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Labeling in vivo of sigma receptors in mouse brain with [3H]‐(+)‐SKF 10,047: Effects of phencyclidine, (+)‐ and (−)‐N‐allylnormetazocine, and other drugs

The sigma receptor, so named because of the distinct pharmacolgical profile produced by its prototypic agonist SKF 10,047 (N‐allynormetazocine), is believed to mediate mania and psychotomimetic effects in man. While this sigma receptor has received extensive biochemical and pharmacological characterization in vitro, little information is available on the nature of the sigma site in vivo. In the present study, we examined the binding of [3H]‐(+)‐SKF 10,047 to sigma receptors in mouse brain in vivo and to sigma receptors in mouse and guinea pig brain in vitro and determined the relative potencies of various drugs in displacing this ligand. Mice were injected with 5 μCi of [3H]‐(+)‐SKF 10,047 into the tail vein. After various time intervals, the mice were decapitated; their brains were rapidly removed, weighed, and homogenized in 50 mM Tris‐HCI buffer, pH 7.7; and total and particulate bound radioactivity were determined. Specifically bound [3H]‐(+)‐SKF 10,047 in the particulate fraction was defined as the difference in total radioactivity in the particulate fraction obtained from vehicle‐injected mice minus the radioactivity in the particulate fraction from haloperidol (2 mg/kg i.p.)‐injected mice. Specifically bound [3H]‐(+)‐SKF 10,047 in the particulate fraction reached peak levels of 30 min after i.v. injection and constituted 90–95% of the total particulate radioactivity. Labeling of the sigma sites could be blocked in vivo by injecting mice i.p. with the drug 30 min before the i.v. injection of the 3H‐ligand. Under these conditions, (+)‐SKF 10,047, (+)‐3‐PPP, cyclazocine, pentazocine, and haloperidol were found to be the most potent compounds in reducing specific [3H]‐(+)‐SKF 10,047 binding. Neuroleptics such as thioridazine and chlorpromazine had good potency, while clozapine, spiperone, and sulpiride were very weak inhibitors in vivo. Specific [3H]‐(+)‐SKF 10,047 binding was also reduced in vivo by imipramine, dl‐propranolol, bupropion, rimcazole, and phenoxybenzamine, but was not reduced by apomorphine and naloxone at doses of 50 mg/kg i.p. Phencyclidine, m‐NH2‐PCP and (−)‐3‐PPP were only weak inhibitors of (+)‐SKF 10,047 binding in vivo. The relative potencies of these agents obtained in vivo correspond well with their relative affinities obtained in vitro in mouse and guinea pig brain for displacing [3H]‐(+)‐SKF 10,047 but not with their relative affinities for displacing TCP in guinea pig brain. Comparison of the dose‐response curves for the drug revealed the presence of perhaps two sites labeled by [3H]‐(+)‐SKF 10,047 in vivo.