Potency Of Muscimol Research Articles

Role of the GABAa and GABAb receptors of the central nucleus of the amygdala in compulsive cocaine-seeking behavior in male rats.

Compulsive cocaine use, defined as the continued use despite the dire consequences, is a hallmark of cocaine addiction. Thus, understanding the brain mechanism regulating the compulsive cocaine-seeking and cocaine-taking behaviors is essential to understand cocaine addiction and the key to identification of the molecular targets for the development of medications against this condition. This study aimed to determine how the GABAa and GABAb receptors of the central nucleus of the amygdala (CeA) regulate the compulsive cocaine-seeking behavior. Male Wistar outbred rats were trained to self-administer intravenous cocaine (0.4mg/kg/infusion) under a chained schedule. The compulsive cocaine-seeking behavior was measured as the cocaine-seeking behavior in the face of footshock punishment. The role of the GABA receptors of CeA in the regulation of such behavior was determined by measuring the dose-dependent effects of the GABAa agonist muscimol or the GABAb agonist baclofen bilaterally microinjected into the CeA on the punished cocaine-seeking behavior. The cocaine-seeking behavior was inhibited by footshock punishment in an intensity-dependent manner. Both muscimol and baclofen dose-dependently increased the punished cocaine-seeking behavior. However, the potency of muscimol but not baclofen was negatively correlated with the effects of punishment. These data indicate that the CeA GABAa receptors play a key role in the regulation of the compulsive cocaine-seeking behavior and suggest that an increase in the function of the GABAa receptors possibly induced by cocaine or genetic factors may be an important mechanism involved in the development of or vulnerability to the compulsive cocaine use and addiction.

Decreased agonist sensitivity of human GABAA receptors by an amino acid variant, isoleucine to valine, in the α1 subunit

Recombinant human GABAA receptors were investigated in vitro by coexpression of cDNAs coding for α1, β2, and γ2 subunits in the baculovirus/Sf-9 insect cell system. We report that a single amino acid exchange (isoleucine 121 to valine 121) in the N-terminal, extracellular part of the α1 subunit induces a marked decrease in agonist GABAA receptor ligand sensitivity. The potency of muscimol and GABA to inhibit the binding of the GABAA receptor antagonist [3H]SR 95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide) was higher in receptor complexes of α1(ile 121)β2γ2 than in those of α1(val 121)β2γ2 (IC50 values were 32-fold and 26-fold lower for muscimol and GABA, respectively). The apparent affinity of the GABAA receptor antagonist bicuculline methiodide to inhibit the binding of [3H]SR 95531 did not differ between the two receptor complex variants. Electrophysiological measurements of GABA induced whole-cell Cl− currents showed a ten-fold decrease in the GABAA receptor sensitivity of α1(val 121)β2γ2 as compared to α1(ile 121)β2γ2 receptor complexes. Thus, a relatively small change in the primary structure of the α1 subunit leads to a decrease selective for GABAA receptor sensitivity to agonist ligands, since no changes were observed in a GABAA receptor antagonist affinity and benzodiazepine receptor binding.

Decreased agonist sensitivity of human GABA A receptors by an amino acid variant, isoleucine to valine, in the α1 subunit

Recombinant human GABA A receptors were investigated in vitro by coexpression of cDNAs coding for α 1, β 2, and γ 2 subunits in the baculovirus/Sf-9 insect cell system. We report that a single amino acid exchange (isoleucine 121 to valine 121) in the N-terminal, extracellular part of the α 1 subunit induces a marked decrease in agonist GABA A receptor ligand sensitivity. The potency of muscimol and GABA to inhibit the binding of the GABA A receptor antagonist [ 3H]SR 95531 (2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium bromide) was higher in receptor complexes of α 1(ile 121) β 2 γ 2 than in those of α 1(val 121) β 2 γ 2 (IC 50 values were 32-fold and 26-fold lower for muscimol and GABA, respectively). The apparent affinity of the GABA A receptor antagonist bicuculline methiodide to inhibit the binding of [ 3H]SR 95531 did not differ between the two receptor complex variants. Electrophysiological measurements of GABA induced whole-cell Cl − currents showed a ten-fold decrease in the GABA A receptor sensitivity of α 1(val 121) β 2 γ 2 as compared to α 1(ile 121) β 2 γ 2 receptor complexes. Thus, a relatively small change in the primary structure of the α 1 subunit leads to a decrease selective for GABA A receptor sensitivity to agonist ligands, since no changes were observed in a GABA A receptor antagonist affinity and benzodiazepine receptor binding.

Inhibition of drug-induced circling by GABA-ergic activity in the nucleus accumbens

Injections of GABA (125–500 μg in 1 μl) or muscimol (40–200 ng in 1 μl) into the nucleus accumbens markedly reduced the amphetamine-induced circling of rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of nigrostriatal dopamine neurons. The potency of muscimol was approximately 10 4 times that of GABA. Muscimol exerted a similar effect when injected in a smaller volume (0.5 μl) at a slower rate (0.11 μl/min), a procedure which was shown to reduce the spread of injected [ 3H]muscimol. Intra-accumbens injections of subconvulsive doses of picrotoxin had no effect on amphetamine-induced circling. Intra-accumbens muscimol (40 ng, 0.5 μl, 0.11 μl/min) also reduced the contralateral circling evoked by apomorphine in rats with unilateral 6-OHDA-induced lesions of the nigrostriatal pathway and bilateral 6-OHDA-induced lesions of the mesolimbic dopamine terminals. These results suggest that GABA-ergic activity in the nucleus accumbens exerts an inhibitory influence on drug-induced circling. At least part of this action is at a step beyond the release of dopamine from mesolimbic terminals.