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The Journal of Neuroscience, October 20, 2004, 24(42):9303-9312; doi:10.1523/JNEUROSCI.1737-04.2004

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Behavioral/Systems/Cognitive
Spontaneous Withdrawal from the Triazolobenzodiazepine Alprazolam Increases Cortical Corticotropin-Releasing Factor mRNA Expression

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

Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322

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-CRF₁ and urocortin I-CRF_2A 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.

Key words: anxiety; anxiolytic; benzodiazepines; cortex; corticotropin-releasing factor; stress

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Received May 6, 2004; revised September 5, 2004; accepted September 9, 2004.

This article has been cited by other articles:

				R. Pastor, C. S. McKinnon, A. C. Scibelli, S. Burkhart-Kasch, C. Reed, A. E. Ryabinin, S. C. Coste, M. P. Stenzel-Poore, and T. J. Phillips From the Cover: Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: A urocortin1-independent mechanism PNAS, July 1, 2008; 105(26): 9070 - 9075. [Abstract] [Full Text] [PDF]

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