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The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal

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Abstract

Rationale

Corticotropin-releasing factor (CRF) is the primary physiologic regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central nervous system CRF neurotransmission, acting primarily via the CRF1 receptor, has been strongly implicated in the pathophysiology of depression and anxiety. Furthermore, there is evidence of enhanced CRF transcription, release, and neuronal activity after the administration of and withdrawal from several drugs of abuse, including cannabis, cocaine, ethanol, and morphine. Treatment with CRF antagonists has been demonstrated to reduce the severity of certain drug withdrawal symptoms, implicating a specific role for activation of CRF neurons in mediating the anxiogenic and stress-like reactions observed after abrupt drug discontinuation.

Objectives/Methods

To extend these findings, we investigated whether pretreatment with the selective CRF1 receptor antagonist R121919 decreases the behavioral and neuroendocrine activation observed after the precipitation of benzodiazepine (BZ) withdrawal in BZ-dependent rats.

Results

Pretreatment with R121919 attenuated the subsequent HPA axis activation, behavioral measures of anxiety, and expression of the CRF gene in the paraventricular nucleus of the hypothalamus, as measured by CRF heteronuclear RNA, which occurs after flumazenil-precipitation of withdrawal from the BZ, lorazepam.

Conclusions

These results indicate that the activation of CRF neuronal systems may be a common neurobiological mechanism in withdrawal from drugs of abuse and moreover, that the CRF1 receptor subtype plays a major role in mediating the effects of CRF on neuroendocrine and behavioral responses during BZ withdrawal. Therefore, CRF1 receptor antagonists may be of therapeutic utility in the treatment of drug withdrawal syndromes.

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Acknowledgments

This work was supported by the National Institutes of Health Grants MH42088, MH58922, and MH069056.

The experiments described in this manuscript comply with the current laws of the USA, in which they were performed.

In addition, the authors wish to thank Donna O’Brien, PhD, for her assistance with conducting aspects of the experiments described in this manuscript.

Financial disclosure

Kelly Skelton, MD PHD serves on the Speakers’ Bureau of AstraZeneca, Bristol-Myers-Squibb, and Pfizer. In the past three years, Charles B. Nemeroff, MD PhD consulted to, served on the Speakers' Bureau and/or Board of Directors, has been a grant recipient, and/or owned equity in one or more of the following: Abbott Laboratories, Acadia Pharmaceuticals, American Foundation for Suicide Prevention (AFSP), American Psychiatric Institute for Research and Educations (APIRE), AstraZeneca, BMC-JRLLC, Bristol-Myers-Squibb, CeNeRx, Corcept, Cypress Biosciences, Cyberonics, Eli Lilly, Entrepreneur's Fund, Forest Laboratories, George West Mental Health Foundation, GlaxoSmithKline, i3 DLN, Janssen Pharmaceutica, Lundbeck, National Alliance for Research on Schizophrenia and Depression (NARSAD), Neuronetics, NIMH, NFMH, NovaDel Pharma, Otsuka, Pfizer Pharmaceuticals, Quintiles, Reevax, UCB Pharma, Wyeth-Ayerst. Curently, Dr. Nemeroff serves on the Scientific Advisory Board for Astra-Zeneca, Johnson & Johnson, Pharma Neuroboost, Forest Laboratories, Quintiles and NARSAD. He is a grant recipient from NIH, NARSAD and AFSP. He serves on the Board of Directors of AFSP, APIRE, NovaDel Pharmaceuticals and the George West Mental Health Foundation. He owns equity in CeNeRx and Reevax. He owns stock or stock options in Corcept, Cypress Biosciences and NovaDel. Michael J. Owens, Ph.D. has received speakers’ honoraria from GlaxoSmithKline, has research grants from Pfizer, GlaxoSmithKline, Merck, Lundbeck, Cyberonics, and Johnson & Johnson, has served (or continues to serve) as a consultant for Bristol-Myers-Squibb, Pfizer, Lundbeck, Sepracor, Johnson & Johnson, Sanofi-Aventis, and Forest Labs, and has the following patent—“A method to estimate transporter occupancy” (provisional filing).

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Authors and Affiliations

  1. Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Kelly H. Skelton, David A. Gutman, K. V. Thrivikraman, Charles B. Nemeroff & Michael J. Owens

  2. Mental Health Service Line, Atlanta VA Medical Center, 5th Floor, 1670 Clairmont Rd, Decatur, GA, 30033, USA

    Kelly H. Skelton

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  1. Kelly H. Skelton
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  2. David A. Gutman
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  3. K. V. Thrivikraman
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  4. Charles B. Nemeroff
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Correspondence to Kelly H. Skelton.

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Skelton, K.H., Gutman, D.A., Thrivikraman, K.V. et al. The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal. Psychopharmacology 192, 385–396 (2007). https://doi.org/10.1007/s00213-007-0713-3

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