Research reportCocaine depresses GABAA current of hippocampal neurons
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.
References (27)
- et al.
Cocaine and lidocaine in combination are synergistic convulsants
Brain Res.
(1996) - et al.
Acute cocaine toxicity: antagonism by agents interacting with adrenoceptors
Pharmacol. Biochem. Behav.
(1990) - et al.
Anticonvulsant modification of cocaine-induced toxicity in the rat
Neuropharmacology
(1990) - et al.
Flumazenil induces seizures and death in mixed cocaine-diazepam intoxication
Ann. Emerg. Med.
(1994) - et al.
Local anesthetics reduce the inhibitory neurotransmitter-induced current in dissociated hippocampal neurons of the rat
Eur. J. Pharmacol.
(1995) - et al.
The dopaminergic, glutamatergic, GABAergic bases for the action of amphetamine and cocaine
Brain Res.
(1995) - et al.
Catecholamines and convulsions
Brain Res.
(1979) - et al.
Cocaine
Pediatr. Clin. North Am.
(1987) - et al.
Acute cocaine toxicity: the effect of agents in non-seizure-induced death
Pharmacol. Biochem. Behav.
(1993) - et al.
Calcium currents in pyramidal neurons acutely dissociated from the rat frontal cortex: a study by nystatin perforated patch technique
Brain Res.
(1993)
2,3-Butanedione monoxime modifies the glycine-gated chloride current of acutely isolated murine hypothalamic neurons
Brain Res.
Molecular mechanisms of local anesthesia: a review
Anesthesiology
Cocaine inhibits GABA release in the VTA through endogenous 5-HT
J. Neurosci.
Cited by (41)
Cannabinoids Rescue Cocaine-Induced Seizures by Restoring Brain Glycine Receptor Dysfunction
2020, Cell ReportsCitation Excerpt :Thus, the present study may provide insights into the clinical treatment design for CISs or other types of seizures aiming at specific brain regions, such as PFC- and hippocampus-related transcranial magnetic stimulation and deep-brain stimulation. With the exception of the GlyR, GABAAR and 5-HT3AR are also potential ligand-gated ion channels targeted by cocaine (Sadek et al., 2017; Esplin and Woodbury, 1961; Carta et al., 2003; Ye et al., 1997). Although cocaine attenuates the function of both channels, such attenuation is not affected by cannabinoids, suggesting that GlyR is specifically involved in the rescue effects of cannabinoids on CISs.
Protective effects of minocycline, doxycycline and tetracycline on seizure and lethality in a mice cocaine toxicity model
2019, American Journal of Emergency MedicineCitation Excerpt :Glutamate has an effect on the development of seizure by facilitating neuronal excitability [21]. It is known that cocaine plays a role in the development of seizure by reversibly binding to postsynaptic GABAA receptors and acting as an inhibitor [22]. Pharmacologically, in cocaine uptake, increased endogenous GABA levels were shown.
Cocaine Enhances Gamma-Aminobutyric Acid Release From Reticular Thalamic Nucleus: Role of T-Type Calcium Channels.
2017, The Neuroscience of Cocaine: Mechanisms and TreatmentAdditive inhibition of human α<inf>1</inf>β<inf>2</inf>γ<inf>2</inf> GABA<inf>A</inf> receptors by mixtures of commonly used drugs of abuse
2013, NeuroToxicologyCitation Excerpt :To investigate drug-induced effects on GABAA-Rs at low receptor occupancy, GABA-responsive oocytes were superfused with saline containing 10 μM GABA (∼EC20) and 1–1000 μM of the test compound (see Figs. 1 and 2 for example recordings). Although with different potencies, all tested drugs inhibited the GABA-evoked current (see Figs. 2 and 3), as observed previously (Hondebrink et al., 2011a; Ye et al., 1997). For all tested drugs, the inhibition of the GABA-evoked current was concentration-dependent (one-way ANOVA, see Fig. 3), with the strongest effect observed at the highest concentration tested (1 mM).
Modulation of human GABA<inf>A</inf> receptor function: A novel mode of action of drugs of abuse
2011, NeuroToxicologyCitation Excerpt :Improvement of these symptoms following benzodiazepine treatment indicates that a decreased GABA-ergic input contributes to symptoms often seen in these patients. However, up to now only cocaine was reported to act as a GABAA-R antagonist, inhibiting the GABA-evoked ion current up to ∼80% (Ye et al., 1997). Though research on drug of abuse-induced effects on GABAA-R function is scarce, available literature indicates that the human GABAA-R could be an important target for some drugs of abuse.