Karyn M Myers1, William A Carlezon. 1. Behavioral Genetics Laboratory, McLean Hospital, and Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts 02478, USA. kmyers@mclean.harvard.edu
Abstract
BACKGROUND: Cues paired with drug administration trigger relapse to drug seeking by inducing conditioned drug craving and withdrawal. Because drug cues hinder abstinence in addicts, therapies that reduce responsiveness to drug cues might facilitate rehabilitation. Extinction is a means of reducing conditioned responses and involves exposure to the conditioned stimulus in the absence of the unconditioned stimulus with which it was paired previously. We examined conditioned withdrawal extinction using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats. METHODS: Morphine-dependent rats were trained to associate an environment with naloxone-precipitated withdrawal. Subsequently, they received extinction training in which they were confined in the previously naloxone-paired environment in the absence of acute withdrawal. In some rats, the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS) was administered before extinction training. RESULTS: Morphine withdrawal-induced CPA persists in the absence of extinction training. Administration of DCS before extinction training facilitates extinction. CONCLUSIONS: D-cycloserine facilitates extinction of morphine withdrawal-associated place aversion. This effect is qualitatively similar to the effect of DCS on extinction of conditioned fear, raising the possibility of common neural mechanisms. This work extends our understanding of drug cue responsivity and provides a rationale for the development of extinction-based treatments for addiction.
BACKGROUND: Cues paired with drug administration trigger relapse to drug seeking by inducing conditioned drug craving and withdrawal. Because drug cues hinder abstinence in addicts, therapies that reduce responsiveness to drug cues might facilitate rehabilitation. Extinction is a means of reducing conditioned responses and involves exposure to the conditioned stimulus in the absence of the unconditioned stimulus with which it was paired previously. We examined conditioned withdrawal extinction using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats. METHODS:Morphine-dependent rats were trained to associate an environment with naloxone-precipitated withdrawal. Subsequently, they received extinction training in which they were confined in the previously naloxone-paired environment in the absence of acute withdrawal. In some rats, the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS) was administered before extinction training. RESULTS:Morphine withdrawal-induced CPA persists in the absence of extinction training. Administration of DCS before extinction training facilitates extinction. CONCLUSIONS:D-cycloserine facilitates extinction of morphine withdrawal-associated place aversion. This effect is qualitatively similar to the effect of DCS on extinction of conditioned fear, raising the possibility of common neural mechanisms. This work extends our understanding of drug cue responsivity and provides a rationale for the development of extinction-based treatments for addiction.
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