The nucleus accumbens (NAc) is a basal forebrain structure located at the crossroads of limbic and motor circuits. The NAc is thought to play an important role in a variety of cognitive processes and has been suggested as a possible site of schizophrenic pathophysiology and antipsychotic drug (APD) action. However, little is known regarding the physiological properties of individual NAc neurons and the regulatory factos which influence their activity. This series of studies will use combinations of extracellular single cell recording, microiontophoresis, electircal stimulation, and anatomical tracing techniques to: (1) identify the neurophysiological properties of individual NAc neurons with respect to their waveforms, firing rates and patterns, topographical distribution, efferent and afferent connections, conduction velocities and absolute refractory periods, (ii) characterize the roles of D-1 and D-2 DA receptors in mediating the neuroregulatory influences of DA within the NAc, (iii) determine the possible interactions between D-1 and D-2 receptors within the NAc and their possible role in neuromodulation, and (iv) explore the possible sites and mechanisms of action of antipsychotic drugs within the NAc and in NAc-A10 feedback processes which have been implicated in mediating APD effects on A10 DA neurons. The rationale for these projects is that identification of the specific neuronal systems involved in the actions of APDs should eventually lead to the development of new treatment strategies which might interact specifically with relevant neuronal systems and avoid systems responsible for the extrapyramidal side effects (EPSE) which complicate pharmocotherapy with standard APDs. The underlying hypothesis directing these studies is that the NAc is an essential site of APD action and that this nucleus reacts to chronic APD treatment in a manner different from that of the nigrostriatal DA system. Thus, the elucidation of the physiology and pharmacology of the NAc, particularly the roles of DA receptors, should greatly advance our understanding of the mechanisms of action of APDS. Hopefully, such understanding will aid in the development of new and better medications for the treatment of schizophrenia. The long-term objective of this project is to identify the particular roles of limbic and motor pathways in initiating, maintaining and altering various aspects of behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040832-03
Application #
3379291
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1987-12-01
Project End
1990-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Hu, X T; White, F J (1997) Dopamine enhances glutamate-induced excitation of rat striatal neurons by cooperative activation of D1 and D2 class receptors. Neurosci Lett 224:61-5
White, F J (1996) Synaptic regulation of mesocorticolimbic dopamine neurons. Annu Rev Neurosci 19:405-36
Wachtel, S R; White, F J (1995) The dopamine D1 receptor antagonist SCH 23390 can exert D1 agonist-like effects on rat nucleus accumbens neurons. Neurosci Lett 199:13-6
Hu, X T; White, F J (1994) Loss of D1/D2 dopamine receptor synergisms following repeated administration of D1 or D2 receptor selective antagonists: electrophysiological and behavioral studies. Synapse 17:43-61
Wolf, M E; White, F J; Nassar, R et al. (1993) Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization. J Pharmacol Exp Ther 264:249-55
Ackerman, J M; Johansen, P A; Clark, D et al. (1993) Electrophysiological effects of putative autoreceptor-selective dopamine agonists on A10 dopamine neurons. J Pharmacol Exp Ther 265:963-70
Wachtel, S R; Brooderson, R J; White, F J (1992) Parametric and pharmacological analyses of the enhanced grooming response elicited by the D1 dopamine receptor agonist SKF 38393 in the rat. Psychopharmacology (Berl) 109:41-8
White, F J (1992) Neurophysiological approaches to receptor pharmacodynamics. NIDA Res Monogr 124:35-55
Henry, D J; White, F J (1992) Electrophysiological correlates of psychomotor stimulant-induced sensitization. Ann N Y Acad Sci 654:88-100
Henry, D J; Wise, R A; Rompre, P P et al. (1992) Acute depolarization block of A10 dopamine neurons: interactions of morphine with dopamine antagonists. Brain Res 596:231-7

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