Functional analysis of brain dopamine systems in a genetic mouse model of Lesch-Nyhan syndrome

The Lesch-Nyhan syndrome is a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disorder is characterized by prominent neurobehavioral abnormalities which appear to result in part from dysfunction of striatal dopamine systems. HPRT-deficient (HPRT-) mutant strains of mice have been produced as animal models for this syndrome, but these animals exhibit none of the neurobehavioral abnormalities seen in Lesch-Nyhan patients. The present studies describe the behavioral responses of three strains of mice carrying one of two mutations in the HPRT gene to agents which interact with brain dopamine systems. HPRT- mice are more sensitive than age- and sex-matched littermates to the motor-activating properties of dopamine-releasing agents (amphetamine, amfonelic acid and methylphenidate), but not dopamine uptake inhibitors (GBR 12909 and nomifensine). The enhanced sensitivity of the HPRT- mice to the dopamine-releasing agents is not caused by dopamine receptor supersensitivity, because the HPRT- mice do not show enhanced motor responses to the direct D1/D2 dopamine receptor agonist apomorphine or to the selective D1 dopamine receptor agonist SKF 38393. The function of regulatory dopamine autoreceptors, as assessed by suppression of spontaneous motor activity by low doses of R(-)-propylnorapomorphine, also appears normal in the HPRT- mice. Biochemical analysis shows that the HPRT- mice have significantly lower levels of dopamine (-45%), but normal levels of tyrosine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 3-methoxytyramine in the caudoputamen. In contrast to the deficit in caudoputamen dopamine, no deficits were noted in the accumbens of the HPRT- mice. These results indicate the existence of an inherent abnormality in the dopamine systems in the brains of HPRT- mice, despite their apparently normal spontaneous behavior.