Gamma-Hydroxybutyric Acid Decreases Intravenous Cocaine Self-Administration in Rats

doi:10.1016/S0091-3057(97)00444-9

Pharmacology Biochemistry and Behavior

Volume 59, Issue 3, March 1998, Pages 697-702

https://doi.org/10.1016/S0091-3057(97)00444-9 Get rights and content

Abstract

Gamma-hydroxybutyric acid (GHB) is an endogenous compound present in mammalian brain suggested as a putative neurotransmitter, which has been shown to affect several aspects of dependence from various classes of drugs of abuse. In the present study, two sets of experiments were performed to investigate the effects of acute pretreatment with GHB on intravenous cocaine self-administration in rats. In the first experiment GHB was administered intragastrically at the doses of 175, 350, and 700 mg/kg to Long–Evans rats trained to self-administer cocaine using nose-poke as operandum. In the second experiment, GHB was administered intraperitoneally at the doses of 100, 200, and 400 mg/kg to Wistar rats trained to self-administer cocaine intravenously using lever-pressing as operandum. In both experiments acute pretreatment with GHB significantly and dose dependently reduced cocaine self-administration. The effectiveness of GHB was similar in both experiments, indicating that the effect of GHB on cocaine self-administration is independent of animal strain, route of administration, and type of operant response required. These results indicate that GHB reduces cocaine-seeking behavior in rats, modulating the acute reinforcing effect of cocaine. The clinical effectiveness of GHB in dependence from various classes of abused drugs warrants further studies to evaluate the possibility that GHB might represent a useful therapeutic agent for cocaine addiction in humans.

Section snippets

Animals

Male Long–Evans rats (Harlan–Nossan), weighing 300–350 g at the start of the experiments, were individually housed with ad lib access to food and water, and maintained on a 12-h reversed light–dark cycle (dark on 0900 to 2100 h). Temperature (22 ± 1°C) and humidity (60%) were constant.

Drugs

Cocaine hydrochloride (Sigma) was dissolved in sterile saline solution in a volume of 0.5 ml/kg/inj. Doses were adjusted by injection volume before each self-administration session, according to the animal’s body

Experiment 1

The effect of acute administration of GHB in rats responding for cocaine self-administration in a continuous reinforcement schedule is shown in Fig. 1. GHB produced a dose-dependent decrease in responding for cocaine or a dose-dependent increase in the interinjection interval, F(3, 20) = 120.3 p < 0.01. Individual mean comparisons with saline revealed that the effect of GHB reached statistical significance at the doses of 350 and 700 mg/kg (Newman–Keuls test), while the lowest dose was

Discussion

The aim of the present study was to investigate whether acute pretreatment with GHB affected IV cocaine self-administration in rats. The present results show that pretreatment with GHB dose-dependently decrased cocaine self-administration in two strains of rats trained under two different operant conditions (nose poking and lever pressing) after both intragastric and intraperitoneal administration.

In the first experiment, GHB pretreatment significantly reduced the intake of cocaine in rats

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Cited by (15)

Anti-aggressive effects of GHB in OF.1 strain mice: Involvement of dopamine D<inf>2</inf> receptors
2007, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Numerous studies indicate that gamma-hydroxybutyric acid (GHB) influences the endogenous dopamine system. Both GHB and most dopaminergic D₂ receptor antagonists are effective anti-aggressive agents in animal models. The present study aimed to investigate the effects of GHB on agonistic behaviour and to implicate D₂ dopamine receptor on these behaviours. For this purpose, the effects of GHB (80, 120 and 160 mg/kg, IP) and tiapride (60 mg/kg) administered alone or in combination were examined on agonistic behaviour elicited by ‘isolation’ in male mice. Individually housed mice were exposed to anosmic “standard opponents” 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. The administration of 80 and 120 mg/kg of GHB reduced threat without impairing motor activity, but the administration of 160 mg/kg of GHB or the co-administration of GHB + tiapride (a selective D₂ receptor antagonist) significantly reduced threat and attack but concomitantly increased immobility. The co-administration of GHB + tiapride had different effects to those observed by the administration of these drugs separately. It is concluded that the anti-aggressive effect of GHB appears to be mediated, at least in part, by D₂ dopamine receptors. This anti-dopaminergic activity is an indirect effect, probably induced by the activation of GHB receptors of low affinity, and in this way, this compound would reduce levels of dopamine without blockading of D₂ postsynaptic dopamine receptors.
Effects of GABAergic modulators on food and cocaine self-administration in baboons
2005, Drug and Alcohol Dependence
Drugs that indirectly alter dopaminergic systems may alter the reinforcing effects of cocaine. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has extensive neural connections in mesolimbic regions that appear to modulate dopamine. The current study evaluated the effects of GABA_B receptor agonists baclofen and CGP44532, the benzodiazepine agonist alprazolam, and the GABA reuptake inhibitor tiagabine on lever responding maintained by low dose cocaine injections (0.032 mg/kg) or by food pellet (1 g) delivery in baboons. The benzodiazepine antagonist flumazenil was tested as a negative control. Cocaine or food was available under a fixed ratio (FR 10) schedule of reinforcement during daily 2-h sessions. During baseline conditions, cocaine and pellets maintained similar numbers of reinforcers per session. Baclofen, CGP44532 and tiagabine dose-dependently reduced the number of cocaine injections, where as the benzodiazepine antagonist flumazenil did not. Baclofen, CGP44532 and tiagabine also produced dose-related decreases in food-maintained behavior. In contrast, the benzodiazepine agonist alprazolam, which positively modulates GABA_A receptors via the benzodiazepine site, produced decreases in cocaine self-injection, but not food-maintained behavior. Thus, the effects of alprazolam were specific for cocaine-maintained behavior, where as the effects of baclofen and CGP44532 were not.
GHB: A new and novel drug of abuse
2001, Drug and Alcohol Dependence
There has been increasing attention in the United States to problems of abuse of gamma-hydroxybutyrate (GHB), with some evidence for problems in other parts of the world as well. In vitro and animal research show that, while GHB shares some properties with abused central nervous system depressant drugs, it has unique aspects of its pharmacology as well, including actions at a specific neural receptor which probably mediates many of its effects. Abuse potential assessment of GHB using standard animal models has not yielded a picture of a highly abusable substance, but little human testing has yet been done. Very little systematic data exist on tolerance and dependence with GHB, but both have been seen in human users. Quantitative data on the prevalence of GHB abuse is incomplete, but various qualitative measures indicate that a mini-epidemic of abuse began in the late 1980s and continues to the present. GHB is often included with the group of ‘club drugs’, and can be used as an intoxicant. It also has been used as a growth promoter and sleep aid and has been implicated in cases of ‘date rape’, usually in combination with alcohol. Undoubtedly the easy availability of GHB and some of its precursors has contributed to its popularity. Recent changes in the control status of GHB in the US may reduce its availability with as yet unknown consequences for the scope of the public health problem. Drug abuse experts need to familiarize themselves with GHB as possibly representing a new type of drug abuse problem with some unique properties.
Gamma-hydroxybutyrate and cocaine administration increases mRNA expression of dopamine D<inf>1</inf> and D<inf>2</inf> receptors in rat brain
1999, Neuropsychopharmacology
The effects of acute and repeated gamma-hydroxybutyrate (GHB) and cocaine administration on D₁ and D₂ dopamine receptor mRNA expression were examined using in situ hybridization histochemistry in different rat brain structures rich in GHB receptors. Six hours after a single GHB administration (500 mg/kg IP), an increase in D₁ and D₂ mRNA expression was observed in almost all regions examined; whereas, acute cocaine injection (20 mg/kg IP) had no effect. Repeated exposure to GHB (500 mg/kg IP twice daily) for 10 days, followed by a 14-h withdrawal period, induced increasing effects on D₁ and D₂ dopamine receptor mRNA expression, similar to those caused by chronic treatment with cocaine (20 mg/kg IP once a day). These effects of GHB and cocaine on dopamine receptor mRNA expression could be a consequence, for both compounds, of the modulation of dopaminergic activity; thus, supporting the benefit of GHB in cocaine substitution therapy.
Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration
2008, Journal of Neuroscience
Multi-faceted aspects of gamma-hydroxybutyric acid: A neurotransmitter, therapeutic agent and drug of abuse
2008, Mini-Reviews in Medicinal Chemistry

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ArticlesGamma-Hydroxybutyric Acid Decreases Intravenous Cocaine Self-Administration in Rats

Abstract

Section snippets

Animals

Drugs

Experiment 1

Discussion

Life Sci.

Prog. Neurobiol.

Life Sci.

Neuroscience

Biochem. Pharmacol.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

Prog. Neurobiol.

Biochem. Pharmacol.

Pharmacol. Biochem. Behav.

Biochem. Pharmacol.

FEBS Lett.

Brain. Res.

Neuropharmacology

Neurochem. Int.

Life Sci.

Eur. J. Pharmacol.

Evaluation of the discriminative stimulus and reinforcing effects of gamma-hydroxybutyrate (GHB)

Psychopharmacology (Berlin)

Suppression of voluntary alcohol intake in rats and alcoholics by gamma-hydroxybutyric acidA nonGABAergic mechanism

The treatment of narcolepsy-catalepsy with nocturnal gamma-hydroxybutyrate

Can. J. Neurol. Sci.

Purification from human brain and some properties of two NADPH-linked aldehyde reductases which reduce succinic semialdehyde to 4-hydroxybutyric acid

J. Neurochem.

Symmetrical generalization between the discriminative stimulus effects of gamma-hydroxybutyric acid and ethanolOccurence within narrow dose ranges

Physiol. Behav.

Articles
Gamma-Hydroxybutyric Acid Decreases Intravenous Cocaine Self-Administration in Rats