Regulation of Central Synaptic Transmission by 5-HT1BAuto- and Heteroreceptors

  1. Hitoshi Morikawa1,
  2. Olivier J. Manzoni2,
  3. John C. Crabbe3 and
  4. John T. Williams1
  1. 1Vollum Institute, Oregon Health Sciences University, Portland, Oregon (H.M., J.T.W.); 2Centre National de la Recherche Scientifique, Montpellier, France (O.J.M.); and 3Portland Alcohol Research Center, Veterans Affairs Medical Center, Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland, Oregon (J.C.C.)

    Abstract

    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 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-HT1B receptor agonist, potently inhibited 5-HT1A 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-HT1B receptor-dependent inhibition of γ-aminobutyric acidB 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-HT1B 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-HT1B receptors in mediating the effects of cocaine on synaptic transmission.

    Footnotes

    • Send reprint requests to: Dr. John T. Williams, Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201. E-mail: williamj{at}ohsu.edu

    • This work was supported by Uehara Memorial Foundation Fellowship, Institut National de la Santé et de la Recherche Médicale, and National Institutes of Health Grant DA04523. The mice were provided from the colony of Dr. Tamara Phillips, supported by National Institute of Health Grant AA11322.

    • Abbreviations:
      IPSP
      inhibitory postsynaptic potential
      GABA
      γ-aminobutyric acid
      EPSC
      excitatory postsynaptic current
      BAPTA
      1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
      NBQX
      2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]-quinoxaline
      AMPA
      α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
      NMDA
      N-methyl-d-aspartate
      DAMGO
      [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
      TFMPP
      N-(3-trifluoromethylphenyl)piperazine
      • Received July 12, 2000.
      • Accepted September 7, 2000.
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    1. Molecular Pharmacology December 1, 2000 vol. 58 no. 6 1271-1278
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