Antagonistic action of pitrazepin on human and rat GABAA receptors

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Abstract
Pitrazepin, 3‐(piperazinyl‐1)‐9H‐dibenz(c,f) triazolo(4,5‐a)azepin is a piperazine antagonist of GABA in a variety of electrophysiological and in vitro binding studies involving GABA and glycine receptors. In the present study we have investigated the effects of pitrazepin, and the GABAA antagonist bicuculline, on membrane currents elicited by GABA in Xenopus oocytes injected with rat cerebral cortex mRNA or cDNAs encoding α1β2 or α1β2γ2S human GABAA receptor subunits. The three types of GABAA receptors expressed were reversibly antagonized by bicuculline and pitrazepin in a concentration‐dependent manner. GABA dose‐current response curves for the three types of receptors were shifted to the right, in a parallel manner, by increasing concentrations of pitrazepin. Schild analyses gave pA2 values of 6.42±0.62, n=4, 6.41±1.2, n=5 and 6.21±1.24, n=6, in oocytes expressing rat cerebral cortex, α1β2 or α1β2γ2S human GABAA receptors respectively (values are given as means±s.e.mean), and the Hill coefficients were all close to unity. All this is consistent with the notion that pitrazepin acts as a competitive antagonist of these GABAA receptors; and that their antagonism by pitrazepin is not strongly dependent on the subunit composition of the receptors here studied. Since pitrazepin has been reported to act also at the benzodiazepine binding site, we studied the effect of the benzodiazepine antagonist Ro 15–1788 (flumazenil) on the inhibition of α1β2γ2S receptors by pitrazepin. Co‐application of Ro 15–1788 did not alter the inhibiting effect of pitrazepin. Moreover, pitrazepin did not antagonize the potentiation of GABA‐currents by flunitrazepam. All this suggests that pitrazepin does not affect the GABA receptor‐chloride channel by interacting with the benzodiazepine receptor site. British Journal of Pharmacology (1999) 127, 57–64; doi:10.1038/sj.bjp.0702504