Non-specific supersensitivity of striatal dopamine receptors after 6-hydroxydopamine lesion of the nigrostriatal pathway

Abstract

6-Hydroxydopamine (6-OHDA) was injected unilaterally into the area of the ascending dopamine pathways in the lateral hypothalamus. Rats immediately developed spontaneous ipsilateral circling which was enhanced by d-amphetamine (0.63-2.5 mg/kg i.p.) and reversed to a contralateral response by apomorphine (0.015-0.5 mg/kg s.c.). These effects were maximal by the 8th postoperative day. At a time when circling responses were established and biochemical determinations showed striatal dopamine levels to be reduced by at least 80% (limbic dopamine depleted by 60%, telencephalic noradrenaline by 35% but no reductions in 5-hydroxytryptamine), the injection of dopamine (50, 100 mug) and apomorphine (12.5, 25 mug) into the striatum ipsilateral to the 6-OHDA lesion induced contralateral circling/asymmetries. These effects were of lower intensity or absent in non-lesioned rats but a consistent increase in potency of dopamine after 6-OHDA could not be demonstrated. However, similar injections of 5-hydroxytryptamine and noradrenaline, which are completely inactive in normal rats, caused more marked contralateral asymmetries/circling at lower intrastriatal doses than dopamine (5-hydroxytryptamine 25-100 mug, noradrenaline 6.25-100 mug). Dyskinesias of the contralateral forelimb were induced by unilateral intrastriatal dopamine (100 mug) in a small proportion of non-lesioned rats: the effects were enhanced when dopamine (50-100 mug) was injected into the striatum ipsilateral to a 6-OHDA lesion. Both potency and intensity of effect were enhanced. Noradrenaline (25-100 mug) also induced contralateral dyskinesias in the 6-OHDA-lesioned rats although similar injections were inactive in non-lesioned rats. 5-Hydroxytryptamine was inactive in this effect in both groups of rats. It is suggested that after 6-OHDA lesion of the nigrostriatal pathway striatal dopamine receptors may change both their sensitivity and specificity.