Virol A, a toxic trans-polyacetylenic alcohol of Cicuta virosa, selectively inhibits the GABA-induced Cl − current in acutely dissociated rat hippocampal CA1 neurons

Abstract

The effects of virol A (VA), a toxic component of Cicuta virosa (water hemlock), on the GABA-induced Cl − current ( I GABA) in acutely dissociated rat hippocampal CA1 neurons were investigated using whole-cell patch-clamp techniques. VA reversibly reduced I GABA and the muscimol (Mus)-induced current ( I Mus) in a concentration-dependent manner. The IC 50 values for VA against I GABA and I Mus were 9.6×10 −7 and 9.8×10 −7 M, respectively. VA shifted the EC 50 value of I GABA from 6.5×10 −6 to 2.1×10 −5 M, whereas it had no effect on the maximum response, thereby suggesting that VA inhibited I GABA in a competitive manner. VA had no apparent effect on current–voltage relationships for I GABA, thus indicating the lack of voltage-dependency. On the other hand, application of VA (10 −6 M) did not additionally reduce the I GABA suppressed by >10 −5 M picrotoxin. VA but not bicuculline accelerated the decay phase of I GABA, as was seen with picrotoxin. Moreover, pre-application of 10 −5 M VA reduced I GABA. VA did not inhibit that induced by glycine (10 −4 M). These results indicate that VA inhibits I GABA by acting both on the GABA agonist site and on the Cl − channel of the GABA A receptor–channel complex. VA is a structurally novel type of compound that selectively inhibits the GABA A receptor–Cl − channel complexes in mammalian central nervous system neurons.