Selection of dopamine antagonists discriminating various behavioral responses and radioligand binding sites.
In order to document the hypothesis that antipsychotics may interact with more than one class of cerebral dopamine receptors, the relative potencies of a series of compounds were compared in three behavioral tests and in binding studies with two radioligands. Apomorphine (0.6 mg/kg) simultaneously elicited in rat two kinds of facial stereotypies (sniffing and licking) and a stereotyped climbing behavior, allowing to compare in the same animals the relative potencies of various antipsychotics against the three behaviors. Only some substituted benzamides (Sulpiride, LUR 2366 and DAN 2163) antagonised at significantly lower dosages climbing than sniffing (or licking). The possibility that this discriminant potency might be related to a distinct affinity for two classes of dopamine receptors was investigated by binding studies on striatal membranes with 3H-apomorphine and 3H-domperidone. From lesion and subcellular fractionation studies, two classes of binding sites both labeled with 3H-domperidone but distinguished by apomorphine i.e. D-2 sites with nM affinity and D-4 sites with microM affinity for the dopamine agonist (according to the nomenclature of Sokoloff et al. 1980 b) appear to be differently localised in striatum. Thus D-2 sites, whose number decreases after kainate lesion, are not significantly modified following cortical lesions and preferentially sediment with heavy primary subcellular fractions. In contrast D-4 sites, less affected by kainate lesions, are significantly decreased following cortical lesions (-30%) and preferentially sediment with the light subcellular fractions. In addition the apparently heterogeneous recognition of total 3H-domperidone binding sites (i.e. the sum of D-2 and D-4 sites) by dopamine and apomorphine persists in the presence of guanosine-5'-triphosphate (pseudo-Hill coefficient of 0.60 instead of 0.55). This suggests that D-2 and D-4 sites cannot be considered as two discrete states of the same receptor strictly convertible one into the other by guanylnucleotides. Whereas most dopamine antagonists inhibited D-2 and D-4 site binding with similar affinities, the three benzamide derivatives with the largest selectivity in behavioral tests displayed 2-3-fold higher affinity for D-4 than for D-2 sites and the ratios of ID50 values of the whole series of antagonists against sniffing (or licking) and climbing behaviors were correlated (P less than 0.01) with the ratios of Ki values regarding D-2 and D-4 site binding. Also, sulpiride and LUR 2366 unlike haloperidol and metoclopramide, inhibited the total specific 3H-domperidone binding in a biphasic manner.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000502:physiology; D004192:Discrimination, Psychological / Q000187:drug effects*; D004294:Domperidone / Q000378:metabolism; D018492:Dopamine Antagonists; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006801:Humans; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D013239:Stereotyped Behavior / Q000187:drug effects; D013347:Subcellular Fractions / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D005971:Glutamates; D018698:Glutamic Acid; D004294:Domperidone; D006160:Guanosine Triphosphate; D001058:Apomorphine