The physiology of dopamine (DA) neuronal systems has been a major topic of investigation due to the hypothesized involvement of these neurons in various clinical and neurological disorders, such as schizophrenia, Parkinson's disease, and the side effects of chronic antipsychotic drug administration. Although in vivo electrophysiological studies have proven valuable in ascertaining the responses of DA neurons to pharmacological intervention in the whole animal, these studies have proven insufficient in uncovering the ionic mechanisms underlying these actions. By using in vitro intracellular recording techniques, is should be possible to characterize the membrane conductance changes which are responsible for regulating spontaneous activity, as well as the ionic mechanism which underlie the responses of DA neurons to drug administration. In order to derive data specific to this neurochemical system, the dopaminergic nature of the neurons recorded must first be established. The direct identification of DA neurons in the slice will be done by combining intracellular injection of fluorescent dyes with catecholamine histofluorescene. Furthermore, morphological characterization of identified DA neurons will be accomplished by intracellular injection of Lucifer yellow and horseradish peroxidase. Injection of dyes into the know postsynaptic target sites of DA neurons prior to recording and intracellular staining will permit comparisons of DA neuron morphology and electrophysiology based upon their sites of termination. The next stage of the study will involve determination of the biophysical properties of DA neurons to establish the electrophysiological bases against which responses to drugs can be measured. Thus, sodium spikes, low threshold and high threshold calcium spikes, and pacemaker depolarizations will be investigated by pharmacological blockade of specific ionic channels. Furthermore, the threshold and voltage dependencies of both active and passive ion fluxes will be determined in order to establish the presence of voltage activated or inactivated conductances. The direct effects of DA on neuronal activity and the involvement of the DA autoreceptor in the regulation of cell firing will be examined by the administration of DA agonists and antagonists. In summary, these studies are designed to identify the nature of DA cell autoregulation of spontaneous activity, with special emphasis on the differential modes of regulation expressed by DA cell subpopulations. It is hoped that these studies will provide insights into methods by which we may pharmacologically manipulate, in a highly specific manner, the activity level of this cell group to aid in the alleviation of a variety of clinical disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH042217-03
Application #
3381345
Study Section
(BPNB)
Project Start
1986-12-01
Project End
1990-11-30
Budget Start
1989-01-01
Budget End
1990-11-30
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Type
Schools of Arts and Sciences
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Onn, S P; Grace, A A (1999) Alterations in electrophysiological activity and dye coupling of striatal spiny and aspiny neurons in dopamine-denervated rat striatum recorded in vivo. Synapse 33:1-15
Todd, C L; Grace, A A (1999) Interaction of benztropine and haloperidol actions on rat substantia nigra dopamine cell electrophysiological activity in vivo. Brain Res Bull 48:219-22
O'Donnell, P; Grace, A A (1998) Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters. Schizophr Bull 24:267-83
O'Donnell, P; Grace, A A (1996) Dopaminergic reduction of excitability in nucleus accumbens neurons recorded in vitro. Neuropsychopharmacology 15:87-97
Lavin, A; Grace, A A (1996) Physiological properties of rat ventral pallidal neurons recorded intracellularly in vivo. J Neurophysiol 75:1432-43
Pucak, M L; Grace, A A (1996) Effects of haloperidol on the activity and membrane physiology of substantia nigra dopamine neurons recorded in vitro. Brain Res 713:44-52
Grace, A A (1995) The tonic/phasic model of dopamine system regulation: its relevance for understanding how stimulant abuse can alter basal ganglia function. Drug Alcohol Depend 37:111-29
Harden, D G; Grace, A A (1995) Activation of dopamine cell firing by repeated L-DOPA administration to dopamine-depleted rats: its potential role in mediating the therapeutic response to L-DOPA treatment. J Neurosci 15:6157-66
O'Donnell, P; Grace, A A (1995) Different effects of subchronic clozapine and haloperidol on dye-coupling between neurons in the rat striatal complex. Neuroscience 66:763-7
O'Donnell, P; Grace, A A (1995) Synaptic interactions among excitatory afferents to nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J Neurosci 15:3622-39

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