Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides

Abstract

Pharmacological and molecular biological tools were used to validate the involvement of σ receptors in the actions of cocaine. Radioligand binding studies demonstrated significant levels of σ receptors in the brain and heart, where cocaine interacts preferentially with the σ 1 subtype. In behavioral pharmacological studies using mice, nine novel σ receptor antagonists significantly attenuated cocaine-induced convulsions, while structural analogs with weak interactions with σ receptors were ineffective. In contrast to the protection provided by the antagonists, a classical σ receptor agonist exacerbated the convulsive effects of cocaine. The antagonists also attenuated cocaine-induced lethality, with the best compound protecting against death even when administered as a post-treatment. At doses where the antagonists had no effect on baseline locomotor activity, they significantly attenuated the locomotor stimulatory effects of cocaine, suggesting their ability to block the psychomotor as well as the toxic effects of cocaine. To further validate that the anti-cocaine effects were achieved by interfering with cocaine’s access to σ receptors, antisense oligodeoxynucleotides against σ 1 receptors were shown to attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the studies support the involvement of σ receptors, particularly the σ 1 subtype, in the behavioral effects of cocaine.