Effects of GABAA receptor partial agonists in primary cultures of cerebellar granule neurons and cerebral cortical neurons reflect different receptor subunit compositions

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Abstract
Based on an unexpected high maximum response to piperidine‐4‐sulphonic acid (P4S) at human α1α6β2γ2 GABAA receptors expressed in Xenopus oocytes attempts to correlate this finding with the pharmacological profile of P4S and other GABAA receptor ligands in neuronal cultures from rat cerebellar granule cells and rat cerebral cortex were carried out. GABA and isoguvacine acted as full and piperidine‐4‐sulphonic acid (P4S) as partial agonists, respectively, at α1β2γ2, α6β2γ2 and α1α6β2γ2 GABA receptors expressed in Xenopus oocytes with differences in potency. Whole‐cell patch‐clamp recordings were used to investigate the pharmacological profile of the partial GABAA receptor agonists 4,5,6,7‐tetrahydroisoxazolo‐(5,4‐c)pyridin‐3‐ol (THIP), P4S, 5‐(4‐piperidyl)isoxazol‐3‐ol (4‐PIOL), and 3‐(4‐piperidyl)isoxazol‐5‐ol (iso‐4‐PIOL), and the competitive GABAA 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, GABA, isoguvacine and P4S showed similar pharmacological profiles in cultured cortical and cerebellar neurones, which are known to express mainly α1, α2, α3, and α5 containing receptors and α1, α6 and α1α6 containing receptors, respectively. 4‐PIOL and iso‐4‐PIOL, which at GABAA receptors expressed in oocytes were weak antagonists, showed cell type dependent potency as inhibitors of GABA mediated responses. Thus, 4‐PIOL was slightly more potent at cortical neurones than at granule neurones and iso‐4‐PIOL was more potent in inhibiting isoguvacine‐evoked currents at cortical than at granule neurons. Furthermore the maximum response to 4‐PIOL corresponded to that of a partial agonist, whereas that of iso‐4‐PIOL gave a maximum response close to zero. It is concluded that the pharmacological profile of partial agonists is highly dependent on the receptor composition, and that small structural changes of a ligand can alter the selectivity towards different subunit compositions. Moreover, this study shows that pharmacological actions determined in oocytes are generally in agreement with data obtained from cultured neurons. British Journal of Pharmacology (2001) 133, 539–549; doi:10.1038/sj.bjp.0704121