Opioid receptor-binding autoradiography was used as a way to map sites of altered
opioid transmission in a rat model of
l-DOPA-induced
dyskinesia. Rats with unilateral
6-hydroxydopamine lesions of the nigrostriatal pathways sustained a 3-week treatment with
l-DOPA (6 mg/kg/day, combined with 12 mg/kg/day
benserazide), causing about half of them to develop dyskinetic-like movements on the side of the body contralateral to the lesion. Autoradiographic analysis of mu-, delta-, and kappa-
opioid binding sites was carried out in the caudate-putamen (CPu), the globus pallidus (GP), the substantia nigra (SN), the primary motor area, and the premotor-cingulate cortex. The
dopamine-denervating lesion alone caused an ipsilateral reduction in
opioid radioligand binding in the CPu, GP, and SN, but not in the cerebral cortex. Chronic
l-DOPA treatment affected
opioid receptor binding in both the basal ganglia and the cerebral cortex, producing changes that were both structure- and receptor-type specific, and closely related to the motor response elicited by the treatment. In the basal ganglia, the most clear-cut differences between dyskinetic and nondyskinetic rats pertained to kappa
opioid sites. On the lesioned side, both striatal and nigral levels of kappa binding densities were significantly lower in the dyskinetic group, showing a negative correlation with the rats'
dyskinesia scores on one hand and with the striatal expression of
opioid precursor mRNAs on the other hand. In the cerebral cortex, levels of mu and delta binding site densities were bilaterally elevated in the dyskinetic group, whereas kappa radioligand binding was specifically increased in the nondyskinetic cases and showed a negative correlation with the rats'
dyskinesia scores. These data demonstrate that bilateral changes in cortical
opioid transmission are closely associated with
l-DOPA-induced
dyskinesia in the rat. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in
opioid radioligand binding suggests that the motor response to
l-DOPA is determined, at least in part, by compensatory adjustments of brain
opioid receptors.