Hong Nie1, Patricia H Janak2. 1. Department of Neurology, Ernest Gallo Clinic & Research Center, University of California San Francisco, Emeryville, CA 94608, USA. 2. Department of Neurology, Ernest Gallo Clinic & Research Center, University of California San Francisco, Emeryville, CA 94608, USA. pjanak@itsa.ucsf.edu.
Abstract
RATIONALE AND OBJECTIVES: Understanding the mechanism of relapse provoked by conditioned and unconditioned stimuli is critical to improving treatments for alcoholism. This study compared the reinstatement of alcohol- or sucrose-seeking by conditioned stimuli and priming injections of the neuroactive steroid, allopregnanolone (ALLO). METHODS: Rats were trained to lever-press for 0.1 ml of 10% ethanol or 5% sucrose solutions. Responding was then extinguished, and subjects were tested for reinstatement of lever-press responding. The effects of priming injections of 0, 1.0, 3.0 and 7.5 mg/kg ALLO were determined in subjects trained to self-administer ethanol, and the response-reinstating effects of priming injections of 3.0 mg/kg ALLO were compared with those of conditioned cue presentation in subjects trained to self-administer either ethanol or sucrose. RESULTS: Priming injections of ALLO dose-dependently reinstated previously extinguished responding for ethanol, as shown by increased responding on the active (ethanol) lever. Contingent presentation of cues previously associated with the reinforcer increased the number of active lever-presses for both ethanol- and sucrose- trained subjects. In contrast, pretreatment with 3.0 mg/kg ALLO increased the number of active lever-presses for subjects that were trained to self-administer ethanol, but not sucrose. CONCLUSIONS: ALLO promotes responding for ethanol, but not sucrose, following a period of abstinence, suggesting that GABA(A) receptor modulation may contribute to processes involved in reinstatement of ethanol-seeking behavior. In contrast, conditioned stimuli reinstate previously extinguished ethanol- and sucrose-seeking behavior, indicating that the mechanisms that subserve cue-induced reinstatement do not depend upon the nature of the positive reinforcer.
RATIONALE AND OBJECTIVES: Understanding the mechanism of relapse provoked by conditioned and unconditioned stimuli is critical to improving treatments for alcoholism. This study compared the reinstatement of alcohol- or sucrose-seeking by conditioned stimuli and priming injections of the neuroactive steroid, allopregnanolone (ALLO). METHODS:Rats were trained to lever-press for 0.1 ml of 10% ethanol or 5% sucrose solutions. Responding was then extinguished, and subjects were tested for reinstatement of lever-press responding. The effects of priming injections of 0, 1.0, 3.0 and 7.5 mg/kg ALLO were determined in subjects trained to self-administer ethanol, and the response-reinstating effects of priming injections of 3.0 mg/kg ALLO were compared with those of conditioned cue presentation in subjects trained to self-administer either ethanol or sucrose. RESULTS: Priming injections of ALLO dose-dependently reinstated previously extinguished responding for ethanol, as shown by increased responding on the active (ethanol) lever. Contingent presentation of cues previously associated with the reinforcer increased the number of active lever-presses for both ethanol- and sucrose- trained subjects. In contrast, pretreatment with 3.0 mg/kg ALLO increased the number of active lever-presses for subjects that were trained to self-administer ethanol, but not sucrose. CONCLUSIONS:ALLO promotes responding for ethanol, but not sucrose, following a period of abstinence, suggesting that GABA(A) receptor modulation may contribute to processes involved in reinstatement of ethanol-seeking behavior. In contrast, conditioned stimuli reinstate previously extinguished ethanol- and sucrose-seeking behavior, indicating that the mechanisms that subserve cue-induced reinstatement do not depend upon the nature of the positive reinforcer.
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