Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations

Yong Li, Xiu Ti Hu, Timothy G. Berney, A. John Vartanian, Christy D. Stine, Marina E. Wolf, Francis J. White

Research output: Contribution to journalArticle

148 Scopus citations

Abstract

Behavioral sensitization to psychomotor stimulants is accompanied by number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates.

Original languageEnglish (US)
Pages (from-to)169-180
Number of pages12
JournalSynapse
Volume34
Issue number3
DOIs
StatePublished - Nov 10 1999

Keywords

  • Dopamine
  • Dopamine D1 receptors
  • Dopamine D2 receptors
  • Excitatory amino acids
  • Nucleus accumbens
  • Ventral tegmental area

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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