Characterization of normal and supersensitive dopamine receptors: Effects of ergot drugs and neuropeptides

Abstract

Dopamine receptors have been characterized by the use of radiolabelled dopamine agonists and antagonists. Using ibotenic acid induced lesions of the striatum, evidence was obtained that³H-N-propylnorapomorphine (³H-NPA) binding sites and³H-bromocriptine binding sites are located both on intrastriatal nerve cells and on extrinsic nerve terminals probably mainly originating in the cerebral cortex. Development of dopamine receptor super-sensitivity as evaluated in 6-hydroxydopamine lesioned rats was associated with an 50% increase in the number of³H-NPA binding sites in the striatum. Furthermore, one year following the 6-hydroxydopamine induced lesion of the dopamine pathways two binding sites for³H-NPA could be demonstrated in the striatum. However, at this time interval the total number of³H-NPA binding sites was not increased. The functional significance of these two binding sites for³H-NPA in the striatum is unknown, but they are probably coupled to the biological effector in view of the marked behavioural supersensitivity demonstrated in these old animals. The dopamine receptor agonists and especially the dopaminergic ergot derivatives have been characterized by studying their affinities for³H-bromocriptine,³H-spiperone,³H-ADTN and³H-NPA binding sitesin vitro. It is suggested that the K_i ratios for agonist and antagonist radioligands may be one useful way to characterize the agonist-antagonist character of the drug. Another important method is to study the effects of dopamine receptor agonists on the specificin vivo binding of³H-spiperone and³H-NPA. The correlation analysis of DA agonist affinities for the four radioligands of DA receptors used in the present study give evidence for the existence of at least 3 types of DA receptors. Actions of dopaminergic ergot drugs have been evaluated at supersensitive dopamine receptors. The findings suggest that the shift to the left of the threshold dose to activate supersensitive dopamine receptors could be due to a lowering of the stereoselectivity of agonist interaction at the dopamine agonist sites of supersensitive dopamine receptors. Such a change may explain the highly preferential action of CF 25-397 at supersensitive dopamine receptors, since its affinity for³H-NPA binding sites was not increased in the present experiments. In agreement with previous work, evidence have also been presented that prolonged treatment with a potent dopaminergic drug, pergolide, can produce a down regulation of normal dopamine receptors by reducing the density of such receptors. Evidence has also been presented that CCK-8 and the desulphated CCK-8 (10⁻⁶ M) canin vitro reduce the number of³H-NPA binding sites in the striatum. These results indicate that cholecystokinin peptides via activation of cholecystokinin receptors can regulate the movements of the³H-NPA binding sites across the plane of the membrane in such a way as to make them less available to the external surface of the membrane. Thus, cholecystokinin peptides and other neuropeptides may represent important neuromodulators and trophic factors in the dopamine synapses of the brain.