The presence of specific high-affinity binding sites for phencyclidine (PCP) in brain and the fact that PCP can produce in man profound behavioral changes often resembling a schizophrenic psychosis requires that substantial efforts be made to determine the effects of PCP on central nervous system processes. The overall goal of the studies described in this proposal is to examine the action of phencyclidine and a recently isolated PCP-like brain peptide on normal neurobiological processes within the rat central nervous system. Specifically, dopamine cell bodies (A10) in the ventral tegmental area and the mesolimbic-mesocortical areas innervated by those DA neurons have been chosen for study. These pathways have been strongly implicated as anatomical and biochemical substrates likely to be involved in schizophrenia. Using electrophysiological methods of extracellular unit recording, microiontophoretic-micropressure administration, and electrical stimulation of selected pathways to identifiable target cells, PCP and the PCP-like peptide will be studied and compared for their selective actions on specific sites and chemical modes of synaptic transmission. Pharmacological manipulations and selective lesioning techniques will be used to discriminate between a preferential presynaptic or postsynaptic site of action as well as to characterize interactions of the test compounds with dopaminergic and noradrenergic systems. Finally, we will determine if PCP and PCP-like peptide neuronal effects differ between naive animals and those chronically treated with systemically administered PCP. The projects outlined here should enable us to characterize the sites, mechanisms and functional consequences of PCP and PCP-like peptide action on selected neuronal pathways. The resulting data will provide essential information concerning PCP's unique pharmacology. In turn, such findings may be useful for the understanding of specific chemical processes involved in the etiology of schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003876-03
Application #
3208664
Study Section
(BPNB)
Project Start
1984-09-01
Project End
1988-08-31
Budget Start
1986-09-01
Budget End
1988-08-31
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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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