Elsevier

Brain Research

Volume 770, Issues 1–2, 3 October 1997, Pages 169-175
Brain Research

Research report
Cocaine depresses GABAA current of hippocampal neurons

https://doi.org/10.1016/S0006-8993(97)00782-8Get rights and content

Abstract

Although blockade of dopamine re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary mechanism of cocaine-induced seizures, it is possible that other neurotransmitters such as γ-aminobutyric acid (GABA) are involved. To examine this possibility, the effects of cocaine on the whole cell GABA current (IGABA) of freshly isolated rat hippocampal neurons were investigated with the patch-clamp technique. Preincubation or acute application of cocaine reversibly suppressed IGABA. The IC50 was 127 μM when cocaine was applied before the application of GABA. The concentration-response relations of cocaine in various GABA concentrations revealed that cocaine inhibited IGABA non-competitively. This effect of cocaine appeared to be independent of voltage. The present study suggests that the GABA receptor/channel complex is also a target for cocaine's action. The suppression of IGABA may contribute to cocaine-induced seizures.

Introduction

Acute cocaine toxicity is most frequently associated with seizures. The cellular mechanisms underlying cocaine-induced seizures are unclear. Although blockade of dopamine (DA) re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary cause of cocaine-induced seizure, discrepancies exist. For example, Mason and Corcoran [18]observed that cocaine continued to induce convulsions even after severe depletion of noradrenaline and DA from rat brain. Therefore, they suggested that cocaine-induced seizures do not involve re-uptake inhibition and are unrelated to the catecholamine systems. Rather, they concluded that cocaine induced seizures by a non-specific toxic mechanism. More recently, Derlet and Albertson [6]demonstrated that adrenoceptor agonists and antagonists could reduce cocaine toxicity. Thus, they suggested that α1-, α2- and β-adrenoceptors are important in the pathogenesis of cocaine toxicity. However, this toxicity is not entirely adrenoceptor mediated because of the lack of absolute antagonism by either α1- or β-antagonists alone or in combination. Furthermore, the non-adrenoceptor vasodilator hydralazine also antagonized cocaine toxicity. These results suggest that additional mechanisms contribute significantly to cocaine-induced seizure activity.

Pharmacologically, cocaine shares major properties with local anesthetics (LA) and psychomotor stimulants. Earlier experiments attributed seizures due to LA to depression of inhibitory neuronal function [23]. Depression of inhibitory restraint allows unopposed excitatory drive 3, 4, 15. Aberrations in GABAA receptors may underlie many human neurological and psychiatric disorders, such as epilepsy [14]. Because the common final pathway of several animal epilepsy models involves the GABAergic system, it is logical to propose that cocaine-induced seizures may involve the depression of GABA receptors (GABARs).

The possible relation between cocaine toxicity and GABARs is further supported by the protective effect of benzodiazepines (BZDs) and barbiturates, positive modulators of GABAA receptors. These two types of drugs are very effective in preventing and treating cocaine-induced seizures 1, 5, 7, 8, 11, 24, 25. In fact, it has been shown in an animal model of acute cocaine intoxication that agents which enhance the GABAergic system in the central nervous system (CNS) provide the greatest protection against cocaine-induced seizures [7]. However, the relation between cocaine and the postsynaptic GABARs is not well understood. The objective of this study was to determine whether cocaine has direct effects on postsynaptic GABARs.

Section snippets

Isolation of neurons and electrophysiologic recording

Hippocampal neurons were freshly isolated from Sprague–Dawley rats as described previously [27]. Briefly, 7–17-day-old rats were subjected to cervical dislocation. Their brains were quickly excised and placed into iced `standard external solution' containing (mM) NaCl 140, KCl 5, MgCl2 1, CaCl2 2, glucose 10, HEPES 10 (pH was adjusted to 7.4 with Tris base and osmolarity to 320 mmol/kg with sucrose). The brain was then glued to the chilled stage of a vibratome (Campden Instrument, UK) and

Effects of cocaine preincubation on the GABA-induced current (IGABA)

Cocaine alone, at concentrations from 1 μM to 6 mM, had no detectable effect on membrane current. This is consistent with the observations of the others [9]. However, cocaine suppressed IGABA when it was applied a short time before a mixture of cocaine and GABA. Fig. 1 presents typical IGABA recorded before (A) and after (B) the application of 50 μM cocaine with varying GABA concentrations. Cocaine suppressed current in response to subsaturating and saturating concentrations of GABA. To further

Discussion

This study demonstrates, for the first time, a direct depressant effect of cocaine on IGABA of rat hippocampal neurons. These results may explain, at least in part, the mechanism of previous observations that both GABA per se and its positive modulators, such as BZDs and barbiturates, are very effective in both prevention and treatment of cocaine toxicity 1, 5, 7, 8, 11, 24, 25. Since both preincubation and acute application of cocaine depressed IGABA, we suggest that cocaine acts on both

Acknowledgements

This work was supported by a research grant from UMD, New Jersey Medical School to J.H.Y. The authors thank Drs. K. Krnjevič, J.P. Dilger and L. Liu for their helpful comments on this work.

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