Effects of UMB24 and (+/-)-SM 21, putative sigma2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

Abstract

Earlier studies have demonstrated that antagonism of sigma1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of sigma2 receptors is unclear because experimental tools to selectively target this subtype are unavailable. To begin addressing this need, we characterized UMB24 (1-(2-phenethyl)-4-(2-pyridyl)-piperazine) and (+/-)-SM 21 (3alpha-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (+/-)-SM 21 display preferential affinity for sigma2 over sigma1 receptors. In behavioral studies, pretreatment of Swiss Webster mice with UMB24 or (+/-)-SM 21 significantly attenuated cocaine-induced convulsions and locomotor activity, but not lethality. When administered alone, (+/-)-SM 21 produced no significant effects compared to control injections of saline, but UMB24 had locomotor depressant actions. Together, the data suggest that sigma2 receptor antagonists have the potential to attenuate some of the behavioral effects of cocaine, and further development of more selective, high affinity ligands are warranted.

Fig. 1

Chemical structures of UMB24 and (±)-SM 21.

Fig. 2

Effects of UMB24 and (±)-SM 21 on cocaine-induced convulsions. Male, Swiss Webster mice were pretreated with UMB24 or (±)-SM 21 (0–10 mg/kg, i.p.) followed 15 min later with a convulsive dose of cocaine (70 mg/kg, i.p.). UMB24 and (±)-SM 21 significantly attenuated cocaine-induced convulsions (*p < 0.05, **p < 0.01, ***p < 0.005).

Fig. 3

Effects of UMB24 and (±)-SM 21 on basal and cocaine-induced locomotor activity. Male, Swiss Webster mice were injected (i.p.) with UMB24 or (±)-SM 21 (0, 0.1 or 1 mg/kg, i.p.) alone or as a 15 min pretreatment to a locomotor stimulatory dose of cocaine (10 mg/kg, i.p.). Horizontal locomotor activity was quantified for 30 min using an automated activity monitoring system. UMB24 produced a significant locomotor depressant effect on its own (#p < 0.01), and also attenuated cocaine-induced locomotor activity (*p < 0.05). (±)-SM 21 had no significant effect of its own on locomotor activity, although it significantly attenuated cocaine-induced locomotor activity (*p < 0.05).