Vol. 58, Issue 6, 1271-1278, December 2000

Regulation of Central Synaptic Transmission by 5-HT_1B Auto- and Heteroreceptors

Hitoshi Morikawa, Olivier J. Manzoni, John C. Crabbe, and John T. Williams

Vollum Institute, Oregon Health Sciences University, Portland, Oregon (H.M., J.T.W.); Centre National de la Recherche Scientifique, Montpellier, France (O.J.M.); and Portland Alcohol Research Center, Veterans Affairs Medical Center, Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon (J.C.C.)

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 -aminobutyric acid_B IPSPs in dopamine neurons was present in wild-type animals and absent in knockout animals. Similar results were obtained in the nucleus accumbens measuring glutamate-mediated excitatory postsynaptic currents in medium spiny neurons. Finally, cocaine, which blocks 5-HT uptake, inhibited IPSPs in the dorsal raphe and the ventral midbrain of wild-type but not knockout mice, whereas cocaine produced comparable inhibition of excitatory postsynaptic currents in the nucleus accumbens of both types of animals. These results indicate that 5-HT_1B receptors function as autoreceptors and heteroreceptors to exert presynaptic inhibition of transmitter release in the central nervous system. Furthermore, this study underscores the role played by presynaptic 5-HT_1B receptors in mediating the effects of cocaine on synaptic transmission.