Pharmacological modulation of GABAB receptors affects cocaine-induced seizures in mice

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Abstract
Rationale Previous data have demonstrated that the convulsant effects of cocaine can be modulated by compounds that increase levels of endogenous γ-aminobutyric acid (GABA) or that directly stimulate GABAA receptors. Objectives To determine whether the convulsant effects of cocaine can be modulated by ligands selective for GABAB receptors in mice. Methods Effects of the GABAB receptor agonist ((±)-baclofen), antagonist (phaclofen), and their combination were tested against clonic seizures induced by cocaine (75 mg/kg). Enantiomers of baclofen were used to confirm stereospecificity of (±)-baclofen’s effects. Pharmacological specificity of (±)-baclofen’s effects was tested by comparison against seizures induced by GBR 12909 (monoamine transporter inhibitor), pentylenetetrazole (GABAA antagonist), N-methyl-d-aspartate (NMDA agonist), and aminophylline (A1/A2 adenosine antagonist). Additionally, effects of (±)-baclofen on kindled seizures induced by repeated administration of cocaine (60 mg/kg every 24 h for 6 days) were evaluated. The inverted screen test was used to assess behavioral side effects of baclofen. Results (±)-Baclofen dose-dependently inhibited acute (ED50=4.1 mg/kg) and kindled (6.4 mg/kg) seizures induced by cocaine at doses somewhat lower than those producing behavioral side effects (11.5 mg/kg), and these effects were stereospecific. (±)-Baclofen suppressed seizures induced by GBR 12909 but not by pentylenetetrazole, NMDA, and aminophylline, suggesting selectivity of its anticonvulsant effects for monoamine-related mechanisms. Finally, phaclofen dose-dependently enhanced the convulsant effects of a threshold dose of cocaine (60 mg/kg). Conclusions Modulation of GABAB receptors can affect seizures induced by cocaine. This molecular mechanism may be involved in seizures induced by cocaine or, alternatively, may function as an independent inhibitory mechanism against seizures arising from blockade of monoamine uptake.