The overall objective of this project is to study factors that predict vulnerability to drug addiction such as sex, hormonal status and prior experience with other addictive behaviors. This work is based on the hypothesis that nondrug substances and events such as preferred foods and exercise may act as rewards that are interchangeable with drugs, and individuals that show high levels of behavior maintained by nondrug events may be more susceptible than others to drug abuse. Sex and hormonal conditions are also important determinants of the rewarding effects of drugs and other substances. Several phases of the addiction process will be modeled: 1) acquisition/vulnerability, 2) maintenance (regulation/reinforcing efficacy - progressive ratio schedule) and 3) reinstatement/relapse. Using these models, behavioral and pharmacological methods for preventing and treating drug abuse will also be tested. Rats will be prepared with indwelling venous catheters, and they will be trained to self-administer infusions of cocaine or heroin. To determine the effects of sex and hormonal status, males vs. females will be compared during the three phases. The effect of ovarian hormones will be examined by comparing intact female rats with and without ovariectomy (OVX) and with OVX and estrogen replacement with estradiol benzoate (EB). To determine whether individual differences in other addictive behavior predicts vulnerability to drug abuse, in Experiment 1 groups of rats will be screened for high or low levels of wheel running, sucrose intake other drug self-administration, and their rate and success of acquisition of drug self-administration, maintenance and reinstatement will be compared. Experiment 2 will compare rats that were selectively bred (in another laboratory) for sweet preference on acquisition, maintenance and reinstatement. Experiment 3 will focus on sex and hormonal differences in acquisition, maintenance and reinstatement. Experiment 4 will examine the effect of nondrug reinforcers (sucrose, wheel-running) as a treatment for drug abuse in males and females during the 3 phases of addiction, and Experiment 5 will follow a similar approach with males, females, the 3 phases of addiction using potential treatment medications, baclofen (a GABAB agonist) and bremazocine, (a kappa opioid receptor agonist). It is hoped that the outcome of these experiments will identify vulnerability factors that have not yet been adequately considered, compare those factors at various phases of addiction, and compare behavioral and pharmacological treatments in groups varying in vulnerability to provide useful information on treatment approaches that selectively reduce drug-seeking behavior.
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