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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021345-03
Application #
3402410
Study Section
Neurology A Study Section (NEUA)
Project Start
1986-09-01
Project End
1991-03-31
Budget Start
1988-09-01
Budget End
1991-03-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Breese, G R; Criswell, H E; Johnson, K B et al. (1994) Neonatal destruction of dopaminergic neurons. Neurotoxicology 15:149-59
Simson, P E; Johnson, K B; Jurevics, H A et al. (1992) Augmented sensitivity of D1-dopamine receptors in lateral but not medial striatum after 6-hydroxydopamine-induced lesions in the neonatal rat. J Pharmacol Exp Ther 263:1454-63
Johnson, K B; Criswell, H E; Jensen, K F et al. (1992) Comparison of the D1-dopamine agonists SKF-38393 and A-68930 in neonatal 6-hydroxydopamine-lesioned rats: behavioral effects and induction of c-fos-like immunoreactivity. J Pharmacol Exp Ther 262:855-65
Fremeau Jr, R T; Duncan, G E; Fornaretto, M G et al. (1991) Localization of D1 dopamine receptor mRNA in brain supports a role in cognitive, affective, and neuroendocrine aspects of dopaminergic neurotransmission. Proc Natl Acad Sci U S A 88:3772-6
Breese, G R; Criswell, H E; Duncan, G E et al. (1990) A dopamine deficiency model of Lesch-Nyhan disease--the neonatal-6-OHDA-lesioned rat. Brain Res Bull 25:477-84
Givens, B S; Breese, G R (1990) Site-specific enhancement of gamma-aminobutyric acid-mediated inhibition of neural activity by ethanol in the rat medial septal area. J Pharmacol Exp Ther 254:528-38
Criswell, H E; Mueller, R A; Breese, G R (1990) Long-term D1-dopamine receptor sensitization in neonatal 6-OHDA-lesioned rats is blocked by an NMDA antagonist. Brain Res 512:284-90
Mueller, R A; McCown, T J; Hunt, R D et al. (1990) Opposite alterations in cerebrospinal fluid uridine after severe cerebral ischemia or intrathecal blood injection. Cell Mol Neurobiol 10:327-36
Breese, G R; Criswell, H E; McQuade, R D et al. (1990) Pharmacological evaluation of SCH-12679: evidence for an in vivo antagonism of D1-dopamine receptors. J Pharmacol Exp Ther 252:558-67
Givens, B S; Breese, G R (1990) Electrophysiological evidence that ethanol alters function of medial septal area without affecting lateral septal function. J Pharmacol Exp Ther 253:95-103

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