The fact that phencyclidine (PCP) continues to be an abused drug which can produce in man profound alterations in behavior, requires that substantial efforts are crucially necessary to understand its effects on central nervous system function. The overall goal of the studies described in this proposal is to determine the mechanism(s) of action of PCP on normal neurobiological processes within the rat central nervous system. Specifically, the effects of PCP on midbrain dopamine neurons (A10) within the ventral tegmental area (VTA) and the influence of VTA afferents on those cells have been selected for study. As with other drugs of abuse (e.g. cocaine), the A10- dopamine neurons and the mesolimbic-mesocortical structures they innervate have been implicated as anatomical and biochemical substrates likely to be involved in the reinforcing properties of PCP. Also, these same structures are considered underpinnings in the pathophysiology of schizophrenia and, as such, plausibly linked to the psychosis-like effects frequently elicited by PCP. In the present proposal, we will use electrophysiological methods of extracellular recording combined with selective lesions and pharmacological manipulations to determine the transmitter identity contribution to either the intensification or diminishment of PCP's unique excitatory/inhibitory effects on VTA neurons. In addition, intracellular recordings from neurons in the in vitro VTA brain slice preparation will be used to provide an indepth analysis of the effects of acute and chronic PCP on neuronal membrane properties, chemical synapses, and voltage sensitive ion conductances of the neuronal A10 dopamine cells. The projects outlined here should enable us to characterize the consequences of PCP on VTA A10 neurons directly, and the relative contributions made various by afferent inputs to these effects. The data derived from these experiments will provide essential information regarding PCP's unique pharmacological actions on this midbrain dopamine containing system. This in turn may help delineate the neurobiological consequence of phencyclidine abuse, and as such possibly lead to a more rational design of treatments for the various behavioral effects and psychopathologies related to PCP abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA003876-04A1
Application #
3208662
Study Section
Special Emphasis Panel (SRCD (10))
Project Start
1984-09-01
Project End
1993-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
4
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Wang, T; French, E D (1995) NMDA, kainate, and AMPA depolarize nondopamine neurons in the rat ventral tegmentum. Brain Res Bull 36:39-43
French, E D (1994) Phencyclidine and the midbrain dopamine system: electrophysiology and behavior. Neurotoxicol Teratol 16:355-62
Wang, T; O'Connor, W T; Ungerstedt, U et al. (1994) N-methyl-D-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies. Brain Res 666:255-62
French, E D; Mura, A; Wang, T (1993) MK-801, phencyclidine (PCP), and PCP-like drugs increase burst firing in rat A10 dopamine neurons: comparison to competitive NMDA antagonists. Synapse 13:108-16
Wang, T; French, E D (1993) Electrophysiological evidence for the existence of NMDA and non-NMDA receptors on rat ventral tegmental dopamine neurons. Synapse 13:270-7
Wang, T; French, E D (1993) Effects of phencyclidine on spontaneous and excitatory amino acid-induced activity of ventral tegmental dopamine neurons: an extracellular in vitro study. Life Sci 53:49-56
Wang, T; French, E D (1993) L-glutamate excitation of A10 dopamine neurons is preferentially mediated by activation of NMDA receptors: extra- and intracellular electrophysiological studies in brain slices. Brain Res 627:299-306
French, E D (1992) Competitive NMDA receptor antagonists attenuate phencyclidine-induced excitations of A10 dopamine neurons. Eur J Pharmacol 217:1-7
French, E D; Ferkany, J; Abreu, M et al. (1991) Effects of competitive N-methyl-D-aspartate antagonists on midbrain dopamine neurons: an electrophysiological and behavioral comparison to phencyclidine. Neuropharmacology 30:1039-46
French, E D; Ceci, A (1990) Non-competitive N-methyl-D-aspartate antagonists are potent activators of ventral tegmental A10 dopamine neurons. Neurosci Lett 119:159-62

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