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Corticotropin-releasing factor (CRF) and alpha 2 adrenergic receptors mediate heroin withdrawal-potentiated startle in rats

Academic Article
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Overview

authors

  • Park, P. E.
  • Vendruscolo, L. F.
  • Schlosburg, J. E.
  • Edwards, S.
  • Schulteis, G.
  • Koob, George

publication date

  • September 2013

journal

  • International Journal of Neuropsychopharmacology  Journal

abstract

  • Anxiety is one of the early symptoms of opioid withdrawal and contributes to continued drug use and relapse. The acoustic startle response (ASR) is a component of anxiety that has been shown to increase during opioid withdrawal in both humans and animals. We investigated the role of corticotropin-releasing factor (CRF) and norepinephrine (NE), two key mediators of the brain stress system, on acute heroin withdrawal-potentiated ASR. Rats injected with heroin (2 mg/kg s.c.) displayed an increased ASR when tested 4 h after heroin treatment. A similar increase in ASR was found in rats 10-20 h into withdrawal from extended access (12 h) to i.v. heroin self-administration, a model that captures several aspects of heroin addiction in humans. Both the α 2 adrenergic receptor agonist clonidine (10 μg/kg s.c.) and CRF1 receptor antagonist N,N-bis(2-methoxyethyl)-3-(4-methoxy-2-methylphenyl)-2,5-dimethyl-pyrazolo[1,5-a] pyrimidin-7-amine (MPZP; 20 mg/kg s.c.) blocked heroin withdrawal-potentiated startle. To investigate the relationship between CRF1 and α 2 adrenergic receptors in the potentiation of the ASR, we tested the effect of MPZP on yohimbine (1.25 mg/kg s.c.)-potentiated startle and clonidine on CRF (2 μg i.c.v.)-potentiated startle. Clonidine blocked CRF-potentiated startle, whereas MPZP partially attenuated but did not reverse yohimbine-potentiated startle, suggesting that CRF may drive NE release to potentiate startle. These results suggest that CRF1 and α 2 receptors play an important role in the heightened anxiety-like behaviour observed during acute withdrawal from heroin, possibly via CRF inducing the release of NE in stress-related brain regions.

subject areas

  • Acoustic Stimulation
  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-2 Receptor Antagonists
  • Analysis of Variance
  • Animals
  • Clonidine
  • Conditioning, Operant
  • Corticotropin-Releasing Hormone
  • Disease Models, Animal
  • Heroin
  • Male
  • Narcotics
  • Norepinephrine
  • Psychoacoustics
  • Pyrimidines
  • Rats
  • Rats, Wistar
  • Receptors, Adrenergic, alpha-2
  • Reflex, Startle
  • Self Administration
  • Substance Withdrawal Syndrome
  • Time Factors
  • Yohimbine
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Research

keywords

  • Acoustic startle response
  • acute heroin withdrawal
  • brain stress system
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Identity

PubMed Central ID

  • PMC3880138

International Standard Serial Number (ISSN)

  • 1461-1457

Digital Object Identifier (DOI)

  • 10.1017/s1461145713000308

PubMed ID

  • 23590881
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Additional Document Info

start page

  • 1867

end page

  • 1875

volume

  • 16

issue

  • 8

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