Regulation of central synaptic transmission by 5-HT1B auto- and heteroreceptors

Although 5-HT1B 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-HT1B receptor knockout mouse was used in the present investigation to assess the function of 5-HT1B receptors in the mod ulation of synaptic transmission in three areas of the central nervous syst em: the dorsal raphe, the ventral midbrain, and the nucleus accumbens. N-(3 -Trifluoromethylphenyl) piperazine, a 5-HT1B receptor agonist, potently inh ibited 5-HT1A receptor-mediated slow inhibitory postsynaptic potentials (IP SPs) in the dorsal raphe of wild-type but not knockout mice. Both synaptica lly released 5-HT and exogenous 5-HT caused a presynaptic inhibition that o utlasted the postsynaptic hyperpolarization only in wild-type mice. In the ventral midbrain, 5-HT1B receptor-dependent inhibition of gamma -aminobutyr ic acid(B) IPSPs in dopamine neurons was present in wildtype animals and ab sent in knockout animals. Similar results were obtained in the nucleus accu mbens measuring glutamate-mediated excitatory postsynaptic currents in medi um spiny neurons. Finally, cocaine, which blocks 5-HT uptake, inhibited IPS Ps in the dorsal raphe and the ventral midbrain of wild-type but not knocko ut mice, whereas cocaine produced comparable inhibition of excitatory posts ynaptic currents in the nucleus accumbens of both types of animals. These r esults indicate that 5-HT1B receptors function as autoreceptors and heteror eceptors to exert presynaptic inhibition of transmitter release in the cent ral nervous system. Furthermore, this study underscores the role played by presynaptic 5-HT1B receptors in mediating the effects of cocaine on synapti c transmission.