Discovery of the central nervous system mechanisms by which drugs influence behavior is important in understanding the basic processes in brain and behavior in general, and more practically because it establishes the knowledge base for the development of medications to treat dependence, as well as identifying potential substrates for biological variability. Studies of the reinforcing effects of drugs have identified that a particular population of dopamine neurons located in the ventral part of the midbrain (ventral tegmental area, VTA) play a major role in drug-taking behavior. However, these dopamine systems are not uniquely involved in drug-taking behavior, but also subserve other motivated behaviors and motor functions. The approach taken in this research is to discover other neuronal systems which likely regulate these dopamine neurons and hence influence drug-taking behavior. Our hypothesis has two parts. First, we propose that the activation of mu opioid receptors in the VTA can have different effects on the self-administration of non-opioid drugs like nicotine and cocaine, depending on the extent of recruitment of GABAergic elements in the VTA by the drug in question. Second, we propose that cholinergic projections from the mesopontine area to the VTA play a role in drug reinforcement when they are activated. This preclinical research uses techniques in which animals are trained to do work (press a lever) to obtain intravenous infusions of nicotine or cocaine. Brain pathways and mechanisms are identified by manipulating the drug-taking behavior with neurochemical lesions of particular neuronal pathways in the brain, or by microinfusions of neurochemicals into certain brain areas. Conceptually the experiments proposed to test the first part of the hypothesis build on the observation that the focal administration of a mu-selective opioid agonist into the VTA alters cocaine self-administration more than nicotine self-administration. Experiments in this application will test whether this observation reflects an effect on the ability of the self-administered drug to reinforce behavior, and whether GABAergic mechanisms are involved. The second part of our hypothesis derives from studies which have shown that selective lesions of the cholinergic cells of the caudal part of the pedunculopontine tegmental nucleus (PPTg), which provide cholinergic input to the VTA, or blocking the effects of nicotine in the PPTg with a nicotinic antagonist, reduce nicotine self-administration. Experiments will examine whether depleting this population of cholinergic cells produces a selective effect on nicotine versus cocaine reinforcement, and whether agents that alter the activity of these cholinergic cells affect reinforcement more generally.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009577-05
Application #
6350491
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (01))
Program Officer
Aigner, Thomas G
Project Start
1997-04-01
Project End
2003-01-31
Budget Start
2001-02-15
Budget End
2002-01-31
Support Year
5
Fiscal Year
2001
Total Cost
$96,611
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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