The occurrence of opiate dependence and withdrawal-represents both a major socioeconomic problem and an obstacle to the optimal use of opiates to relieve human suffering. We have discovered a restricted group of closely anatomically connected limbic structures that are selectively activated metabolically during opiate withdrawal. The pattern of activation is similar whether withdrawal is precipitated or abstinent. The temporal profile of activation of these structures during withdrawal correlates closely with the behavioral manifestations of opiate withdrawal. In addition, our findings using quantitative autoradiographic methods do not support a role for regulation of opiate receptor number or affinity as a key molecular mechanism for the emergence of dependence. We propose to extend our studies of regional cerebral glucose utilization (RCGU) by the 2-deoxyglucose (2-DG) autoradiographic method to address two additional questions: Is the development of opiate dependence and the occurrence of withdrawal dependent upon the structural and functional integrity of those limbic structures selectively activated during opiate withdrawal? Does the development of opiate dependence and withdrawal require the functional integrity of ascending noradrenergic, dopaminergic, or serotonergic forebrain systems? We will measure RCGU and behavior during precipitated withdrawal in rats with ibotenate lesions of several limbic structures and in rats with specific neurotoxic lesions of ascending noradrenergic, dopaminergic, or serotonergic neurons. In addition, we will continue to seek underlying molecular mechanisms for the development of opiate dependence by addressing the question of whether the development of opiate dependence is associated with specific regional modification of the synthesis of enkephalin. We will synthesize an oligonucleotide probe for preproenkephalin, label the probe with 125I and perform in situ hybridization studies in naive and dependent rat brains. The studies should provide important new insights into the mechanisms of opiate dependence and withdrawal, and more importantly, could provide new pharmacological approaches to the control of dependence development.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003787-04
Application #
3208435
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1985-07-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
4
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Adams, R E; Wooten, G F (1994) Regional cerebral glucose utilization in withdrawal following systemic and intracerebroventricular sufentanil administration. Neurochem Res 19:1243-8
Adams, R E; Wooten, G F (1993) Is morphine dependence mediated exclusively by the Mu receptor? Neurochem Res 18:1041-5
Pollack, A E; Wooten, G F (1992) D2 dopaminergic regulation of striatal preproenkephalin mRNA levels is mediated at least in part through cholinergic interneurons. Brain Res Mol Brain Res 13:35-41
Wolf, S S; Brashear, H R; Levesque, C A et al. (1992) Quantitative autoradiography of hemicholinium-3 binding sites in human amygdala. Brain Res 574:349-52
Pollack, A E; Wooten, G F (1992) Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors. Brain Res Mol Brain Res 12:111-9
Adams, R E; Wooten, G F (1990) Dependence and withdrawal following intracerebroventricular and systemic morphine administration: functional anatomy and behavior. Brain Res 518:6-10
Bekenstein, J W; Lenn, N J (1990) Hemicholinium-3 binding sites in subnuclei of the rat interpeduncular nucleus: quantitative in vitro autoradiography. Brain Res Bull 24:181-4
Trugman, J M; Pronsky, C J; Wooten, G F (1990) Basal ganglia dopamine depletion does not alter D1 dopamine receptor binding properties. Adv Neurol 53:107-10
Bekenstein, J W; Wooten, G F (1989) Hemicholinium-3 binding sites in rat brain: a quantitative autoradiographic study. Brain Res 481:97-105
Cutlip, A C; Lenn, N J; Wooten, G F (1988) Behavioral and metabolic alterations in the opiate withdrawal syndrome induced by lesions of fasciculus retroflexus. Brain Res 451:54-8

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