RELEASE OF [H-3] DOPAMINE FROM GUINEA-PIG STRIATAL SLICES IS MODULATED BY SIGMA(1) RECEPTOR AGONISTS

Sigma receptors are found in motor and limbic areas in the brains of h umans, non-human primates, and rodents. The most extensive pharmacolog ical studies of ligand binding to sigma receptors have utilized brain tissue from guinea pigs, where two subtypes of sigma receptor, designa ted sigma(1) and sigma(2), have been identified. Few functional roles for sigma receptors have been described. Their location in guinea pig striatum, a terminal field of dopaminergic projections arising from th e substantia nigra, suggested that this tissue would be a logical choi ce in which to examine physiological properties of sigma receptor acti vation. We found that sigma(1) receptor agonists inhibited N-methyl-D- aspartate-stimulated [H-3]dopamine release from guinea pig striatal sl ices in a concentration-dependent manner. The inhibition by sigma(1) r eceptor agonists was reversed by a selective sigma(1) receptor antagon ist, as well as by a non-subtype-selective sigma receptor antagonist. The ability of agonists working through sigma, receptors, but not thro ugh sigma(2) receptors, to inhibit the stimulated release of catechola mines appears to be a unique characteristic of guinea pig striatum. We have previously reported that in rat striatum and hippocampus, as wel l as in guinea pig nucleus accumbens, prefrontal cortex, and hippocamp us, activation of either sigma receptor subtype inhibits such release. Stimulated release of [H-3]dopamine from guinea pig striatum was also inhibited by the phencyclidine receptor agonist dizocilpine, but this inhibition was not reversed by the sigma receptor antagonists. Theref ore, the inhibition produced by sigma receptor agonists was not mediat ed via the phencyclidine binding site within the N-methyl-D-aspartate- operated cation channel. Our findings support the hypothesis that sigm a receptor activation provides a mechanism of modulating dopamine rele ase from striatum, and that striatal tissue from guinea pigs appears t o be an appropriate model for characterizing sigma(1) receptor-mediate d effects.