Effects of σ1 receptor ligand MS-377 on D2 antagonists-induced behaviors

Abstract ( R )-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone l -tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for σ 1 receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D 2 receptor antagonists (D 2 antagonists) in concurrent administration, and then the involvement of σ receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are σ receptor agonists, and WAY-100,635, which is a 5-HT 1A receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D 2 antagonists, but it does not deteriorate the adverse effect. Moreover, σ 1 receptors are involved in this potentiation of the efficacy of D 2 antagonists by MS-377.