Reinstatement of cocaine seeking by hypocretin (orexin) in the ventral tegmental area: independence from the local corticotropin-releasing factor network

Biol Psychiatry. 2009 May 15;65(10):857-62. doi: 10.1016/j.biopsych.2009.01.018. Epub 2009 Feb 28.

Abstract

Background: Hypocretin (Hcrt), an arousal- and feeding-associated peptide, is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine seeking. Each is presumed to act, at least in part, through actions local to the VTA. Here, we examined the possibility that VTA perfusion of Hcrt reinstates cocaine seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF.

Methods: Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA.

Results: Ventral tegmental area perfusion of Hcrt-1 or footshock stress reinstated cocaine seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist, but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks footshock-induced reinstatement and glutamate release.

Conclusions: While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine seeking.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cocaine / administration & dosage*
  • Cocaine / pharmacology
  • Dopamine / metabolism
  • Drug Interactions
  • Electroshock
  • Glutamic Acid / metabolism
  • Intracellular Signaling Peptides and Proteins / administration & dosage
  • Intracellular Signaling Peptides and Proteins / pharmacology*
  • Kynurenic Acid / administration & dosage
  • Kynurenic Acid / pharmacology
  • Male
  • Neuropeptides / administration & dosage
  • Neuropeptides / pharmacology*
  • Orexin Receptors
  • Orexins
  • Phenylurea Compounds / antagonists & inhibitors
  • Rats
  • Rats, Long-Evans
  • Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, Kainic Acid / antagonists & inhibitors
  • Receptors, Neuropeptide / antagonists & inhibitors
  • Self Administration
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / metabolism*

Substances

  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Phenylurea Compounds
  • Receptors, Corticotropin-Releasing Hormone
  • Receptors, G-Protein-Coupled
  • Receptors, Kainic Acid
  • Receptors, Neuropeptide
  • SB 408124
  • Glutamic Acid
  • Kynurenic Acid
  • Cocaine
  • Dopamine