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Although 5-HT_1B receptors are believed to be expressed on nerve terminals, their precise mode of action is not fully understood because of the lack of selective antagonists. The 5-HT_1B receptor knockout mouse was used in the present investigation to assess the function of 5-HT_1B receptors in the modulation of synaptic transmission in three areas of the central nervous system: the dorsal raphe, the ventral midbrain, and the nucleus accumbens. N-(3-Trifluoromethylphenyl)piperazine, a 5-HT_1B receptor agonist, potently inhibited 5-HT_1A receptor-mediated slow inhibitory postsynaptic potentials (IPSPs) in the dorsal raphe of wild-type but not knockout mice. Both synaptically released 5-HT and exogenous 5-HT caused a presynaptic inhibition that outlasted the postsynaptic hyperpolarization only in wild-type mice. In the ventral midbrain, 5-HT_1B receptor-dependent inhibition of γ-aminobutyric acid_B IPSPs in …