u-50488 and 1-3-ditolylguanidine

[3H]-Nemonapride has been the ligand of choice to label D4 dopamine receptors. Its specificity was questioned when it was discovered that sigma (sigma) sites were also labeled by [3H]-nemonapride. To further characterize the binding of [3H]-nemonapride, three areas of calf brain (striatum, frontal cortex and cerebellum) were examined. In all three areas, [3H]-nemonapride labeled multiple sites. Dopaminergic and sigma sites were the most prominent. The sigma binding profile was sigma-1 like with a Ki binding profile as follows (in order of decreasing potency): haloperidol, PPAP, pentazocine, DTG, U-50488, R(+)-3-PPP. Experiments using sulpiride and pentazocine to block striatal dopaminergic and sigma sites, respectively, revealed additional, not previously characterized binding sites for [3H]-nemonapride. One component which was present in striatum but not in frontal cortex or cerebellum, had affinity for some neuroleptics and WB-4101, but not for typical serotonergic agents. Thus, [3H]-nemonapride has no selectivity for dopamine receptors unless stringent experimental conditions are met.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adrenergic alpha-Antagonists; Animals; Anticonvulsants; Benzamides; Binding, Competitive; Brain; Cattle; Cerebellum; Cerebral Cortex; Corpus Striatum; Dioxanes; Dopamine Agonists; Dopamine Antagonists; Guanidines; Haloperidol; In Vitro Techniques; Isotope Labeling; Narcotic Antagonists; Pentazocine; Piperidines; Propylamines; Pyrrolidines; Receptors, Dopamine D2; Receptors, sigma; Sulpiride; Tritium

The present study was designed to investigate the effects of the mu-opioid morphine, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)- cyclohexyl]-benzene acetamide, methane sulfonate hydrate (U-50488H), a kappa-selective opioid receptor agonist, and 1,3-di-(2-tolyl)guanidine (DTG), sigma-receptor agonist, on the discriminative stimulus properties of cocaine in the rat trained to discriminate 10 mg/kg of cocaine from its vehicle in a shock avoidance paradigm. Morphine (1-5.6 mg/kg), U-50488H (1-10 mg/kg) or 1,3-di-(2-tolyl) guanidine (1 and 10 mg/kg) alone did not produce any stimulus effects in common with cocaine. In contrast, morphine (5.6 mg/kg) and DTG (10 mg/kg), unlike U-50488H (10 mg/kg), significantly shifted the stimulus-generalization curve for cocaine to the left. These results suggest that agonists for mu-opioid- and sigma-receptors augment the discriminative stimulus properties of cocaine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Analysis of Variance; Animals; Avoidance Learning; Cocaine; Discrimination Learning; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Guanidines; Male; Morphine; Rats; Receptors, Opioid