The occurrence of opiate tolerance, dependence, and withdrawal represents both a major socioeconomic problem and an obstacle to the optimal use of opiates to relieve human suffering. We have identified a discrete group of limbic structures that are metabolically active during opiate withdrawal. The degree of metabolic changes in the these structures is a direct function of both cumulative morphine dose and the naloxone dose employed to precipitate withdrawal. We propose to extend our studies of regional cerebral glucose utilization (RCGU) by the 2-deoxyglucose autoradiographic method in rats during opiate withdrawal to more critically evaluate the significance of our findings. RCGU will be characterized as a function of time after the last morphine dose during abstinent withdrawal and time after naloxone-precipitated withdrawal. RCGU will also be studied during morphine withdrawal in paralyzed ventilated rats, after high thoracic cord transection, after vagotomy, and after intracerebroventricular administration of opiate agonists to isolate central drug effects and responses, and to infer differences between direct and indirect drug effects on RCGU. In addition, we propose to determine regional brain binding properties (Kd, Bmax) for different classes of opiate receptors in multiple brain regions in morphine dependent and withdrawing rats in vivo and in vitro. In vitro studies will be accomplished by quantitative film autoradiography with tritium-containing plastic standards; in vivo studies will be accomplished by the co-administration of H-3-labeled ligands with competing ligands and the subsequent determination of regional drug binding. Anatomical co-localization of brain regions participating in opiate withdrawal (RCGU changes) and central sites of opiate action (binding sites) will be accomplished by autoradiographic techniques in adjacent tissue sections. These studies should provide answers to several critical questions: Is there a specific functional-anatomical substrate for the opiate withdrawal syndrome? To what degree is opiate dependence a consequence of central drug effects? Is there a spatial relationship among opiate binding sites and those regions showing changes in RCGU during withdrawal? Are there regional changes in the affinity (Kd) or capacity (Bmax) for any opiate receptor subtype in dependent brains which might reflect the molecular basis for opiate tolerance and dependence?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA003787-01A1
Application #
3208434
Study Section
(DABB)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
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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