Effects of GABAB receptor agonists on cocaine hyperlocomotor and sensitizing effects in rats

doi:10.1016/S1734-1140(09)70166-5

Pharmacological Reports

Volume 61, Issue 6, November–December 2009, Pages 1042-1049

https://doi.org/10.1016/S1734-1140(09)70166-5 Get rights and content

Abstract

The present study was designed to find out whether pharmacological activation of GABA_B receptors played a role in cocaine sensitization. To this end, male Wistar rats were injected with baclofen or 3-aminopropyl(methyl)phosphinic acid (SKF 97541), the potent and selective GABA_B receptor agonists. The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. Baclofen (1.25, 2.5 and 5 mg/kg), administered for 5 days prior to cocaine, dose-dependently attenuated cocaine sensitization. When injected in the same treatment regimen, SKF 97541 (0.03 mg/kg) reduced the development of cocaine sensitization. To examine the effects of baclofen and SKF 97541 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. Either baclofen (2.5 and 5 mg/kg) or SKF 97541 (0.1 mg/kg) decreased sensitization to cocaine. Our findings implicate a role of GABA_B receptors in locomotor responses to cocaine. More specifically, they show that stimulation of GABA_B receptors exerted inhibitory actions on acute locomotor responses to cocaine and on the expression of cocaine sensitization, what may offer a therapeutic potential of GABA_B receptor agonists in the treatment of cocaine dependence.

Introduction

In humans, repeated abuse of cocaine and other psychostimulants lead to addiction and psychosis. In rodents, repeated exposure to such drugs induces among others enhancement of stimulating effects on locomotor activity (i.e., behavioral sensitization), the model thought to reflect neuroadaptations that contribute to addiction [27, 30]. A number of data indicate that the major role in cocaine locomotor responses including development of behavioral sensitization plays the mesocorticolimbic dopamine system [12, 20, 28] consisting of the dopamine cell bodies and terminals located in the ventral tegmental area and inter alia in the nucleus accumbens, respectively. Locomotor hyperactivity in rats may mimic cocaine-induced hyperexcitability in humans, while cocaine sensitization is believed to reflect the cocaine-induced paranoia in human cocaine addicts and to be one of the main cause of drug relapse [30, 37, 38]. Thus, finding drugs that modulate the development and/or expression of sensitization to cocaine might be theoretically and clinically important.

However, dopaminergic system is only one component of the neuronal circulatory that mediates cocaine behavioral sensitization, recent finding indicate that a significant effects of other neurotransmitter systems, e.g., excitatory amino acids or γ-aminobutyric acid (GABA) [40, 42], in this phenomenon. Regarding the latest neurotransmitter, it is the major inhibitory transmitter in the mammalian central nervous system where acts on two receptor classes: ionotropic (GABA_A and GABA_C) and metabotropic GABA_B receptors. GABA_B receptors have been found in every brain region including the mesocorticolimbic circulation [4, 5, 29] where play a primary role in decreasing dopamine release [8, 9, 29, 36]. In fact, preclinical findings show that the GABA_B receptor stimulation in the ventral tegmental area decreases extracellular do-pamine in the terminal areas [43, 44] and antagonizes cocaine-induced dopamine release in the nucleus accumbens [15]. Furthermore, in rodents the GABA_B receptor agonist baclofen blocks cocaine-induced hyperlocomotion [27] and the drug developed conditioned hyperlocomotion [25]. Importantly, pharmacological stimulation of GABA_B receptors attenuates cocaine-reinforced responding in a self-administration procedures [10, 11, 19, 39] as well as both cocaine-induced and cocaine-associated cueinduced reinstatement of seeking behavior [11, 13, 16]. Recent findings indicate several modulations (increases or decreases) in GABA_B receptor binding in limbic regions during reinstatement of cocaine seeking behavior in rats [21].

The present study was undertaken to investigate whether GABA_B receptor stimulation may also control expression of locomotor and sensitizing effects by cocaine in male Wistar rats. In pharmacological analyses we used baclofen [6, 17, 22] and 3-aminopropyl (methyl)phosphinic acid (SKF 97541) [17, 22], the potent (K_i = 4.57 nM and IC₅₀ = 16 nM, respectively) and selective GABA_B receptor agonists, and administered them either acutely in the cocaine-induced locomotor hyperactivation and before the cocaine challenge dose that induces cocaine sensitization (expression of locomotor sensitization) or concurrently with chronic cocaine treatment (development of locomotor sensitization).

Section snippets

Animals

The experiment was performed on male Wistar rats (derived from licensed breeder, Warszawa, Poland) weighing 280–300 g. The animals were kept at a room temperature of 20 ± 1°C and at 50% humidity under a 12-h light/dark cycle (the lights on at 6.00 a.m.), 8 per cage in standard plastic rodent cages (57 × 35 × 20 cm). The animals had free access to food (Labo-feed pellets) and water during the 7-day habituation period. All experiments were conducted during the light phase of the light-dark cycle (between

Basal locomotor activity

Following injection of baclofen in a dose of 5 mg/kg (but not in doses of 1.25 or 2.5 mg/kg), a significant decrease in basal locomotor activity was observed, while SKF 97541 (0.01, 0.03 and 0.1 mg/kg) did not alter the basal locomotor activity in rats (Tab 1).

Cocaine-induced hyperactivity

Cocaine (10 mg/kg) significantly (at least two-fold) enhanced the locomotor activity of rats as compared to the effect of saline-treated animals (Fig. 1).

A significant group effect was detected by ANOVA for pretreatment with baclofen (F(4,30) =

Discussion

The findings of the present study indicate that mechanisms dependent on pharmacological stimulation of GABA_B receptors seem to engaged in the locomotor behaviors induced by acute and repeated treatment with cocaine. In fact, the selective GABA_B receptor agonists baclofen [6, 17, 22] and SKF 97541 [17, 22] attenuated the acute locomotor responses to cocaine and counteracted the development and expression of cocaine sensitization.

Our present results that GABA_B receptor agonists attenuated both

Acknowledgment

The study was supported by the statutory funds of Institute of Pharmacology Polish Academy of Sciences (Kraków, Poland).

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Effects of GABAB receptor agonists on cocaine hyperlocomotor and sensitizing effects in rats

Abstract

Introduction

Section snippets

Animals

Basal locomotor activity

Cocaine-induced hyperactivity

Discussion

Acknowledgment

Trends Pharmacol Sci

Neuroscience

Pharmacol Biochem Behav

Drug Alcohol Depend

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Neuroscience

Neuroscience

Curr Opin Neurobiol

Brain Res Rev

Brain Res Bull

Pharmacol Res

Baclofen blocks the development of sensitization to the locomotor stimulant effect of amphetamine

Behav Pharmacol

The GABAB agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine

Behav Pharmacol

A GABABagonist reverses the behavioral sensitization to morphine in rats

Psychopharmacology

Molecular structure and physiological functions of GABAB receptors

Physiol Rev

Spatial distribution of GABABR1 receptor mRNA and binding sites in the rat brain

J Comp Neurol

A potential role for GABABagonists in the treatment of psychostimulant addiction

Alcohol Alcohol

The GABABantagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat

Psy-chopharmacology

Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats

Psychopharmacology

The GABABreceptor agonist baclofen attenuates cocaine- and heroin-seeking behavior by rats

Neuropsychopharmacology

GABAB receptor-mediated modulation of the firing pattern of ventral tegmental area dopamine neurons in vivo

Naunyn-Schmiedeberg’s Arch Pharmacol

Effects of GABA_B receptor agonists on cocaine hyperlocomotor and sensitizing effects in rats

The GABA_B agonist baclofen blocks the expression of sensitisation to the locomotor stimulant effect of amphetamine

A GABA_Bagonist reverses the behavioral sensitization to morphine in rats

Molecular structure and physiological functions of GABA_B receptors

Spatial distribution of GABA_BR1 receptor mRNA and binding sites in the rat brain

A potential role for GABA_Bagonists in the treatment of psychostimulant addiction

The GABA_Bantagonist CGP56433A attenuates the effect of baclofen on cocaine but not heroin self-administration in the rat

The GABA_Breceptor agonist baclofen attenuates cocaine- and heroin-seeking behavior by rats

GABA_B receptor-mediated modulation of the firing pattern of ventral tegmental area dopamine neurons in vivo