Differential interactions of GABA agonists, depressant and convulsant drugs with [35S]-t-butylbicyclophosphorothionate binding sites in cortex and cerebellum.

Effects of three GABA agonists, four GABA antagonists and convulsants (picrotoxinin, alpha-dihydropicrotoxinin [DHP], pentamethylenetetrazole [PTZ] and isopropylbicyclophosphate ester) and three depressant drugs (pentobarbital, (+)etomidate and etazolate) were investigated on [35S]t-butylbicyclophosphorothionate (TBPT) in cortex and cerebellum. All the convulsants tested were equipotent in inhibiting [35S]TBPT binding in cortex and cerebellum. Convulsants like picrotoxinin inhibited [35S]-TBPT binding competitively in both cortex and cerebellum. In contrast, gamma-aminobutyric acid (GABA) agonists (muscimol, GABA and 4,5,6,7-tetrahydroisoxazol[5,4-C]pyridine-3-ol [THIP]), and depressants like etazolate, (+)etomidate and pentobarbital were more potent inhibitors of [35S]TBPT binding in cerebellum than in cortex. GABA inhibition of [35S]TBPT binding appears to be mediated through a low-affinity site. GABA and pentobarbital inhibited [35S]TBPT binding in cortex and cerebellum noncompetitively. Depressants like pentobarbital appear to interact with the TBPT sites allosterically. These results suggest that depressant and convulsant drugs that modulate GABAergic transmission interact differently with the TBPT binding sites in cortex and cerebellum.