Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions

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Abstract
The relative roles of D1 and D2 dopamine receptor stimulation in mediating the antiparkinsonian effects of dopaminergic drugs remain unclear. To determine the functional metabolic consequences of selective dopamine receptor stimulation, we used 2-deoxyglucose (2-DG) autoradiography to examine the effects of the D1 agonist SKF-38393 and the D2 agonist LY-171555 on regional cerebral glucose utilization (RCGU) in rats with unilateral 6-hydroxydopamine (6-OHDA) substantia nigra lesions. SKF-38393 (0.5-25.0 mg/kg) and LY-171555 (0.01-5.0 mg/kg) produced indistinguishable behavioral responses, including vigorous contralateral rotation. Treatment with each drug similarly increased glucose utilization, dose-dependently, in the parafascicular thalamus, subthalamic nucleus, deep layers of the superior colliculus, and lateral midbrain reticular formation ipsilateral to the nigral lesion; glucose utilization was decreased in the ipsilateral lateral habenula. By contrast, the D1 and D2 agonists differentially altered glucose utilization in the entopeduncular nucleus (EP) and the substantia nigra pars reticulata (SNr). SKF-38393, 5.0 and 25.0 mg/kg, increased glucose utilization 127 and 275%, respectively, in the pars reticulata ipsilateral to the lesion. LY-171555, 1.0 and 5.0 mg/kg, caused maximal contralateral turning, yet did not alter glucose utilization in the ipsilateral SNr. The glucose utilization response of the ipsilateral EP paralleled that of the SNr demonstrating large increases following administration in SKF-38393 and minimal change following the use of LY-171555. The results demonstrate that the selective D1 agonist reproduces the marked glucose utilization increases (2-3-fold above control values) in the EP and SNr that were previously observed using L-DOPA and apomorphine in this model, whereas the selective D2 agonist does not. Because both nuclei are selectively rich in D1 receptors, with D1:D2 ratios of 20-30:1, the data suggest that the glucose utilization increases observed with L-DOPA result, at least in part, from a direct stimulation of D1 receptors in these nuclei and do not reflect an exclusive drug effect on striatal dopamine receptors. Given the magnitude of the glucose utilization response, the findings suggest that D1 receptors in the EP and SN, become functionally supersensitive following 6-OHDA substantia nigra lesion. The ability of selective D1 and D2 agonists to differentially regulate metabolic activity in these 2 major basal ganglia output nuclei may be of physiologic and therapeutic significance.