexibility, perhapsmore so in females. We explore these possibilities using a rat model of recovery we developed. Likein the real world, in this model high and low levels of drinking are controlled not by changing ethanolavailability, but rather by changing the contingencies governing the availability of alternatives, in thiscase food. In the presence of one stimulus, food is costly and drinking predominates. In the presenceof another, food is easily available and little drinking occurs, simulating recovery. After severalconsecutive recovery sessions in which rats only encounter low cost food conditions, presenting thehigh-cost food stimulus no longer controls responding for ethanol. Instead rats persist at respondingfor food, indicating this response has become habitual and control by the high-cost food stimulus hasweakened. We propose examining whether chronic intermittent ethanol exposure slows thedevelopment of recovery, and whether this effect is greater in females. Further, we compare effects ofnicotine to those of epibatidine and PNU-282987, which preferentially activate ?4?2 and ?7 receptors,respectively. Finally, we examine effects of delivering nicotine into the hippocampus and cingulate andcompare these to those following administration into the thalamus (not expected to influence cognitiveflexibility). This project explores an innovative target for relapse prevention: medications intended tospeed new habit formation, such as might occur during behavioral therapy. This strategy mayreduce relapse during the early, critical period of recovery, thus improving therapeutic outcomes.