title: Robust presynaptic serotonin 5-HT(1B) receptor inhibition of the striatonigral output and its sensitization by chronic fluoxetine treatment.
abstract: The striatonigral projection is a striatal output pathway critical to motor control, cognition, and emotion regulation. Its axon terminals in the substantia nigra pars reticulata (SNr) express a high level of serotonin (5-HT) type 1B receptors (5-HT(1B)Rs), whereas the SNr also receives an intense 5-HT innervation that expresses 5-HT transporters, providing an anatomic substrate for 5-HT and selective 5-HT reuptake inhibitor (SSRI)-based antidepressant treatment to regulate the striatonigral output. In this article we show that 5-HT, by activating presynaptic 5-HT(1B)Rs on the striatonigral axon terminals, potently inhibited the striatonigral GABA output, as reflected in the reduction of the striatonigral inhibitory postsynaptic currents in SNr GABA neurons. Functionally, 5-HT(1B)R agonism reduced the striatonigral GABA output-induced pause of the spontaneous high-frequency firing in SNr GABA neurons. Equally important, chronic SSRI treatment with fluoxetine enhanced this presynaptic 5-HT(1B)R-mediated pause reduction in SNr GABA neurons. Taken together, these results indicate that activation of the 5-HT(1B)Rs on the striatonigral axon terminals can limit the motor-promoting GABA output. Furthermore, in contrast to the desensitization of 5-HT1 autoreceptors, chronic SSRI-based antidepressant treatment sensitizes this presynaptic 5-HT(1B)R-mediated effect in the SNr, a novel cellular mechanism that alters the striatonigral information transfer, potentially contributing to the behavioral effects of chronic SSRI treatment.
authors: Department of Pharmacology, University of Tennessee College of Medicine, Memphis, Tennessee.
authors: Shengyuan
authors: S
authors: Ding
authors: Department of Pharmacology, University of Tennessee College of Medicine, Memphis, Tennessee.
authors: Li
authors: L
authors: Li
authors: Department of Pharmacology, University of Tennessee College of Medicine, Memphis, Tennessee fzhou3@uthsc.edu.
authors: Fu-Ming
authors: FM
authors: Zhou
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000187:drug effects; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017729:Presynaptic Terminals / Q000187:drug effects*; D044302:Receptor, Serotonin, 5-HT1B / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005473:Fluoxetine; D044302:Receptor, Serotonin, 5-HT1B; D012701:Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: 5-HT1B receptor sensitization; basal ganglia; medium spiny neuron; selective serotonin reuptake inhibitor; substantia nigra pars reticulata