Research into the central nervous system mechanisms of drug reinforcement has centered on a particular population of dopamine neurons located in the ventral midbrain. Research with animal models has established that these mesolimbic dopamine cells play a major role in drug-seeking behavior and has led on occasion to testing of dopaminergic agents as """"""""medications"""""""" to assist in reducing drug abuse disorders. While the central role of dopamine systems in drug reinforcement has become evident, the ubiquitous involvement of dopamine systems in motivated behavior and motor functions speaks to the need for the development of highly selective interventions in the dopamine system if medications specific for drug-use disorders are to be obtained. To support a strategic approach to the testing of pharmacotherapeutic agents for potential benefit in drug abuse treatment, additional knowledge is essential. The approach to be taken in this research is to discover other neuronal systems which physiologically regulate mesolimbic dopamine neurons. In this case, the promise is that highly selective interventions might be crafted which would mimic the action of the normal physiological inputs to those dopamine cells which themselves are critical in initiating and maintaining drug-taking behavior. This preclinical research will employ primarily the techniques of behavioral pharmacology and neuroscience to understand how two particular neurochemical systems can control the dopamine processes which mediate cocaine and nicotine addiction. One system of interest is cholinergic. Previous studies have demonstrated that nicotine activates the mesolimbic dopamine projection neurons as do other drugs such as cocaine, but does so by targeting nicotinic receptors in the vicinity of the dopamine cell bodies. This site of action for nicotine implicates known cholinergic inputs in nicotine reinforcement, and generally in the regulation of mesolimbic dopaminergic cells. Therefore, one strategy in this research is to examine the influence of the cholinergic system on drug reinforcement, using animal models in which the subjects self-administer nicotine or cocaine. Secondly, it is apparent that cocaine reinforcement can be reduced by treatment with opiate antagonists administered systemically, and recent research has shown that mu-type opiate receptors in the ventral tegmental area are critical in this effect. The second strategy in this research is, then, to investigate the mechanisms by which opiates regulate the mesolimbic dopamine systems in cocaine reinforcement.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009577-03
Application #
2872074
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Aigner, Thomas G
Project Start
1997-04-01
Project End
2000-01-31
Budget Start
1999-02-01
Budget End
2000-01-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Centre for Addiction and Mental Health
Department
Type
DUNS #
City
Toronto
State
ON
Country
Canada
Zip Code
M5S2S-1
Rahman, Shafiqur; Lopez-Hernandez, Gretchen Y; Corrigall, William A et al. (2008) Neuronal nicotinic receptors as brain targets for pharmacotherapy of drug addiction. CNS Neurol Disord Drug Targets 7:422-41
Rahman, S; Zhang, J; Engleman, E A et al. (2004) Neuroadaptive changes in the mesoaccumbens dopamine system after chronic nicotine self-administration: a microdialysis study. Neuroscience 129:415-24
Rahman, S; Zhang, J; Corrigall, W A (2004) Local perfusion of nicotine differentially modulates somatodendritic dopamine release in the rat ventral tegmental area after nicotine preexposure. Neurochem Res 29:1687-93
Corrigall, William A; Coen, Kathleen M; Zhang, Jianhua et al. (2002) Pharmacological manipulations of the pedunculopontine tegmental nucleus in the rat reduce self-administration of both nicotine and cocaine. Psychopharmacology (Berl) 160:198-205
Picciotto, Marina R; Corrigall, William A (2002) Neuronal systems underlying behaviors related to nicotine addiction: neural circuits and molecular genetics. J Neurosci 22:3338-41
Corrigall, W A; Coen, K M; Zhang, J et al. (2001) GABA mechanisms in the pedunculopontine tegmental nucleus influence particular aspects of nicotine self-administration selectively in the rat. Psychopharmacology (Berl) 158:190-7
Jose Lanca, A; Sanelli, T R; Corrigall, W A (2000) Nicotine-induced fos expression in the pedunculopontine mesencephalic tegmentum in the rat. Neuropharmacology 39:2808-17
Lanca, A J; Adamson, K L; Coen, K M et al. (2000) The pedunculopontine tegmental nucleus and the role of cholinergic neurons in nicotine self-administration in the rat: a correlative neuroanatomical and behavioral study. Neuroscience 96:735-42
Corrigall, W A; Coen, K M; Adamson, K L et al. (2000) Response of nicotine self-administration in the rat to manipulations of mu-opioid and gamma-aminobutyric acid receptors in the ventral tegmental area. Psychopharmacology (Berl) 149:107-14
Corrigall, W A (1999) Nicotine self-administration in animals as a dependence model. Nicotine Tob Res 1:11-20

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