This proposal is focused on studying the newly discovered Orphanin/Nociceptin system (OFQ system), a new peptidergic system, evolutionarily related to the endogenous opioids but exhibiting distinct biochemical, anatomical and functional properties. The working hypothesis is that the OFQ systems plays a role in the regulation of the biology of stress responsiveness, the biology of reward mechanisms, and the interactions between stress and reward mechanisms as they impact on drug-related behavior. This hypothesis is based on several lines of anatomical and functional evidence gathered to date. However, much remains to be learned about some of the fundamental features of this system before pursuing these functional questions. Thus, this application proposes to determine whether stress (novelty and restraint) regulates OFQ or its associated receptor, ORL1, in particular brain regions, and to ascertain the ability of OFQ in these stress-sensitive regions to modulate the limbic- hypothalamo-pituitary-adrenal (LHPA) axis) (Aim I). It explores the anatomical features of the OFQ system in the context of the mesocorticolimbic dopaminergic system, where it appears to be highly expressed, and addresses the issue of whether or not OFQ and ORL1 are present within dopaminergic neurons, and whether they are located in circuits which could modulate dopaminergic transmission (Aim II). Finally, in the context of the above circuits, it examines the way this system is modulated by chronic administration of opiates and psychostimulants under conditions which lead to sensitization to these drugs. In turn, it asks whether OFQ is able to alter the course of drug sensitization in stressful and non-stressful conditions (Aim III). A combination of molecular, anatomical, and behavioral tools will be used to address these questions. Together, these studies will not only shed light on the functioning of this novel peptidergic system, but will also provide new insights on the important interface between stress mechanisms, dopaminergic mechanisms, and substance abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA008920-09
Application #
6624752
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Pilotte, Nancy S
Project Start
1994-06-01
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
9
Fiscal Year
2003
Total Cost
$277,443
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Psychiatry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Neal Jr, Charles R; Weidemann, Gabrielle; Kabbaj, Mohamed et al. (2004) Effect of neonatal dexamethasone exposure on growth and neurological development in the adult rat. Am J Physiol Regul Integr Comp Physiol 287:R375-85
Isgor, Ceylan; Shieh, Kun-Ruey; Akil, Huda et al. (2003) Colocalization of estrogen beta-receptor messenger RNA with orphanin FQ, vasopressin and oxytocin in the rat hypothalamic paraventricular and supraoptic nuclei. Anat Embryol (Berl) 206:461-9
Uslaner, Jason M; Norton, Camille S; Watson, Stanley J et al. (2003) Amphetamine-induced c-fos mRNA expression in the caudate-putamen and subthalamic nucleus: interactions between dose, environment, and neuronal phenotype. J Neurochem 85:105-14
Neal Jr, Charles R; VanderBeek, Brian L; Vazquez, Delia M et al. (2003) Dexamethasone exposure during the neonatal period alters ORL1 mRNA expression in the hypothalamic paraventricular nucleus and hippocampus of the adult rat. Brain Res Dev Brain Res 146:15-24
Devine, D P; Hoversten, M T; Ueda, Y et al. (2003) Nociceptin/orphanin FQ content is decreased in forebrain neurones during acute stress. J Neuroendocrinol 15:69-74
Ostrander, M M; Badiani, A; Day, H E W et al. (2003) Environmental context and drug history modulate amphetamine-induced c-fos mRNA expression in the basal ganglia, central extended amygdala, and associated limbic forebrain. Neuroscience 120:551-71
Neal Jr, Charles R; Owens, Constance E; Taylor, Larry P et al. (2003) Binding and GTPgammaS autoradiographic analysis of preproorphanin precursor peptide products at the ORL1 and opioid receptors. J Chem Neuroanat 25:233-47
Ferguson, Susan M; Norton, Camille S; Watson, Stanley J et al. (2003) Amphetamine-evoked c-fos mRNA expression in the caudate-putamen: the effects of DA and NMDA receptor antagonists vary as a function of neuronal phenotype and environmental context. J Neurochem 86:33-44
Owens, Constance E; Akil, Huda (2002) Determinants of ligand selectivity at the kappa-receptor based on the structure of the orphanin FQ receptor. J Pharmacol Exp Ther 300:992-9
Neal Jr, C R; Akil, H; Watson Jr, S J (2001) Expression of orphanin FQ and the opioid receptor-like (ORL1) receptor in the developing human and rat brain. J Chem Neuroanat 22:219-49

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