Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans

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Abstract

Drugs affecting central γ-aminobutyric acid (GABA) systems may have promise as treatments for cocaine addiction. In the present study, tiagabine (Gabatril®), a GABA reuptake inhibitor, was investigated for its ability to modify the discriminative-stimulus, reinforcing, subject-rated, performance and cardiovascular effects of oral cocaine in non-treatment seeking cocaine users. Initially, acute doses of 4 mg tiagabine were tested alone and in combination with oral cocaine in four participants to establish the safety of cocaine–tiagabine combinations. A higher dose of tiagabine (8 mg) was then tested in a larger group (n = 6). Participants learned to discriminate 150 mg of oral cocaine. The effects of cocaine (0–150 mg, p.o.) administered alone and in combination with tiagabine were then determined. Subject-rated, performance and cardiovascular measures were obtained at regular intervals. The reinforcing effects of cocaine, tiagabine and cocaine–tiagabine combinations were assessed using the Multiple-Choice Procedure. Cocaine alone produced prototypical behavioral and physiological effects (i.e., functioned as a discriminative and reinforcing stimulus, produced stimulant-like subject-rated effects, improved performance and increased heart rate). In general, acute administration of tiagabine did not alter the effects of oral cocaine. These findings suggest that tiagabine would not be effective at preventing continued cocaine use by blocking its acute, abuse-related effects.

Introduction

Cocaine binds to dopamine (DA), serotonin and norepinephrine transporters (DAT, 5-HTT and NET), preventing the reuptake of these monoamines from the synapse. Preclinical research has implicated DAT as the primary mediator of the behavioral effects of cocaine (Wise, 1998). Because of the predominant role of DA, one strategy in the development of a pharmacotherapy for cocaine addiction has been to investigate drugs that modulate DA systems. Neuroanatomical and neurochemical studies suggest that central DA systems are under the inhibitory control of γ-aminobutyric acid (GABA) (Churchill et al., 1992, Gerasimov et al., 2000, Kalivas et al., 1990, Morgan and Dewey, 1998).

Preclinical laboratory research has shown that GABAergic drugs attenuate the behavioral effects of cocaine under a variety of behavioral arrangements. For example, increasing extracellular GABA levels with γ-vinyl-GABA reduced cocaine self-administration in rats when responding was maintained under fixed-ratio and progressive-ratio schedules (Kushner et al., 1999). Similarly, the discriminative-stimulus effects of cocaine were attenuated in monkeys by GABA modulators selective for the benzodiazepine and barbiturate sites of the GABAA receptor (Negus et al., 2000). The results from these studies suggest that drugs acting at central GABA systems may be viable targets for the development of a treatment for cocaine addiction.

Clinical studies that have investigated the efficacy of GABAergic compounds in cocaine users seeking treatment have yielded some encouraging results (e.g., Brodie et al., 2003, Gonzalez et al., 2003, Ling et al., 1998; Myrick et al., 2001a, Myrick et al., 2001b). A recently published study evaluated the clinical efficacy of tiagabine, a GABA transporter inhibitor, to reduce cocaine use in methadone-stabilized cocaine users (Gonzalez et al., 2003). Ten-week treatment with tiagabine (maintained at 24 mg/day, divided b.i.d.) modestly decreased the percentage of weekly cocaine-positive urines during weeks 9 and 10 compared to placebo.

One possible mechanism by which tiagabine might produce a clinically significant effect is through blockade of the acute effects of cocaine. If the abuse-related effects of cocaine, such as the discriminative-stimulus, reinforcing, subject-rated and/or performance effects, can be attenuated by tiagabine, then behaviors maintained by cocaine may extinguish over time. A shift rightward or downward in the cocaine dose–effect curves for these measures would be indicative of this, and would suggest that tiagabine may have therapeutic value. This possibility was examined in the present experiment.

Initially, the safety of acute administration of tiagabine alone and tiagabine–cocaine combinations was evaluated in non-treatment seeking cocaine users under controlled laboratory conditions (Experiment 1). Following an interim analysis, it was determined that 4 mg of tiagabine and various doses of oral cocaine (0, 25, 50, 100 and 150 mg) could be safely administered concurrently, but it appeared that tiagabine did not attenuate the behavioral effects of cocaine. Next, a higher dose of tiagabine (8 mg) was tested on the discriminative-stimulus, reinforcing, subject-rated, performance and cardiovascular effects of oral cocaine in a larger group of participants (Experiment 2).

Section snippets

Participants

Eleven adult participants with recent histories of cocaine use (i.e., cocaine positive urine at the time of initial screening) were recruited via newspaper ads, flyers and word-of-mouth to participate in this study. One participant requested to leave for reasons unrelated to the study procedures and was discharged after less than a week of participation. Data from that individual were not included in the analyses. Four participants (one female and three males) completed Experiment 1 and six

Drug-discrimination performance

The four participants in the 4 mg tiagabine group met the discrimination criterion in an average of 5.8 sessions (range 4–9). The six participants in the 8 mg tiagabine group met the discrimination criterion in an average of 6.8 sessions (range 4–11). There was a significant effect of cocaine, but not tiagabine, on the percent cocaine-appropriate responding in the 4 mg [F4,12 = 6.50, P < 0.01] and 8 mg groups [F4,20 = 13.44, P < 0.01]. Cocaine increased drug-appropriate responding as a function of

Discussion

GABAergic drugs have been shown to modulate central DA systems, and may therefore be useful for the treatment of cocaine abuse and dependence. The GABA reuptake inhibitor tiagabine, which elevates extracellular GABA in the brain (Fink-Jensen et al., 1992), was administered to human participants in combination with oral cocaine to determine if tiagabine could attenuate the behavioral effects of cocaine. Initially, a 4 mg dose of tiagabine was administered to cocaine users, alone and in

Acknowledgements

We would like to thank Frances Wagner, R.N., Brad Coooper, Shelly Gray, Jamie Haga, Matt Weaver and Allison Weber for excellent medical and technical assistance. This research was supported by National Institute on Drug Abuse, grant DA 13567 awarded to Craig R. Rush; National Institute on Mental Health Training, grant MH 015730 awarded to Joshua A. Lile (trainee); and National Center for Research Resources, grant M01 RR02602 awarded to the General Clinical Research Center.

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