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Many antidepressant drugs interact with sigma receptors and accumulating evidence suggests that these proteins mediate antidepressant-like effects in animals and humans. sigma Receptors are localized in brain regions affected in depression, further strengthening the hypothesis that they represent logical drug development targets. In this study, two novel sigma receptor agonists (UMB23, UMB82) were evaluated for antidepressant-like activity in mice. First, radioligand binding studies confirmed that the novel compounds had preferential affinity for sigma receptors. Second, the forced swim test, a well established animal model for screening potential antidepressant drugs, showed that both compounds dose-dependently reduced immobility time. The sigma receptor antagonist BD1047 attenuated the antidepressant-like effects of UMB23 and UMB82. Third, locomotor activity suggested that the effects of UMB23 and UMB82 in the forced swim test were not due to non-specific motor activating effects. Together, the data provide further evidence that sigma receptor agonists represent a possible new class of antidepressant medication.

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.