Dopamine agonist induced self-multilative biting behavior in monkeys with unilateral ventromedial tegmental lesions of the brainstem: Possible pharmacological model for Lesch-Nyhan syndrome

Abstract

We have investigated the effects of various dopamine (DA) agonists on induction of abnormal involuntary movements (AIM) in a group of monkeys which had denervated nigro-striatal DA neurons for 10–14 years rendered by a unilateral surgical ventromedial tegmental (VMT) lesion of the brainstem. The surgical lesions were placed when the monkeys were 2–4 years old. The administration of mixed DA agonists, such as l-DOPA, apomorphine (Apo) and abeorphine 201–678, elicit a self-multilative biting behavior (SMB) of the forelimb digits contralateral to the lesion, and spasticity of the contralateral hindlimb. These dysfunctions resemble, in some aspects, the neurological disturbances associated with Lesch-Nyhan syndrome. The SMB behavior was elicited by mixed DA agonists which predominantly stimulate D 1, but not D 2 DA receptors, and was prevented or abolished by the D 1 DA antagonist SCH 23390 or by the D 1 and D 2 DA antagonist fluphenazine (Flu), but not by the D 2 antagonist (±)sulpiride. These results suggest that DA agonist-induced SMB behavior is mediated by D 1 and/or by both D 1 and D 2 DA receptor pathways. To study the relationships between HPRT, the defective enzyme in Lesch-Nyhan syndrome, and the DA neuronal systems, we have measured the effects of nigro-striatal DA degeneration and intrastriatal neuronal degeneration on HPRT activity. The unilateral 6-OHDA-induced nigro-striatal DA degeneration does not significantly alter the HPRT activity on the lesioned side of the striatum, while the quinolinic acid-induced intrastriatal neuronal degeneration significantly reduces the enzyme activity. These results suggest that HPRT is localized on intrastriatal neurons which are also known to contain DA receptors. It is postulated that HPRT deficiency in Lesch-Nyhan syndrome results in abnormal guanine nucleotide metabolism which may affect the regulation of DA receptors.