Evaluation of the reinforcing and discriminative stimulus effects of γ-hydroxybutyrate in rhesus monkeys

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Abstract

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS and fulfils at least some of the criteria for a neurotransmitter. Its effects are generally similar to those of CNS depressants and include ataxia, sleep and anesthesia. It has also been suggested that GHB is a drug of abuse. The present experiment was designed to evaluate GHB in procedures predictive of abuse and dependence potential in rhesus monkeys. Three monkeys were surgically prepared with indwelling silicone venous catheters and allowed to self-administer methohexital or saline in twice-daily experimental sessions. Other groups of monkeys were trained in drug discrimination paradigms to discriminate d-amphetamine (AMPH; n=4), pentobarbital (PB; n=3) or triazolam (n=3) from saline. Another group was maintained on diazepam daily and trained to discriminate flumazenil from saline (n=2). GHB (0.01–10 mg/kg per injection) maintained self-administration marginally above saline levels at one dose (3.2 or 10 mg/kg) in two of the three monkeys tested. GHB (1.0–178 mg/kg, subcutaneously (s.c.) or intragastrically (i.g.)) did not reliably substitute as a discriminative stimulus for any of the training conditions. Taken together with previous results, the present experiment suggests that GHB has, at most, low potential for abuse.

Introduction

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS (Cash et al., 1979, Vayer et al., 1988) and fulfils at least some of the criteria for a neurotransmitter (Cash, 1994). In contrast to most neurotransmitters, however, it crosses the blood brain barrier and has behavioral effects after peripheral administration. Its effects are generally of the CNS depressant type and include ataxia, sleep and anesthesia (Laborit, 1973, Cash, 1994).

GHB was originally proposed to be useful as an anesthetic (Laborit, 1964, Laborit, 1973). More recently, it has been reputed to have anabolic effects via stimulation of growth hormone and has been used by body builders attempting to enhance performance (Dyer, 1991). Based upon case reports, it has also been suggested that GHB is a drug of abuse (Food and Drug Administration, 1991, Frederick et al., 1995). It has also been noted that consumption of GHB can impair performance of complex tasks, such as driving (Stephens and Baselt, 1994). Results from preclinical studies have been equivocal with regard to the abuse potential of GHB. For example, Beardsley et al. (1996)reported that GHB failed to maintain intravenous self-administration in monkeys experienced in the self-administration of phencyclidine. Cross-generalization with ethanol as a discriminative stimulus has been reported over a narrow dose range (Colombo et al., 1995b) and GHB has recently been reported to induce a conditioned place preference in rats (Martellotta et al., 1997). It should also be noted that there is both preclinical and clinical evidence indicating that GHB may be useful in the treatment of alcohol dependence (Fadda et al., 1989, Gallimberti et al., 1992).

The present experiments were conducted at the request of the National Institute on Drug Abuse to the Drug Evaluation Committee of the College on Problems of Drug Dependence to evaluate GHB further in procedures predictive of abuse and dependence potential in rhesus monkeys. In particular, the present study examined GHB in monkeys that were experienced in the self-administration or discrimination of a barbiturate, or were physically dependent upon a benzodiazepine. It was expected that the apparent abuse potential of GHB that was reported in prior studies would be evident in the procedures employed since these procedures are sensitive to the reinforcing, discriminative stimulus, and dependence-producing effects of a wide variety of drugs. Further, these procedures have high predictive validity for abuse and dependence potential in humans.

Section snippets

Subjects

Subjects were rhesus monkeys (Macaca mulatta: n=3), weighing between 8.0 and 12 kg, and with a history of self-administration of sodium methohexital and saline. Water was continuously available and the monkeys were given 10–15 Purina monkey chow biscuits twice daily to maintain their adult body weights. Monkeys were surgically prepared with indwelling silicone venous catheters using 10 mg/kg i.m. ketamine and 2.0 mg/kg i.m. xylazine as anesthetics. Catheters were implanted in jugular (internal

Reinforcing effects

The number of injections of GHB was approximately the same as the number of injections of saline and was considerably less than the number of injections taken of methohexital (Table 1). Self-administration of GHB was more than two standard deviations above the mean for saline injections in two cases: 10 mg/kg per injection in monkey 3577, and 3.2 mg/kg per injection in monkey 3575. At the highest dose of GHB tested (10 mg/kg per injection) monkey 3577 took a total of 250 mg/kg in the morning

Discussion

At doses up to 10 mg/kg per injection, GHB either did not function as a positive reinforcer, or maintained responding only slightly above saline levels in rhesus monkeys that were maintained on a baseline of methohexital self-administration. Since only one dose maintained responding in two monkeys, and rate of responding was low, it seems likely that GHB was, at most, only a weak positive reinforcer. Beardsley et al. (1996)reported a lack of reinforcing effects with GHB tested up to 3.0 mg/kg

Acknowledgements

This research was supported by NIDA grants DA-09139 (W.L. Woolverton), DA-09163 (G. Winger) and DA-09157 (C.P. France), and the College on Problems of Drug Dependence. W.L. Woolverton and C.P. France are recipients of NIDA Independent Scientist Awards (W.L. Woolverton, DA-00161; C.P. France, DA-00211). Studies were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Universities at which they were conducted and the Guide for the Care and Use of

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