Earlier studies have demonstrated that antagonism of σ 1 receptors attenuates the convulsive, lethal, locomotor stimulatory and rewarding actions of cocaine in mice. In contrast, the contribution of σ 2 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 (3α-tropanyl-2-(4-chorophenoxy)butyrate) in receptor binding and behavioral studies. Receptor binding studies confirmed that UMB24 and (±)-SM 21 display preferential affinity for σ 2 over σ 1 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 σ 2 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.

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