Recent developments indicate that cell bodies in the caudate nucleus that synthesize prodynorphin peptides form a substantial projection to the substantia nigra. The presence of a projection system originating in the basal ganglia suggests that prodynorphin peptides might be involved in extrapyramidal motor function. The demonstration of motor effects after substantia nigra microinjections also supports a role of these peptides in the generation or patterning of movement. To determine the role of prodynorphin products in this pathway, we propose to carry out electrophysiological and behavioral studies in rats. In particular, we will identify the types of cells (output cells, dopamine cells, etc.) in the substantia nigra that are affected by iontophoretic application of the various products of prodynorphin. We will also use electrical stimulation combined with recording methods to determine the sites of action of the endogenously-released peptides. Additionally, we will conduct behavioral studies to verify the electrophysiology and to more directly observe the functional properties of this family of neurotransmitters in the subtantia nigra. The systems under investigation are of particular importance in the field of neurology. Pathology of the extrapyramidal motor system is a crucial factor in diseases such as Parkinson's disease and Huntington's chorea. The substantia nigram, a target of the proposed research, is of particular relevance in Parkinson's disease since marked pathology occurs in this nucleus. Therefore, a delineation of the actions of neurotransmitters active in this system might lead to rational therapies for a number of extrapyramidal disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS021745-01A1
Application #
3403255
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Arts and Sciences
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
Thompson, L A; Walker, J M (1990) Inhibitory effects of the kappa opiate U50,488 in the substantia nigra pars reticulata. Brain Res 517:81-7
Walker, J M; Bowen, W D; Thompson, L A et al. (1988) Distribution of opiate receptors within visual structures of the cat brain. Exp Brain Res 73:523-32
Bowen, W D; Walker, J M; Yashar, A G et al. (1988) Altered haloperidol-sensitive sigma receptors in the genetically dystonic (dt) rat. Eur J Pharmacol 147:153-4
Matsumoto, R R; Brinsfield, K H; Patrick, R L et al. (1988) Rotational behavior mediated by dopaminergic and nondopaminergic mechanisms after intranigral microinjection of specific mu, delta and kappa opioid agonists. J Pharmacol Exp Ther 246:196-203
Walker, J M; Matsumoto, R R; Bowen, W D et al. (1988) Evidence for a role of haloperidol-sensitive sigma-'opiate' receptors in the motor effects of antipsychotic drugs. Neurology 38:961-5
Matsumoto, R R; Lohof, A M; Patrick, R L et al. (1988) Dopamine-independent motor behavior following microinjection of rimorphin in the substantia nigra. Brain Res 444:67-74
Matsumoto, R R; Walker, J M (1988) Inhibition of rubral neurons by a specific ligand for sigma receptors. Eur J Pharmacol 158:161-5
Walker, J M; Ghessari, A; Peters, B A et al. (1987) Functional aspects of multitransmitter neurons. Studies of interactions among pro-opiomelanocortin products. Pain Headache 9:160-77
Walker, J M; Coy, D H; Young, E A et al. (1987) [D-Ala2, (F5) Phe4]-dynorphin 1-13-NH2 (DAFPHEDYN): a potent analog of dynorphin 1-13. Peptides 8:811-7
Walker, J M; Bowen, W D; Atkins, S T et al. (1987) Mu-opiate binding and morphine antagonism by octapeptide analogs of somatostatin. Peptides 8:869-75

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