The research in this proposal will elucidate mechanisms underlying changes that occur in the functional properties of neurons due to the process of aging. Experiments will focus on a part of the basal ganglia, the neostriatum, because this area of the brain is involved in pathological conditions associated with aging. In the first two specific aims of this proposal, the nature and time-course of the age-related changes in the responses of neostriatal neurons to application of excitatory amino acid neurotransmitters, some of their receptor agonists and dopamine will be assessed. Experiments will concentrate on determining how the ability of dopamine to modulate the actions of excitatory amino acid neurotransmitter systems is affected by aging. These neurophysiological studies will be performed using the in vitro neostriatal brain slice preparation in rats. Intracellular recording techniques have been used to ascertain how the basic passive and active membrane properties of neostriatal cells and their responses to activation of local synaptic inputs are altered by the aging process. In the proposed studies, experiments will compare how these electrophysiological properties are affected by application of amino acids and dopamine in young (3 months), middle-aged (12 months) and aged (>24 months) rats. In the third specific aim, morphological methods will be used to assess the arrangement of afferents containing glutamate and dopamine markers in the neostriatum. These studies will determine the age-related changes in the relationships between glutamate and dopamine containing terminals contacting physiologically identified neostriatal neurons. A second morphological experiment will assess, at cellular and subcellular levels, age-induced changes in expression of D2 dopamine receptors using antibodies directed against peptide fragments of the receptor protein. Together, the proposed studies will indicate at a functional cellular level, how neurotransmitter action is altered during aging and how these changes relate to morphological alterations. The information obtained from these studies is important because pathologies of the neostriatum are involved in age-related neurological disorders exemplified by Parkinson's Disease and Huntington's Disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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University of California Los Angeles
Other Domestic Higher Education
Los Angeles
United States
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Crawford, C A; Levine, M S (1997) Dopaminergic function in the neostriatum and nucleus accumbens of young and aged Fischer 344 rats. Neurobiol Aging 18:57-66
Colwell, C S; Levine, M S (1997) Histamine modulates NMDA-dependent swelling in the neostriatum. Brain Res 766:205-12
Cepeda, C; Li, Z; Levine, M S (1996) Aging reduces neostriatal responsiveness to N-methyl-D-aspartate and dopamine: an in vitro electrophysiological study. Neuroscience 73:733-50
Altemus, K L; Levine, M S (1996) Potassium channel blockade does not alter the modulatory effects of dopamine in neostriatal slices. Brain Res 718:212-6
Colwell, C S; Levine, M S (1996) Glutamate receptor-induced toxicity in neostriatal cells. Brain Res 724:205-12
Levine, M S; Altemus, K L; Cepeda, C et al. (1996) Modulatory actions of dopamine on NMDA receptor-mediated responses are reduced in D1A-deficient mutant mice. J Neurosci 16:5870-82
Colwell, C S; Altemus, K L; Cepeda, C et al. (1996) Regulation of N-methyl-D-aspartate-induced toxicity in the neostriatum: a role for metabotropic glutamate receptors? Proc Natl Acad Sci U S A 93:1200-4
Colwell, C S; Altemus, K L; Levine, M S (1996) Metabotropic glutamate receptor activation selectively limits excitotoxic damage in the intact neostriatum. Brain Res 726:223-6
Levine, M S; Li, Z; Cepeda, C et al. (1996) Neuromodulatory actions of dopamine on synaptically-evoked neostriatal responses in slices. Synapse 24:65-78
Cromwell, H C; Levine, M S (1996) Neocortical damage alters synaptic responses of neostriatal neurons in vitro. Neuroscience 75:361-72

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