In the last decade a large body of research has documented a range of structural brain abnormalities in schizophrenic patients, suggesting that schizophrenia can be view as a neurodegenerative disorder. However, it is unclear that any dominant neuropathology defines the disease. This may be because the disease is characterized by several subgroups with diverse etiologic causes. Alternatively, some of the reported neurochemical changes may precede other pathophysiologies. This proposal describes a series of studies, utilizing the techniques of quantitative neurotransmitter autoradiography, histochemistry, and immunocytochemistry to visualize and quantify the neurochemical and neuropathological changes occurring in different clinical populations of schizophrenics. The project will initially focus on documenting changes in the dopaminergic, cholinergic and serotonergic systems and their relationship to neurocytological changes in specified regions of schizophrenic brain tissue. Specifically, to address whether the neuropathological picture is consistent with two clinical populations of schizophrenics. One population having dopamine receptor dysregulation in striatal regions that can be correlated with a predominance of positive symptoms. The other population, with both negative and positive symptoms having, in addition, a neurohemical """"""""isolation"""""""" of the hippocampus. Studies are designed to follow-up on the results of the autoradiographic studies by utilizing two approaches to further document and substantiate the neurodegenerative changes in schizophrenia. Comparison to appropriate control tissue, including neuroleptic- treated and non-neuroleptic treated controls will be utilized. Secondly, other neurological disorders will be examined for the similarity or disimilarity to the neurochemical disturbances of schizophrenia. Immunocytochemical studies and Golgi studies will be used to assess the degree and range of neuronal changes in those specific brain regions that are determined by neurotransmitter autoradiography to be most importantly involved in the disorder. The results from these experiments will be of use in identifying potential therapeutic approaches to different clinical populations of schizophrenics, and the development of new approaches for examining the neurochemical and neuropathological basis of other neurological and neuropsychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29MH043852-01
Application #
3474920
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1988-05-01
Project End
1993-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Neal-Beliveau, B S; Joyce, J N (1998) Behavioral responsitivity to dopamine receptor agonists after extensive striatal dopamine lesions during development. Dev Psychobiol 32:313-26
Gurevich, E V; Bordelon, Y; Shapiro, R M et al. (1997) Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch Gen Psychiatry 54:225-32
Rioux, L; Frohna, P A; Joyce, J N et al. (1997) The effects of chronic levodopa treatment on pre- and postsynaptic markers of dopaminergic function in striatum of parkinsonian monkeys. Mov Disord 12:148-58
Gurevich, E V; Kordower, J; Joyce, J N (1997) Dopamine D2 receptor mRNA is expressed in maturing neurons of the human hippocampal and subicular fields. Neuroreport 8:3605-10
Goldsmith, S K; Joyce, J N (1996) Dopamine D2 receptors are organized in bands in normal human temporal cortex. Neuroscience 74:435-51
Gurevich, E V; Joyce, J N (1996) Comparison of [3H]paroxetine and [3H]cyanoimipramine for quantitative measurement of serotonin transporter sites in human brain. Neuropsychopharmacology 14:309-23
Goldsmith, S K; Joyce, J N (1995) Alterations in hippocampal mossy fiber pathway in schizophrenia and Alzheimer's disease. Biol Psychiatry 37:122-6
Frohna, P A; Rothblat, D S; Joyce, J N et al. (1995) Alterations in dopamine uptake sites and D1 and D2 receptors in cats symptomatic for and recovered from experimental parkinsonism. Synapse 19:46-55
Murray, A M; Weihmueller, F B; Marshall, J F et al. (1995) Damage to dopamine systems differs between Parkinson's disease and Alzheimer's disease with parkinsonism. Ann Neurol 37:300-12
Goldsmith, S K; Joyce, J N (1994) Dopamine D2 receptor expression in hippocampus and parahippocampal cortex of rat, cat, and human in relation to tyrosine hydroxylase-immunoreactive fibers. Hippocampus 4:354-73

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