Non-additivity of D2 receptor proliferation induced by dopamine denervation and chronic selective antagonist administration: evidence from quantitative autoradiography indicates a single mechanism of action.
Experiments were conducted to investigate whether chronic dopamine (DA) D2 receptor blockade and DA denervation exert additive effects on striatal D2 receptor density. We employed for the first time chronic treatment with a pure D2 antagonist, metoclopramide, and measured regional striatal DA receptor binding with quantitative receptor autoradiography. Rats with extensive unilateral DA denervation induced by intracerebral 6-hydroxydopamine (6-OHDA) were injected daily for 21 days with either metoclopramide (30 mg/kg i.p.) or saline. Following a 72-h drug wash-out period, rats were sacrificed and brain sections through the caudate-putamen and nucleus accumbens were incubated with [3H]spiroperidol or [3H]SCH 23390 to assay D2 and D1 receptors, respectively. Autoradiographic analysis revealed that chronic metoclopramide 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 6-OHDA-treated hemisphere. In addition, chronic metoclopramide and 6-OHDA treatment by themselves exhibited remarkably parallel anterior-posterior gradients in their effects on D2 receptor density. D1 receptor density was not affected by metoclopramide treatment but was slightly reduced in the DA-denervated hemisphere. [3H]Mazindol labelling of high-affinity DA uptake sites indicated that the extent of DA denervation was greater than 98% in both saline- and metoclopramide-treated rats. These findings are consistent with the view that chronic D2 receptor blockade and DA denervation act via a single, common mechanism to increase D2 receptor density. Work from other laboratories, in which additive effects of denervation and chronic neuroleptic treatment have been purported, may have resulted from incomplete denervation. Experimental discrepancies may also be due to differing means by which the mesotelencephalic dopaminergic neurons are injured.
LaHoste
G J
GJ
Department of Psychobiology, University of California, Irvine 92717.
Marshall
J F
JF
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D018492:Dopamine Antagonists; D006892:Hydroxydopamines; D008297:Male; D008454:Mazindol / Q000378:metabolism; D008787:Metoclopramide / Q000494:pharmacology*; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2
D018492:Dopamine Antagonists; D006892:Hydroxydopamines; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D016627:Oxidopamine; D008454:Mazindol; D008787:Metoclopramide; D004298:Dopamine