CHRONIC ETICLOPRIDE AND DOPAMINE DENERVATION INDUCE EQUAL NONADDITIVE INCREASES IN STRIATAL D2-RECEPTOR DENSITY - AUTORADIOGRAPHIC EVIDENCE AGAINST THE DUAL MECHANISM HYPOTHESIS

In an attempt to resolve experimental discrepancies regarding the mode of action of D2 receptor regulation following denervation or chronic receptor blockade, rats with extensive unilateral destruction of the mesotelencephalic dopaminergic projections induced by intracerebral 6-hydroxydopamine were injected daily for 21 days with either saline or the potent, selective D2 antagonist eticlopride (0.5 mg/kg, i.p.). Four days after the last injection of eticlopride or saline, rats were killed, and brain sections through the caudate-putamen and nucleus accumbens septi were incubated with [H-3]spiroperidol or (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol ([H-3]SCH 23390) to assay D2 and D1 receptors, respectively. Autoradiographic analysis revealed that chronic eticlopride treatment increased the density of D2 sites in the intact hemisphere for all regions examined without further augmenting the already increased density of D2 receptors seen in the dopamine-denervated hemisphere. D2 receptor density was independent of functional sensitivity as evidenced by the fact that rats treated chronically with eticlopride rotated contralateral to the 6-hydroxydopamine lesion following systemic administration of the selective D2 agonist quinpirole during the neuroleptic wash-out period, despite the fact that D2 receptor binding was not significantly different in the left and right hemispheres of these subjects. D1 receptor density was not affected by eticlopride treatment but was significantly reduced in the dopamine-denervated hemisphere. [H-3]Mazindol labeling of high-affinity DA uptake sites indicated that the extent of dopamine denervation was greater than 97% in both saline- and eticlopride-treated rats. These findings are consistent with the view that chronic D2 receptor blockade and dopamine denervation increase D2 receptor density via a single, common mechanism. Data from other laboratories, in which additive effects of denervation and chronic antagonist treatment have been reported, may have resulted from incomplete denervation. Experimental discrepancies may also be due to differing means by which the mesotelencephalic dopaminergic neurons are injured.