This FIRST award utilizes well-documented techniques to investigate the role of corticotropin-releasing factor (CRF) neurons in both the therapeutic actions of benzodiazepines as well as the physiological effects associated with abrupt discontinuation of benzodiazepines. In the last decade considerable evidence from a number of investigators using different experimental approaches has accrued consistent with the hypothesis that CRF mediates the endocrine, behavioral and autonomic responses of mammals to stress. Based upon previous preclinical studies which revealed that exposure to stress and treatment with anxiolytic benzodiazepines produce opposite effects on CRF neurons, this proposal seeks to characterize the dose-response effects of various drugs which are active at the benzodiazepine receptor including agonists, partial agonists, antagonists and inverse agonists for their actions on CRF neurons after both acute and chronic administration. In addition, because benzodiazepine withdrawal is associated with physiological symptoms reminiscent of a classic """"""""stress response"""""""", this proposal will seek to investigate whether CRF neurons are involved in the acute drug withdrawal phase. Can intermittent administration of the benzodiazepine antagonist flumazenil during chronic benzodiazepine treatment attenuate drug withdrawal via effects on CRF neurons? Finally, does central administration of a CRF antagonist modify the drug withdrawal phase by altering CRF neuronal activity as measured neurochemically or behaviorally? Currently, the best estimates of CRF neuronal activity are concurrent measurement of CRF concentrations, CRF mRNA expression, and CRF receptor binding in discrete brain regions previously implicated in mediating the actions of CRF. Additional measures of hypothalamic CRF activity will be obtained by measuring plasma ACTH and corticosterone concentrations. These studies will provide further information on the role(s) of CRF in the CNS, and in particular the role of CRF in potentially mediating a portion of the therapeutic (anxiolytic) and deleterious (drug withdrawal) actions of benzodiazepines. Such studies have important implications for the development of novel treatments for anxiety disorders as well as the development of novel agents to ameliorate drug withdrawal symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DA008705-01A1
Application #
2121372
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1994-09-30
Project End
1999-08-31
Budget Start
1994-09-30
Budget End
1995-08-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Emory University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Rosenblum, Leonard A; Smith, E L P; Altemus, Margaret et al. (2002) Differing concentrations of corticotropin-releasing factor and oxytocin in the cerebrospinal fluid of bonnet and pigtail macaques. Psychoneuroendocrinology 27:651-60
Smith, Eric L P; Batuman, Olcay A; Trost, Ronald C et al. (2002) Transforming growth factor-beta 1 and cortisol in differentially reared primates. Brain Behav Immun 16:140-9
Rosenblum, L A; Forger, C; Noland, S et al. (2001) Response of adolescent bonnet macaques to an acute fear stimulus as a function of early rearing conditions. Dev Psychobiol 39:40-5
Skelton, K H; Nemeroff, C B; Owens, M J (2000) A comparison of plasma alprazolam concentrations following different routes of chronic administration in the Sprague-Dawley rat: implications for psychotropic drug research. Psychopharmacology (Berl) 151:72-6
Skelton, K H; Owens, M J; Nemeroff, C B (2000) The neurobiology of urocortin. Regul Pept 93:85-92
Skelton, K H; Nemeroff, C B; Knight, D L et al. (2000) Chronic administration of the triazolobenzodiazepine alprazolam produces opposite effects on corticotropin-releasing factor and urocortin neuronal systems. J Neurosci 20:1240-8
Vythilingam, M; Anderson, G M; Owens, M J et al. (2000) Cerebrospinal fluid corticotropin-releasing hormone in healthy humans: effects of yohimbine and naloxone. J Clin Endocrinol Metab 85:4138-45
Owens, M J; Nemeroff, C B (1998) The serotonin transporter and depression. Depress Anxiety 8 Suppl 1:5-12
Heim, C; Owens, M J; Plotsky, P M et al. (1997) Persistent changes in corticotropin-releasing factor systems due to early life stress: relationship to the pathophysiology of major depression and post-traumatic stress disorder. Psychopharmacol Bull 33:185-92
Ladd, C O; Owens, M J; Nemeroff, C B (1996) Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 137:1212-8

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