EVIDENCE FOR A NON-GABAERGIC ACTION OF QUATERNARY-SALTS OF BICUCULLINE ON DOPAMINERGIC-NEURONS

Intracellular recordings were made from neurones, presumed to be dopam inergic, in the rat midbrain slice preparation. Bicuculline methiodide (BMI) and methochloride (BMC) reversibly blocked the slow, apamin-sen sitive component of the afterhyperpolarization in these cells. The IC5 0 for this effect was about 26 mu M. In comparison, BMC antagonized th e input resistance decrease evoked by muscimol (3 mu M) with an IC50 o f 7 mu M. The base of bicuculline was less potent in blocking the slow afterhyperpolarization. SR95531 -propyl]-3-amino-6-paramethoxy-phenyl -pyridazinium bromide), another competitive GABA(A) antagonist, and pi crotoxin, a non-competitive GABA(A) antagonist, also blocked the actio n 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. M oreover, 100 mu M SR95531 did not affect the blockade of the afterhype rpolarization by BMC. This blockade persisted in the presence of tetro dotoxin and was apparently not due to a reduction of calcium entry, su ggesting that it involved a direct action on the channels which mediat e this afterhyperpolarization. These results strongly suggest that qua ternary salts of bicuculline act on more than one target in the centra l nervous system. Thus, the involvement of GABA(A) receptors in a give n effect cannot be proven solely on the basis of its blockade by these agents.