The actions of 2-hydroxy-saclofen at presynaptic GABAB receptors in the rat hippocampus (original) (raw)

The actions of 2-hydroxy-saclofen (2-OH-S), a recently developed analog of baclofen, were studied at presynaptic GABAB receptors in the rat hippocampal slice. Baclofen (0.5-20 pM) reduces the amplitude of excitatory postsynaptic potentials (EPSPs) recorded from hippocampal CA 1 pyramidal neurons. In the presence of 200-500 pM 2-OH-S, the synaptic depressant action of baclofen is significantly reduced. These data show that 2-OH-S is an effective antagonist at presynaptic GABAB receptors on excitatory terminals in the hippocampus. There are two main classes of receptor for 7-aminobutyric acid (GABA) in the mammalian central nervous system (CNS) [3, 4, 16]. GABAA receptors are oligomeric receptor proteins that form an integral C1-ion channel [25, 27]; less is currently known about GABAB receptors, which are selectively activated by baclofen (pchlorophenyl-GABA). Baclofen has both pre-and postsynaptic actions in the nervous system. Activation of postsynaptic GABAa receptors on central neurons elicits an increase in membrane K ÷ conductance [13, 24] that results in a hyperpolarizing response to baclofen and GABA [17, 21, 29], These receptors have been shown to mediate the 'late' inhibitory postsynaptic potential (IPSP) in hippocampus and other brain regions [11, 15, 18, 23, 28]. Baclofen exerts a depressant action on synaptic transmission in the spinal cord [8], hippocampus [26], neocortex [17] and dorsal raphe [6], that is believed to result primarily from the activation of presynaptic GABAB receptors. GABAa receptors mediate a decrease in voltage-dependent Ca: ÷ currents [10], that may explain the presynaptic effect of the drug. It was recently proposed that there are pharmacological differences between pre-and postsynaptic GABAB receptors in the CNS [6, 12, 14, 27]. The phosphonic acid analog of baclofen, phaclofen