Gabapentin maintenance decreases smoked cocaine-related subjective effects, but not self-administration by humans
Introduction
Knowledge that brain λ-aminobutyric acid (GABA) is involved in the regulation of dopaminergic neurons has spurred a tremendous amount of research in the area of cocaine treatment medication development. Interest in this area has increased, in part, because midbrain dopaminergic neurons have been proposed to be integrally involved in the modulation of cocaine-related behaviors, including self-administration (for review, see Koob, 1992). Because dopamine-containing neurons are under tonic GABAergic inhibition, it has been suggested that pharmacological enhancement of GABA’s actions on central nervous system (CNS) dopamine would reduce cocaine reinforcement. A burgeoning database provides support for this hypothesis. For example, several researchers have reported that GABA agonists markedly decrease cocaine self-administration by laboratory animals (e.g., Campbell et al., 1999, Kushner et al., 1999).
In a series of studies, Roberts and his colleagues have shown that baclofen, a selective GABAB agonist, dose-dependently decreased cocaine self-administration by rats under progressive-ratio schedules of reinforcement, and that this effect was independent of any generalized motoric impairing effect (Roberts et al., 1996, Roberts and Andrews, 1997; Brebner et al., 2000a, Brebner et al., 2000b). Nonselective GABA agonists have also been shown to alter cocaine-related effects in laboratory animals. The irreversible inhibitor of GABA transaminase vigabatrin, for instance, inhibited cocaine-stimulated increases in striatal dopamine in baboon and rats (Dewey et al., 1998, Schiffer et al., 2003), reduced the expression of cocaine conditioned place preference in rats (Dewey et al., 1998), attenuated cocaine-associated lowering of brain stimulation reward thresholds in rats (Kushner et al., 1997), and decreased cocaine self-administration by rats (Kushner et al., 1999, Stromberg et al., 2001).
In contrast to the large database obtained with laboratory animals, published data from research evaluating the effects of GABA agonists on cocaine-related behaviors in humans are scarce. The majority of data obtained using human research volunteers have been collected under non-blind conditions. In one such trial, Ling et al. (1998) reported that baclofen maintenance (60 mg/d) decreased self-reported cocaine craving and use, as well as the number of cocaine positive urines. Although the effects of vigabatrin have not been assessed in human cocaine-associated behaviors, the effects of another nonselective GABA agonist, gabapentin, have been investigated. Gabapentin has been shown to increase the rate of CNS GABA synthesis and to enhance GABA release in laboratory animals (Loscher et al., 1991, Gotz et al., 1993); it has also been demonstrated to elevate brain GABA concentrations in humans (Petroff et al., 2000). Gabapentin is approved as adjunctive therapy for the treatment of partial and secondary generalized tonic-clonic seizures in adults and has a favorable side effect profile. Two anecdotal case reports describe cocaine-dependent patients who substantially reduced their cocaine use and experienced markedly less cocaine craving after the initiation of treatment with gabapentin (Markowitz et al., 1997, Raby, 2000). Furthermore, in a recent open-label trial using gabapentin (1200 mg/d) in cocaine-dependent patients, Myrick et al. (2001) reported that both the frequency of cocaine craving and urines positive for cocaine significantly decreased from baseline.
Although the above suggests that human cocaine self-administration would be decreased by maintenance on a GABAergic medication, there are no published data from controlled laboratory studies assessing pharmacological enhancement of CNS GABA on cocaine-related effects in humans. The purpose of this study was to examine the effects of oral gabapentin maintenance (0, 600, and 1200 mg/d) on human cocaine self-administration and cocaine-associated cardiovascular and subjective effects using a choice procedure. During this 48-day inpatient/outpatient study, non-treatment seeking cocaine abusers were maintained on gabapentin and four doses of smoked cocaine (0, 12, 25, and 50 mg) were each tested twice under each gabapentin condition. We hypothesized that cocaine self-administration, cardiovascular, and subjective effects would be decreased as a function of gabapentin maintenance condition.
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Participants
Seven Black research participants (six males and one female), 32–43 (mean = 37.5) years of age, were solicited through word-of-mouth referral and newspaper advertisements in New York, NY. All participants were current crack cocaine smokers and none expressed a desire for treatment for cocaine dependence at the time of study participation. Participants reported spending $153.57±32.93 (mean±S.D.) per week on cocaine (the current cost of street cocaine in the New York City area is $25–40 per
Results
Active or placebo cocaine was chosen 420 times, with 53 doses not given because of elevated cardiovascular measures. Of those doses withheld, 15 were withheld under the placebo gabapentin maintenance condition, 15 were withheld under the 600 mg gabapentin maintenance condition, and 23 were withheld under the 1200 mg gabapentin maintenance condition. Doses were more likely to be withheld when the higher cocaine doses were available: 2 withheld when 12 mg was available, 24 withheld when 25 mg was
Discussion
Data from the present investigation show that some cocaine-related subjective-effect ratings were significantly attenuated when participants were maintained on gabapentin (600 and 1200 mg). These decreases were greater during the second exposure to each cocaine dose compared to the first exposure. Gabapentin did not, however, decrease cocaine self-administration or cocaine-associated cardiovascular effects. In fact, choice to self-administer the 12 mg cocaine dose was increased when participants
Acknowledgements
Professor Marian W. Fischman, who died before the completion of this manuscript, provided invaluable guidance on the design of this study. She is missed immensely. The nursing assistance of Claudia Tindall and Laura Burr, and technical assistance of Paul Toth is gratefully acknowledged. This research was supported by Grant DA-06234 from the National Institute on Drug Abuse. Research participants resided on the Irving Center for Clinical Research of the Columbia Presbyterian Medical Center
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