D-Cycloserine Facilitation of Cocaine - Cue Extinction

Cocaine dependence remains a serious problem in the United States today and in spite of two decades of intense research, efficacious pharmacotherapeutic treatments have not been identified. Cocaine-associated environmental cues can elicit drug craving and exposure to cocaine-related cues is likely to be involved in relapse. 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 (Botreau et al., 2006). Exploration of DCS in facilitating extinction of response to drug-related cues in humans is needed. 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. In addition, to examine the neural substrates of extinction learning, a sub-set of individuals that are willing and eligible will undergo fMRI scanning procedures before and after the extinction protocol.

Inclusion criteria

• Subjects must be able to provide informed consent and function at an intellectual level sufficient to allow accurate completion of all assessment instruments.
• Subjects must meet DSM-IV criteria for current cocaine dependence. Subjects may meet criteria for abuse, but not dependence on any other substance with the exceptions of nicotine and alcohol. Because of the high comorbidity of cocaine with alcohol and nicotine dependence, excluding nicotine and alcohol dependence would seriously compromise the feasibility of recruitment. Nicotine use immediately prior to the cue exposure/extinction session will be controlled. Although individuals who meet criteria for alcohol dependence will be accepted for study participation, anyone who has a measurable blood alcohol level on the day of the sessions will be excluded as acute alcohol intake can increase serum levels of DCS and lower the seizure threshold.
• Use of one of the following methods of birth control by female subjects: birth control pills, barrier methods (diaphragm or condoms with spermicide or both), surgical sterilization, use of an intra-uterine contraceptive device, or complete abstinence from sexual intercourse.
• Subjects must live within a 50-mile radius of the research facility and have reliable transportation.
• Subjects must consent to remain abstinent from all drugs of abuse (except nicotine) prior to the first session and through the final session.
• Subjects must consent to random assignment to the DCS vs. placebo conditions.
• For fMRI participants, subjects must be right-handed.

Exclusion criteria

• Women who are pregnant, nursing or of childbearing potential and not practicing an effective means of birth control.
• Subjects with evidence of or a history of significant hematological, endocrine, cardiovascular, pulmonary, renal, gastrointestinal, or neurological disease including insulin-dependent diabetes, as these conditions may affect heart rate or skin conductance measurement.
• Subjects with a history of or current psychotic disorder, current major depressive disorder, bipolar affective disorder or a severe anxiety disorder as these may impact cue reactivity.
• Subjects who are unwilling or unable to maintain abstinence from alcohol and other drugs of abuse (except nicotine) prior to and between the cue procedures.
• Subjects meeting DSM-IV criteria for substance dependence (other than nicotine, alcohol or cocaine as appropriate) within the past 60 days.
• Subjects currently taking B-blockers, anti-arrhythmic agents, psychostimulants or any other agents known to interfere with heart rate and skin conductance monitoring.
• Known or suspected hypersensitivity to DCS.
• Individuals taking medications that could adversely interact with study medications, including, but not limited to ethionamide, isoniazid, or amino acid supplements.
• Subjects with a history of epilepsy or seizure disorder.
• Subjects with significant liver impairment, as DCS may increase serum transaminases.
• For fMRI participants, the need for maintenance or acute treatment with any psychoactive medication including anti-seizure medications which could potentially interfere with fMRI.
• For fMRI participants, clinically significant psychiatric or medical problems that would impair participation or limit ability to participate in scan.