Intrastriatal administration of sigma ligands inhibits basal dopamine release in vivo.
In this study, using the new sigma(1/2) (sigma(1/2)) compound MR200, its parent drug haloperidol and the sigma ligand 1,3-di-o-tolylguanidine (DTG), we have investigated the role of striatal sigma 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 sigma(1) (1.5 nM) and sigma(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 sigma(1) receptors. Intrastriatal application of MR200 at 10, but not 0.1 or 1 microM, 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 microM MR200 administration. DTG at 100, but not 10 microM, significantly reduced DA release (-40%). Haloperidol, whilst increasing DA release at 1 microM, induced a delayed decrease in DA release after 10 microM application. Finally, haloperidol (10 microM) did not modify the inhibitory effect of 10 microM MR200. These results show that striatal sigma receptors control striatal DA release in resting conditions.
Laboratoire de Neuropsychobiologie des Désadaptations, Unité Mixte de Recherche-Centre National de la Recherche Scientifique 5541, Université Victor Segalen Bordeaux 2, Bordeaux, France.
Delphine
D
Moison
Philippe
P
De Deurwaerdère
Alfredo
A
Cagnotto
Agostino
A
Marrazzo
Orazio
O
Prezzavento
Giuseppe
G
Ronsisvalle
Tiziana
T
Mennini
Umberto
U
Spampinato
D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003521:Cyclopropanes / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008845:Microinjections; D017072:Neostriatum / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000187:drug effects*
C479880:(+)-methyl 2-((4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)methyl)-1-phenylcyclopropanecarboxylate; D003521:Cyclopropanes; D018492:Dopamine Antagonists; D006146:Guanidines; D010880:Piperidines; D017480:Receptors, sigma; D015102:3,4-Dihydroxyphenylacetic Acid; D006220:Haloperidol; C050232:1,3-ditolylguanidine; D004298:Dopamine