Evidence for a non-GABAergic action of quaternary salts of bicuculline on dopaminergic neurones

Intracellular recordings were made from neurones, presumed to be dopaminergic, in the rat midbrain slice preparation. Bicuculline methiodide (BMI) and methochloride (BMC) reversibly blocked the slow, apamin-sensitive component of the afterhyperpolarization in these cells. The IC50 for this effect was about 26 mu M. In comparison, BMC antagonized the input resistance decrease evoked by muscimol (3 mu M) with an IC50 of 7 mu M. The base of bicuculline was less potent in blocking the slow afterhyperpolarization. SR95531 (2-[carboxy-3'-propyl]-3-amino-6-paramethoxy-phenyl-pyridazinium bromide), another competitive GABA(A) antagonist, and picrotoxin, a non-competitive GABA(A) antagonist, also blocked the action of muscimol (IC(50)s: 2 and 12 mu M respectively), but had no effect on the afterhyperpolarization at a concentration of up to 100 mu M. Moreover, 100 mu M SR95531 did not affect the blockade of the afterhyperpolarization by BMC. This blockade persisted in the presence of tetrodotoxin and was apparently not due to a reduction of calcium entry, suggesting that it involved a direct action on the channels which mediate this afterhyperpolarization. These results strongly suggest that quaternary salts of bicuculline act on more than one target in the central nervous system. Thus, the involvement of GABA(A) receptors in a given effect cannot be proven solely on the basis of its blockade by these agents.