The present experiments represent a logical continuation of our current research efforts to gain a better understanding of the actions and mechanis s of action of nicotine in the mammalian central nervous system. Our strateg is to use a combination of neurochemical, biochemical and electrophysiological approaches to study the actions and mechanism of actio of nicotine on dopamine neurons of freely-moving, unanesthetized rats as we l as the cellular mechanisms involved in the release of dopamine from culture cell lines. During the present grant period, we examined the effect of nicotine on the firing rate of the cell bodies and the release of DA from t e terminals. We observed that nicotine increases the firing rate of A10 neurons to a greater extent than A9, that chronic treatment resulted in a change from stimulation to inhibition of the firing rate, while the release of DA from the terminals was enhanced. The objectives of Specific Aims 1-3 are to examine the mechanisms of these effects of chronic nicotine and to obtain further evidence for a greater sensitivity of A10 over A9 neurons. A combination of electrophysiological and neurochemical studies will be carried out in the freely-moving, unanesthetized rat.
Specific Aim 1 will determine the mechanism for the enhancement of the nicotine-induced release of DA from the striatum of freely-moving rats chronically exposed to nicotine. We will measure the number of spontaneously active DA cells, nicotinic-cholinergic receptors as well as DA content, release and synthesi .
Specific Aim 2 will examine the nicotine-induced release of DA from termina s of the mesolimbic DA pathway in freely-moving rats acutely and following chronic exposure to nicotine. We will measure the release of newly- synthesized DA using push-pull perfusion and by tissue 3MT.
Specific Aim 3 will define the electrophysiological effects of nicotine on mesolimbic DA neurons following chronic treatment with nicotine. In the final Specific Aim, we will carry out biochemical studies (DA release, cAMP accumulation, receptor binding) as well as electrophysiological recordings in the PC12 cells, PC12 mutants and primary cultures of bovine chromaffin cells as mode systems to come to an understanding of potential intracellular mechanisms involved in the release of DA. Biochemical studies will address the hypothesis that the nicotine-induced release of DA is involved in activatio of a calmodulin-sensitive adenylate cyclase leading to an increase in cAMP. These experiments will provide useful new information on the chronic effect and mechanisms of action of nicotine on dopamine neurotransmission in freel - moving, unanesthetized animals and in the intracellular mechanisms involved in the nicotine-induced release of dopamine. They will also further define the importance of the mesolimbic, mesocortical dopamine pathway as the biological substrate for dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA002668-10
Application #
3207504
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1980-07-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
10
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Courtney, N D; Howlett, A C; Westfall, T C (1991) Dopaminergic regulation of dopamine release from PC12 cells via a pertussis toxin-sensitive G protein. Neurosci Lett 122:261-4
Courtney, N D; Howlett, A C; Westfall, T C (1991) Regulation of nicotine-evoked dopamine release from PC12 cells. Life Sci 48:1671-8
Westfall, T C; Han, S P; Chen, X L et al. (1990) Presynaptic peptide receptors and hypertension. Ann N Y Acad Sci 604:372-88
Westfall, T C (1990) The physiological operation of presynaptic inhibitory autoreceptors. Ann N Y Acad Sci 604:398-413
Westfall, T C; Chen, X L; Ciarleglio, A et al. (1990) In vitro effects of neuropeptide Y at the vascular neuroeffector junction. Ann N Y Acad Sci 611:145-55
Heritch, A J; Henderson, K; Westfall, T C (1990) Effects of social isolation on brain catecholamines and forced swimming in rats: prevention by antidepressant treatment. J Psychiatr Res 24:251-8
Westfall, T C; Mereu, G; Vickery, L et al. (1989) Regulation by nicotine of midbrain dopamine neurons. Prog Brain Res 79:173-85
Westfall, T C; Martin, J; Chen, X L et al. (1988) Cardiovascular effects and modulation of noradrenergic neurotransmission following central and peripheral administration of neuropeptide Y. Synapse 2:299-307
Mereu, G; Yoon, K W; Boi, V et al. (1987) Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine. Eur J Pharmacol 141:395-9
Westfall, T C; Badino, L; Naes, L et al. (1987) Alterations in the field stimulation-induced release of endogenous norepinephrine from the coccygeal artery of spontaneously hypertensive and Wistar-Kyoto rats. Eur J Pharmacol 135:433-7

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