Library

Notes: Summary In order to document the hypothesis that anti-psychotics 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 clicited 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 μM affinity for the dopamine agonist (according to the nomenclature of Sokoloff et al. 1980b) 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 heterogenous 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〈0.01) with the ratios of K i 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. However, the distinction by sulpiride and LUR 2366 of low and high affinity sites did not superimpose that of D-2 and D-4 sites, as distinguished by agonists. In this test the relative proportion of low affinity sites was 2-fold higher than that of D-2 sites and K i values for high affinity sites were lower than that for D-4 sites. Also the heterogeneity of 3H-domperidone sites regarding affinity of LUR 2366 persisted in the presence of low concentrations of apomorphine. Hence low affinity sites for discriminant benzamide derivatives may exist in two forms, distinguished by agonists and possibly interconvertible by GTP. Thus the hypothesis that two classes of central dopamine receptor can be distinguished by some substituted benzamides, but perhaps display no great difference in affinity of agonists in their physiological state, fits partic-ularly well with behavioral data.

Notes: Summary The experimental conditions allowing to elicit by administration of dopamine agonists a climbing behavior in rats, apparently analogous to the stereotyped cage climbing behavior previously described in mice (Protais et al. 1976), have been established. Among the various strains of rats studied i.e. Sprague-Dawley, Long Evans and Wistar, the latters were selected as the most responsive to the dopamine agonist apomorphine. However, even in the Wistar strain, only about 60% of animals responded to a test-dose of 0.4 mg/kg apomorphine by adopting in a sustained manner the typical upright position against the walls of a suitable experimental cage. Hence responsive rats were preselected 4 days before the experimental sessions and finally rated during a 60-min observation period. Increasing the test-dose of apomorphine led to a biphasic effect, the spontaneous climbing behavior being decreased at low dosage and, then, both the percentage of climbing animals and the duration of the behavior were progressively increased at higher dosages. A scoring system based on an all-or-none evaluation of the frequency of stereotyped climbing episods over the 1 h observation period was finally adopted allowing to establish dose response curves to apomorphine and its more potent derivative N-propylnorapomorphine. Dexamphetamine (associated to L-Dopa) also produced the stereotyped climbing behavior. The latter was completely abolished in animals treated with the “atypical” antipsychotic sulpiride. The effects of lesioning various cerebral dopaminergic areas on the apomorphine-induced behavior were investigated. The response was not significantly altered following bilateral thermocoagulations of the striatum (restricted lesions), globus pallidus, nucleus interstitialis of the striae terminalis, amygdala, nucleus lateralis septi or nucleus accumbens. Intrastriatal injections of 6-hydroxydopamine were without significant effect while large striatal thermocoagulations abolished the stereotyped behavior but were accompanied by a profound motor deficiency. Bilateral lesioning of the substantia nigra by either thermocoagulation or 6-hydroxydopamine, the latter leading to a 60% decrease in 3H-dopamine uptake in striatum without significant modification in nucleus accumbens, resulted in a hypersensitive response to apomorphine. Hence, these experiments do not allow to identify a single brain area where dopamine receptors mediating the climbing behavior are located although they suggest that the receptors involved receive a dopaminergic input originating from the substantia nigra.