Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression

Kelly H. Skelton, Charles Nemeroff, Michael J. Owens

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Corticotropin-releasing factor (CRF) is the major physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and plays a key role in coordinating the mammalian stress response. Substantial data implicates hyperactivity of CRF neuronal systems in the pathophysiology of depression and anxiety disorders. Enhanced CRF expression, release, and function have also been demonstrated during acute withdrawal from several drugs of abuse. Previous studies revealed that chronic administration of the anxiolytic alprazolam reduced indices of CRF and CRF1 receptor function. Conversely, measures of urocortin I and CRF2 receptor function were increased. To further scrutinize these findings, we sought to determine whether CRF neuronal systems are activated during spontaneous withdrawal from the triazolobenzodiazepine alprazolam in dependent rats and to characterize the time course, extent, and regional specificity of the patterns of activation. After 14 d of alprazolam administration (90 mg·kg-1·d -1), spontaneous withdrawal produced activation of the HPA axis, as well as suppression of food intake and weight loss that peaked 24-48 hr after withdrawal. Remarkably, CRF mRNA expression in the cerebral cortex was markedly (>300%) increased over the same time period. Other indices of CRF-CRF 1 and urocortin I-CRF2A function, altered by chronic alprazolam treatment as previously described, returned to pretreatment levels over 96 hr. The physiologic significance of this dramatic induction of cortical CRF mRNA expression, as well as whether this occurs during withdrawal from other drugs of abuse is yet to be determined. The marked increase in CRFergic neurotransmission is hypothesized to play a major role in benzodiazepine withdrawal.

Original languageEnglish
Pages (from-to)9303-9312
Number of pages10
JournalJournal of Neuroscience
Volume24
Issue number42
DOIs
StatePublished - Oct 20 2004
Externally publishedYes

Fingerprint

Alprazolam
Corticotropin-Releasing Hormone
Messenger RNA
Urocortins
Street Drugs
Corticotropin-Releasing Hormone Receptors
Anti-Anxiety Agents
Anxiety Disorders
Benzodiazepines
Synaptic Transmission
Cerebral Cortex
Weight Loss
Eating
Depression

Keywords

  • Anxiety
  • Anxiolytic
  • Benzodiazepines
  • Cortex
  • Corticotropin-releasing factor
  • Stress

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Spontaneous withdrawal from the triazolobenzodiazepine alprazolam increases cortical corticotropin-releasing factor mRNA expression. / Skelton, Kelly H.; Nemeroff, Charles; Owens, Michael J.

In: Journal of Neuroscience, Vol. 24, No. 42, 20.10.2004, p. 9303-9312.

Research output: Contribution to journalArticle

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