title: The CRF1 receptor antagonist R121919 attenuates the neuroendocrine and behavioral effects of precipitated lorazepam withdrawal.
abstract: BACKGROUND
  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 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 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.
  
  
  OBJECTIVE
  To extend these findings, we investigated 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 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 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.
authors.affiliation: Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA 30322, USA. kelly.skelton@va.gov
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Skelton
authors.forename: David A
authors.initials: DA
authors.lastname: Gutman
authors.forename: K V
authors.initials: KV
authors.lastname: Thrivikraman
authors.forename: Charles B
authors.initials: CB
authors.lastname: Nemeroff
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owens
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000009:adverse effects*; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D005442:Flumazenil; D015870:Gene Expression / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000009:adverse effects*; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008140:Lorazepam / Q000009:adverse effects*; D008297:Male; D009474:Neurons / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011743:Pyrimidines / Q000494:pharmacology*; D012332:RNA, Heterogeneous Nuclear / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D013312:Stress, Physiological / Q000188:drug therapy / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D019966:Substance-Related Disorders
chemical_list: D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives; D011743:Pyrimidines; C412383:R 121919; D012332:RNA, Heterogeneous Nuclear; D018019:Receptors, Corticotropin-Releasing Hormone; D005442:Flumazenil; D008140:Lorazepam