Intrastriatal administration of sigma ligands inhibits basal dopamine release in vivo

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In this study, using the new sigma 1/2 (σ 1/2) 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 σ 1 (1.5 nM) and σ 2 (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 σ 1 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.