DEFECTS IN DOPAMINERGIC PATHWAY AFFECT CONTRACTILITY OF COLON FROM HYPOXANTHINE-GUANINE PHOSPHORIBOSYLTRANSFERASE (HPRT) KNOCKOUT MICE.

Abstract

Lesch-Nyhan disease is an X-linked neurobehavioral and metabolic disorder caused by lack of hypoxanthine phosphoribosyltransferase (HPRT), a housekeeping enzyme responsible for recycling purines. The mechanisms underlying the neuropathology are not well understood, but the main neurochemical defect, in central nervous system, is linked to a dysfunction of dopaminergic pathway. In the enteric nervous system the dopaminergic nerves are a subset neurons of regulating gut motility, thus we investigated possible changes in colonic motility of HPRT ¯mice related to the dopaminergic control. We evaluated, in vitro, the mechanical activity of circular muscle strips from wild type and HPRT – mouse colon, and by Western blotting analysis, the expression of D1 receptors, dopamine transporter and tyrosine hydroxylase. Dopamine (DA) induced a reduction of the spontaneous and neural-evoked cholinergic contraction amplitude, being less effective in HPRT- mice. SCH-23390, D1 receptor antagonist, reduced DA inhibitory effects in both preparations, whilst sulpiride, D2 receptor antagonist, had no effect. SCH-23390 enhanced significantly basal tone, amplitude of spontaneous and the neural-evoked cholinergic contractions in wild type, but not in HPRT- mice, where just a slight increase of the neural cholinergic contraction amplitude was observed. Western blotting analysis showed a reduced expression of D1 receptors in HPRT- mice. Our results point out, in HPRT- mouse colon, a significant reduction in the DA effects and in the role of dopaminergic receptor that can affect colonic motility.