Dopamine Receptor Upregulation in Lesch-Nyhan Syndrome: A Postmortem Study

Abstract

The brains of two patients with Lesch-Nyhan syndrome (LNS) were studied. The concentration of dopamine was decreased in the caudate nucleus of LNS patients. Immunohistochemical methods revealed that the dopamine (DA) D1 and D2 receptor and methionine-enkephalin immunoreactivities (IRs) were increased in the putamen, and less significantly in the caudate nucleus. The D1 and D2 receptor IRs of the cingulate cortex, the tryptophan-hydroxylase IR in the dorsal nucleus of the midbrain, as well as the substance P and methionine-enkephalin IRs of the nociception-conducting structures, including the periaqueductal gray and spinal trigeminal nucleus, were not changed. Tyrosine-hydroxylase IR was not decreased in the substantia nigra of the LNS patients. Therefore, the cause of the decreased dopaminergic activity in LNS may not be involved in the production of tyrosine hydroxylase in the substantia nigra. Developmental abnormalities due to the DA defect at an early age might exist in the postsynaptic structure in the striatum.

Disappearance of self-mutilation in a patient with Lesch—Nyhan syndrome after bilateral chronic stimulation of the globus pallidus internus

“…Neurochemical studies have demonstrated 60 to 90% reductions in the dopamine content of the basal ganglia in LNS, 2,6,17 and such dopaminergic denervation may cause self-mutilation. 13,14 The upregulation of the striatal dopamine receptor has been shown by immunohistochemical studies 13,14 performed in LNS, and is similar to findings in PD. 3,7 The age at which dopaminergic neurons are disrupted may explain the differing symptoms observed in PD and LNS.…”

“…There are several hypotheses about the mechanisms of self-destructive behavior in LNS, 11,12,15 although they all remain no more than speculation and may be contradictory. 13 Saito and Takashima 14 reported that the pathophysiological findings for the neurobehavioral features of LNS are similar to those for levodopainduced dyskinesias in PD. Neurochemical studies have demonstrated 60 to 90% reductions in the dopamine content of the basal ganglia in LNS, 2,6,17 and such dopaminergic denervation may cause self-mutilation.…”

Lesch-Nyhan disease: from mechanism to model and back again

“…The dopamine neurons of this brain region in particular seem to be adversely affected by the deficiency in HPRT. Neurochemical studies in autopsied LND brains reveal a 60-80% loss of dopamine in the basal ganglia (Lloyd et al, 1981;Saito et al, 1999). Neuroimaging studies of affected patients reveal similar reductions in other markers of dopamine neurons in the same region (Ernst et al, 1996;Wong et al, 1996).…”

Lesch-Nyhan Syndrome: Models, Theories, and Therapies

“…Animal studies using dopamine antagonists were able to attenuate self-injury in multiple animal models of self-harm, including 6-OHDA-lesioned rats and unilateral ventromedial tegmental lesions in monkey models [Goldstein et al, 1986;Duncan et al, 1987;Criswell et al, 1989;Allen et al, 1998;Moy et al, 2001Moy et al, , 2004. Further, postmortem brains of LNS patients show increases in dopamine receptors [Saito et al, 1999], and HPRT-deficient mice are hypersensitive to dopamine-releasing agents [Jinnah et al, 1991[Jinnah et al, , 1992.…”