The Lesch-Nyhan syndrome (LNS) is characterized by a deficiency of the enzyme, HGPRT, motor dysfunction, mental retardation, hyperuricemia, self-mutilation behavior (SMB) and a loss of dopaminergic neurons. In rats, neonatal destruction of dopaminergic neurons with 6-hydroxy-dopamine (6-OHDA) increases susceptibility for SMB when D-1 dopamine receptors are activated, suggesting that neonatal-6-OHDA treatment is a model of the central dopamine deficiency of LNS. The present grant explores how this enzyme and altered purine mechanisms may interact with dopaminergic function. We plan to determine the relative amount of HGPRT in dopamine-containing (or other) neurons by measuring HGPRT activity after neurotoxin treatment. We will also determine if purine compounds, which accumulate in LNS, influence the function of dopaminergic neurons in developing rats. Recent studies have revealed that an adenosine agonist, NECA, will antagonize SMB produced by the dopamine agonist, L-DOPA, after 6-OHDA treatment. Therefore, the ability of relatively specific adenosine agonists to block L-DOPA-induced behaviors as well as those produced by D-1 and D-2 dopamine receptor agonists will be investigated. We will explore if antagonism of adenosine receptors will produce SMB in neonatally-6-OHDA-treated rats or increase the effectiveness of dopamine agonists to induce this and other behaviors. In vitro experiments are proposed in 6-OHDA-lesioned rats to measure striatal adenosine receptor characteristics and the ability of adenosine agonists to interact with D-1 dopamine agonist activation of striatal adenylate cyclase. Possible involvement of GTP in the supersensitivity of D-1 dopamine receptors in neo-natally-6-OHDA-treated rats will also be examined. Electrophysiological studies are planned to characterize interactions of adenosine and a selected dopamine agonist at the cellular level in striatum of control and lesioned animals. This multidisciplinary evaluation of dopamine-purine interactions should allow us: (1) to assess if HGPRT is contained in dopaminergic neurons and if purine compounds influence development of dopaminergic neurons; (2) to determine if 6-OHDA treatment alters adenosine receptors, their function, or action of GTP on adenylate cyclase activity; and (3) to define how alterations in an adenosine receptor subtype will influence specific dopamine receptor subtype mediated responses. Data collected in these three areas will increase our basic understanding of purine-dopamine interactions and could provide new strategies for treating SMB and other symptoms in LNS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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University of North Carolina Chapel Hill
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Chapel Hill
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