Intrastriatal administration of sigma ligands inhibits basal dopamine release in vivo

In this study, using the new sigma1/2 (σ1/2) compound MR200, its parent drug haloperidol and the σ ligand 1,3-di-o-tolylguanidine (DTG), we have investigated the role of striatal σ receptors in the control of basal dopamine (DA) outflow, by coupling in vitro binding experiments and in vivo microdialysis in the striatum of halothane-anesthetized rats. MR200 with respect to haloperidol, exhibits high affinity for σ1 (1.5 nM) and σ2 (21.9 nM) receptors, but only negligible affinity for DA receptors. Compared to DTG, MR200 has similar selectivity across neurotransmitter systems, and 46 times higher affinity for σ1 receptors. Intrastriatal application of MR200 at 10, but not 0.1 or 1 μM, elicited a pronounced decrease in striatal DA release (-45% of control values). This inhibitory effect was preceded by a transient increase in DA release (+50% over baseline) after 100 μM MR200 administration. DTG at 100, but not 10 μM, significantly reduced DA release (-40%). Haloperidol, whilst increasing DA release at 1 μM, induced a delayed decrease in DA release after 10 μM application. Finally, haloperidol (10 μM) did not modify the inhibitory effect of 10 μM MR200. These results show that striatal σ receptors control striatal DA release in resting conditions.