INTERHEMISPHERIC MODULATION OF DOPAMINE-RECEPTOR INTERACTIONS IN UNILATERAL 6-OHDA RODENT MODEL

A critical assumption in the unilateral B-hydroxydopamine (6-OHDA) mod el is that interactions between the intact and denervated hemispheres do not influence the response to insult. The present study examined th is issue by assessing the effects of unilateral substantia nigra 6-OHD A lesions in rats that previously had received corpus callosum transec tions, a treatment designed to minimize interhemispheric influences. Q uantitative autoradiography in the caudate-putamen ipsilateral to the lesion revealed that corpus callosum transection did not alter the inc rease in D-2-like receptors ([I-125]-epidepride-labeled sites) that is induced by unilateral 6-OHDA lesion. There were no effects of either 6-OHDA lesion or transection on D-1 receptor density ([I-125]-SCH23982 autoradiography). As a functional endpoint, dopamine-stimulated cAMP efflux was measured in superfused striatal slices. In this paradigm, t he net effect of dopamine (DA) represents a combination of D-1 recepto r-mediated stimulation and D-2 receptor-mediated inhibition. 6-OHDA le sion increased cAMP efflux induced by exposure to 100 mu M DA alone; c orpus callosum transection did not alter this effect. An interaction b etween 6-OHDA lesion and transection status was revealed, however, by comparison of results obtained with DA alone vs. DA plus the D-2 antag onist sulpiride (to block the D-2 inhibitory effects of 100 mu M DA). This comparison revealed two important effects of 6-OHDA lesion in rat s with an intact corpus callosum: 1) a moderate decrease in dopamine D 1 receptor-mediated stimulation; and 2) a dramatic decrease in the abi lity of D-2 receptors to inhibit this stimulation. Corpus callosum tra nsection prevented these effects of 6-OHDA. These results provide a bi ochemical demonstration of D-1:D-2 receptor uncoupling in unilateral 6 -OHDA lesioned rats, and suggest that interhemispheric influences (e.g ., contralateral cortico-striatal glutamatergic projections) may contr ibute to lesion-induced alterations in D-1:D-2 receptor interactions. (C) 1995 Wiley-Liss, Inc.