ORIGINAL INVESTIGATION The CRF 1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal Kelly H. Skelton & David A. Gutman & K. V. Thrivikraman & Charles B. Nemeroff & Michael J. Owens Received: 1 October 2006 / Accepted: 13 January 2007 / Published online: 13 February 2007 # Springer-Verlag 2007 Abstract Rationale Corticotropin-releasing factor (CRF) is the pri- mary physiologic regulator of the hypothalamic-pituitary- adrenal (HPA) axis and serves to globally coordinate the mammalian stress response. Hyperactivity of central ner- vous system CRF neurotransmission, acting primarily via the CRF 1 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 canna- bis, 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 investi- gated whether pretreatment with the selective CRF 1 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 subse- quent 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-precip- itation 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 CRF 1 receptor subtype plays a major role in mediating the effects of CRF on neuroendocrine and behavioral responses during BZ withdrawal. Therefore, CRF 1 receptor antagonists may be of therapeutic utility in the treatment of drug withdrawal syndromes. Keywords Anxiety . Benzodiazepines . Corticotropin-releasing factor . HPA axis . Stress . Withdrawal The neuropeptide corticotropin-releasing factor (CRF), the major physiological regulator of the hypothalamic-pitui- tary-adrenal (HPA) axis, mediates the endocrine response to stress. Substantial evidence has accumulated to support the hypothesis that in extrahypothalamic limbic structures and brainstem nuclei, CRF additionally functions as a neuro- transmitter and serves to mediate the behavioral, immune, and autonomic components of the stress response. In addition to this key role, there is considerable evidence implicating CRF in the pathophysiology of mood and anxiety disorders (Owens and Nemeroff 1991). Preclinical data generated in laboratory animals demon- strates that either central administration of CRF or transgenic overexpression produces behavioral evidence of heightened anxiety (Dunn and Berridge 1990; Heinrichs et al. 1997a). In humans, elevated concentrations of CRF have been observed in the cerebrospinal fluid (CSF) of drug-free Psychopharmacology (2007) 192:385–396 DOI 10.1007/s00213-007-0713-3 K. H. Skelton : D. A. Gutman : K. V. Thrivikraman : C. B. Nemeroff : M. J. Owens Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA K. H. Skelton (*) Mental Health Service Line, Atlanta VA Medical Center, 5th Floor, 1670 Clairmont Rd, Decatur, GA 30033, USA e-mail: kelly.skelton@va.gov