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.