Pharmacology of the GABAergic system: effects of progabide, a GABA receptor agonist

Stimulation of GABA receptors (e.g. by progabide, a new GABA receptor antagonist, or by muscimol) enhances the liberation of norepinephrine in limbic forebrain areas of the rat and reduces 5-hydroxytryptamine turnover. On repeated administration, this latter effect is associated with an up-regulation of 5-HT2 receptors as it occurs after electroconvulsive shock. The monoaminergic changes induced by progabide, though dissimilar from those induced by tricyclics, are probably connected with the antidepressant action on the compound observed in double-blind clinical trials. In the basal ganglia, GABA receptor agonists reduce dopamine turnover and potentiate the cataleptogenic action of neuroleptics. They also antagonize the sterotypic behaviour induced by dopaminomimetics, indicating an additional action beyond the dopamine synapse. On repeated co-administration with neuroleptics, progabide antagonizes the tolerance to the cataleptogenic action, the supersensitivity to dopaminomimetics, and the increase in 3H-spiperone binding which are caused by sustained neuroleptic treatment. This appears to be the basis for the clinical action of progabide in neuroleptic-induced dyskinesia, L-dopa-induced involuntary movements, and possibly mania. GABA receptor agonists decrease cellular excitability in several animal models and antagonize seizures, whatever their origin (GABA-mediated or GABA unrelated mechanisms). Progabide has been shown to be effective in various forms of epilepsy in double-blind and long-term clinical trials. The compound exerts a therapeutic action in patients resistant to "classical" antiepileptic drugs, in the virtual absence of major side effects.