Emerging data supports the role of glutamate in extinction learning. D-cycloserine (DCS), a partial glutamate agonist, facilitates extinction of associative learning in animal models of fear-conditioning and clinical studies of exposure treatment for anxiety disorders. A recent study demonstrated DCS acceleration of extinction of cocaine-induced conditioned place preference in rats. The proposed study will extend these innovative and promising findings from the basic science arena and anxiety disorders field in a proof of concept investigation of DCS facilitation of extinction of response to cocaine-related cues in a human laboratory paradigm.
The specific aims of this application are: 1. To explore the impact of acute administration of D-cycloserine (DCS) on response to cocaine-related cues in cocaine-dependent individuals. 2. To explore the impact of number of doses and schedule of DCS administration on the extinction of response to cocaine-related cues in cocaine-dependent individuals. 3. To preliminarily explore the durability of DCS-facilitated extinction of response to cocaine-related cues it is hypothesized that the administration of DCS before cocaine cue exposure sessions will decrease cocaine craving and physiologic reactivity in response to cocaine-related cues. To test the hypotheses, 72 cocaine- dependent individuals will be randomized to DCS or placebo administration before three one-hour cocaine cue exposure sessions over a seven-day period. Cue exposure sessions will be held on days one, four and seven. One group will receive DCS (50 mg) before each session;one group will receive DCS (50 mg) before sessions on days one and seven and placebo before the day four session;one group will receive placebo before all three sessions. Multiple assessments of craving and physiologic reactivity will be obtained during and after each session. Primary outcome measures will be subjective and physiologic response to cocaine cues. A follow-up cue exposure session will be conducted one week after the third exposure session to assess durability of effect. Cocaine craving, self-report of cocaine use and a UDS will be collected. In summary, this pilot, proof of concept study will explore the application to addictions of an innovative treatment approach which has shown promise in the treatment of anxiety disorders. Exposure-based treatments in the addictions field are supported by animal models and have broad theoretical support, but the translation into clinical practice has been disappointing. Successful pharmacologic facilitation of extinction of response to drug-related cues may reinvigorate research on exposure-based treatment for addictions. If DCS proves successful in this preliminary study, further trials exploring the parameters of the DCS effect will be planned. Future studies could explore the impact of DCS on the generalizability or persistence of extinction training which could greatly enhance the clinical applicability of exposure-based treatments. New treatments are needed for cocaine dependence. Cocaine-related environmental cues are likely to be involved in relapse. In this study, an innovative pharmacologic approach to decreasing the response to cocaine cues will be tested.
