Effects of GABA(A) receptor partial agonists in primary cultures of cerebellar granule neurons and cerebral cortical neurons reflect different receptor subunit compositions

1 Based on an unexpected high maximum response to piperidine-4-sulphonic ac id (P4S) at human alpha1 alpha6 beta2 gamma2 GABA(A) receptors expressed in Xenopus oocytes attempts to correlate this finding with the pharmacologica l profile of P4S and other GABA(A) receptor ligands in neuronal cultures fr om rat cerebellar granule cells and rat cerebral cortex were carried out. 2 GABA and isoguvacine acted as full and piperidine-4-sulphonic acid (P4S) as partial agonists, respectively, at alpha1 beta2 gamma2, alpha6 beta2 gam ma2 and alpha1 alpha6 beta2 gamma2 GABA receptors expressed in Xenopus oocy tes with differences in potency. 3 Whole-cell patch-clamp recordings were used to investigate the pharmacolo gical profile of the partial GABA(A) receptor agonists 4,5,6,7-tetrahydrois oxazolo-(5,4-c)pyridin (THIP), P4S, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), and 3-(3-piperidyl)isoxazol-5-ol (iso-4-PIOL), and the competitive GABA(A) receptor antagonists Bicuculline Methbromide (BMB) and 2-(3-carboxypropyl)- 3-amino-6-methoxyphenyl-pyridazinium bromide (SR95531) on cerebral cortical and cerebellar granule neurons. In agreement with findings in oocytes, GAB A, isoguvacine and P4S showed similar pharmacological profiles in cultured cortical and cerebellar neurones, which are known to express mainly alpha1, alpha2, alpha3, and alpha5 containing receptors and alpha1, alpha6 and alp ha1 alpha6 containing receptors, respectively. 4 4-PIOL and iso-4-PIOL, which at GABA(A) receptors expressed in oocytes we re weak antagonists, showed cell type dependent potency as inhibitors of GA BA mediated responses. Thus, 4-PIOL was slightly more potent at cortical ne urones than at granule neurones and iso-4-PIOL was more potent in inhibitin g isoguvacine-evoked currents at cortical than at granule neurons. Furtherm ore the maximum response to 4-PIOL corresponded to that of a partial agonis t, whereas that of iso-4-PIOL gave a maximum response close to zero. 5 It is concluded that the pharmacological profile of partial agonists is h ighly dependent on the receptor composition, and that small structural chan ges of a ligand can alter the selectivity towards different subunit composi tions. Moreover, this study shows that pharmacological actions determined i n oocytes are generally in agreement with data obtained from cultured neuro ns.