effects of vigabatrin on cocaine self-administration

Conditions: Cocaine Dependence

Summary: the objective of this study is to determine if vigabatrin will decrease cocaine self-administration, cardiovascular effects, subjective effects and craving compared to placebo.

two recent open label clinical trials have reported that the anticonvulsant, gamma vinyl-gaba (gvg; vigabatrin), decreases relapse to cocaine use (brodie et al., 2003, 2005). vigabatrin increases neural gaba levels by irreversibly inhibiting the primary gaba degradation enzyme, gaba-transaminase; the hypothesized mechanism by which vigabatrin decreases cocaine relapse is by increasing gaba levels, thereby decreasing the effects of cocaine and cocaine-associated environmental cues on extracellular dopamine concentrations in the mesolimbic dopaminergic pathway (morgan and dewey, 1998). we are proposing to use our model of repeated dose cocaine self-administration to assess the interaction between vigabatrin and smoked cocaine under controlled laboratory conditions. this 57-day outpatient/inpatient /outpatient/inpatient protocol will evaluate the effects of vigabatrin maintenance (0, 3 g/day) on cocaine craving, subjective effects, and self-administration using a within-subjects design. non-treatment seeking cocaine-dependent volunteers will be maintained outpatient for 14 days of vigabatrin maintenance prior to beginning each inpatient study phase. during the inpatient phases, volunteers will live on a hospital clinical research unit and will participate in laboratory sessions in which they will have the opportunity to purchase doses of smoked cocaine (0, 12, 25, 50 mg; $5/administration). in addition to measuring cocaine self-administration, we will measure the cardiovascular and subjective effects of repeated cocaine administration and cocaine craving under each vigabatrin maintenance condition. determining vigabatrin's effects on a range of smoked cocaine doses will provide essential data on the mechanism of the vigabatrin-cocaine interaction.

Eligibility criteria:
inclusion criteria: * meets dsm-iv criteria for current cocaine abuse * average use of smoked cocaine is at least 2x/week for past 6 mos; currently spends at least $70 per week on cocaine * has patterns of smoked cocaine use in terms of frequency and amounts which parallel or exceed those administered in the study * age 21-45 * able to give informed consent, and comply with study procedures * agrees to practice an effective form of contraception exclusion criteria: * current seizure disorder or heart disease * currently meeting dsm-iv criteria for all major psychiatric/psychotic disorders. volunteers with a history of depression or psychosis will also be excluded (p. 43, investigator's brochure) * dependence on substances other than cocaine or nicotine * request for drug treatment * judged to be noncompliant with study protocol * clinical laboratory tests outside normal limits that are unacceptable to the study physician (e.g., bp \> 140/90; bun, creatinine, lfts \> 1.5 uln; hematocrit \< 34 for women, \< 36 for men; pseudocholinesterase deficiency) * current parole or probation * recent history of significant violent or suicidal behavior * pregnancy or lactation * baseline visual field defects

Keywords: vigabatrin gaba levels smoked cocaine