Motor effects of two sigma ligands mediated by nigrostriatal dopamine neurons

(+)-Pentazocine, a potent sigma ligand that lacks affinity for PCP receptors, produced dose-dependent contralateral circling behavior following microinjections in the substantia nigra of rats. This effect was attenuated by 6-hydroxydopamine (6-OHDA) lesions of ascending dopamine neurons and enhanced by systemic injections of amphetamine, 6-OHDA lesions also attenuated the circling produced by another selective sigma ligand, 1,3-di-o-tolylguanidine (DTG). These findings suggest that sigma receptors are involved in the neural control of movement and the regulation of the ascending dopamine system. Since all typical antipsychotic drugs tested bind to sigma receptors with Ki values less than 1 microM, these findings further suggest that sigma receptors may mediate some of the motor side effects of antipsychotic drug therapy.