A single in vivo cocaine administration impairs 5-HT(1B) receptor-induced long-term depression in the nucleus accumbens

J Neurochem. 2013 Jun;125(6):809-21. doi: 10.1111/jnc.12227. Epub 2013 Mar 19.

Abstract

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward-based decision-making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5-hydroxytryptamine (5-HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5-HT or 5-HT1B receptor agonist CP 93129 induced a long-term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5-HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5-HT or CP 93129. The inhibition was blocked when a selective dopamine D1 receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129-induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP-dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5-HT1B receptor-mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5-HT1B receptors and thereby impairs the induction of LTD by 5-HT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / pharmacology*
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Glutamic Acid / metabolism
  • In Vitro Techniques
  • Long-Term Synaptic Depression / drug effects*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Neurons / drug effects
  • Neurons / physiology
  • Nucleus Accumbens / drug effects*
  • Nucleus Accumbens / physiology
  • Receptor, Serotonin, 5-HT1B / physiology*
  • Receptors, Dopamine D1 / agonists
  • Receptors, Presynaptic / physiology*
  • Serotonin / pharmacology
  • Serotonin Receptor Agonists / pharmacology
  • Signal Transduction
  • Synaptic Transmission

Substances

  • Receptor, Serotonin, 5-HT1B
  • Receptors, Dopamine D1
  • Receptors, Presynaptic
  • Serotonin Receptor Agonists
  • Serotonin
  • Glutamic Acid
  • Cyclic AMP-Dependent Protein Kinases
  • Cocaine