Modulation of amphetamine-stimulated (transporter mediated) dopamine release in vitro by sigma2 receptor agonists and antagonists.

Some sigma receptor ligands have been shown to bind with low affinity to the dopamine transporter and to inhibit [3H]dopamine uptake. It has not previously been shown whether any of these compounds influence release of dopamine via facilitated exchange diffusion. To further examine the nature of the interaction between sigma receptor ligands and the dopamine transporter, the effects of sigma receptor ligands on amphetamine-stimulated [3H]dopamine release were examined in slices prepared from rat caudate putamen. In the absence of exogenous Ca2+, both (+)-pentazocine and (-)-pentazocine potentiated amphetamine-stimulated [3H]dopamine release at concentrations consistent with their affinities for sigma2 receptors. In contrast, BD737 (1S.2R-(-)-cis-N-¿2-(3,4-dichlorophenyl)ethyl¿-N-methyl-2-(1-pyrrolidiny l)cyclohexylamine), a sigma1 receptor agonist, had no effect on amphetamine-stimulated release. Neither isomer of pentazocine alone had any effect on basal [3H]dopamine release under these conditions. Three antagonists at sigma receptors, one of which is non-selective for subtypes, and two of which are sigma2-selective, all blocked the enhancement of stimulated release produced by (+)-pentazocine. Enhancement of stimulated release by (-)-pentazocine was similarly blocked by sigma2 receptor antagonists. Our data support the contention that it is possible to regulate transporter-mediated events with drugs that act at a subpopulation of sigma receptors pharmacologically identified as the sigma2 subtype.

Functional and binding properties of sigma receptors in rat cerebellum.

Autoradiographic studies have shown that sigma receptors are enriched in the locus coeruleus, the origin of noradrenergic projections to the cerebellum, as well as in the Purkinje, molecular, and granular layers and the interpositus cerebellar nucleus of the cerebellum itself. In contrast, the cerebellum is relatively poor in phencyclidine (PCP) binding sites, which have been historically confused with sigma sites. The high ratio of sigma to PCP receptors in cerebellum is advantageous for discriminating sigma-mediated physiological effects. sigma agonists and antagonists have been shown to regulate N-methyl-D-aspartate (NMDA)-stimulated norepinephrine release in hippocampus, which is innervated by locus coeruleus projections. We now report that sigma drugs also regulate norepinephrine release from cerebellum. In contrast to findings in the hippocampus, where regulation is via sigma 1 and sigma 2 receptors, sigma-mediated regulation in cerebellum seems to be primarily via sigma 1 receptors. In radioligand binding studies, we find that sigma receptors primarily of the sigma 1 type are present in the cerebellum. We further report that binding to sigma receptors in cerebellum is not affected by the addition of NMDA or glycine or by the presence of NMDA antagonists, suggesting that sigma receptors are not located within the NMDA-operated cation channel in this brain region.