Gonzalez LA, Gatch MB, Taylor CM, Bell-Horner CL, Forster MJ, Dillon GH
Carisoprodol-mediated modulation of GABAA receptors: in vitro and in vivo studies. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2009 Feb 24.
Carisoprodol is a frequently prescribed muscle relaxant. In recent years, this drug has been increasingly abused. The effects of carisoprodol have been attributed to its metabolite, meprobamate--a controlled substance that produces sedation via GABAA receptors (GABAAR). Given the structural similarities between carisoprodol and meprobamate, we used electrophysiological and behavioral approaches to investigate whether carisoprodol directly affects GABAAR function. In whole-cell patch clamp studies, carisoprodol allosterically modulated and directly activated human alpha1beta2gamma2 GABAAR function in a barbiturate-like manner. At millimolar concentrations, inhibitory effects were apparent. Similar allosteric effects were not observed for homomeric rho1 GABA or glycine alpha1 receptors. In the absence of GABA, carisoprodol produced picrotoxin-sensitive, inward currents that were significantly larger than those produced by meprobamate, suggesting carisoprodol may directly produce GABAergic effects in vivo. When administered to mice via intraperitoneal or oral routes, carisoprodol elicited locomotor depression within 8 to 12 minutes following injection. Intraperitoneal administration of meprobamate depressed locomotor activity in the same time frame. In drug discrimination studies with carisoprodol-trained rats, the GABAergic ligands pentobarbital, chlordiazepoxide, and meprobamate each substituted for carisoprodol in a dose-dependent manner. In accordance with findings in vitro, the discriminative stimulus effects of carisoprodol were antagonized by a barbiturate antagonist, bemegride, but not by the benzodiazepine site antagonist flumazenil. Collectively, the results of our studies in vivo and in vitro suggest the barbiturate-like effects of carisoprodol may not be due solely to its metabolite, meprobamate. Furthermore, the functional traits we have identified likely contribute to the abuse potential of carisoprodol.
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