Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells

Baclofen has been used as an antispastic agent for over a decade, yet its mechanism of action is still not fully understood. While early iontophoretic studies revealed a depression of neuronal activity, more recent studies have emphasized a presynaptic depression of transmitter release, both in the peripheral and central nervous system, possibly resulting from a blockade of calcium channels. Although baclofen is structurally similar to the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), none of its actions seem to be antagonized by the GABA antagonist, bicuculline. However, recent experiments have indicated that baclofen binds to a class of bicuculline-resistant GABA receptors, termed GABAB receptors. Here, we have analysed the action of baclofen on the membrane potential of CA1 hippocampal pyramidal cells in vitro and report that it directly hyperpolarizes these cells in a potent, stereoselective manner which is resistant to bicuculline methiodide. This response is associated with a decrease in neuronal input resistance and may involve an increase in potassium conductance.