Effects of alpha-2 adrenoceptor agonists and antagonists on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway

The present study examined the influence of alpha-2 adrenoceptor ligands on circling behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway. The alpha-2 adrenoceptor agonists, clonidine and UK 14304, inhibited both the ipsilateral rotation induced by the indirect dopaminergic agonist, methylphenidate, and the contralateral circling induced by the direct dopaminergic agonist, apomorphine. In contrast, the alpha-2 adrenoceptor antagonists, idazoxan and (+/-)-efaroxan, enhanced the circling induced by either methylphenidate or apomorphine. The facilitating activity of efaroxan was stereoselective because the (+)-enantiomer mimicked the effect of (+/-)-efaroxan, whereas the (-)-enantiomer was essentially inactive, thus indicating a mediation by alpha-2 adrenoceptors. Upon administration alone, the above-mentioned compounds did not modify spontaneous circling behavior, except for UK 14304, which decreased, and (+)-efaroxan, which slightly increased, the ipsilateral rotation. We conclude that activation and antagonism of alpha-2 adrenoceptors inhibit and enhance, respectively, the circling behavior evoked by both direct and indirect dopaminergic agonists. Although a modulation of dopamine release may be involved in some of these drug effects, the effects on apomorphine-induced circling indicate an influence of alpha-2 adrenoceptor compounds on nigrostriatal neurotransmission at sites downstream from the dopaminergic neurons themselves. These findings support the notion of a potential benefit of alpha-2 adrenoceptor antagonists in the treatment of Parkinson's disease.