Regulation of [3H]dopamine release from rat striatal slices by sigma receptor ligands.

Sigma receptors have been located in several areas of the brain that control motor function, including on the dopaminergic projections from substantia nigra to striatum. In the current study, the regulation of N-methyl-D-aspartate-stimulated [3H]dopamine release from slices of rat striatum by several sigma ligands has been tested. Both isomers of the benzomorphans SKF10,047 and pentazocine inhibited the stimulated release of dopamine in a concentration-related manner. All these compounds probably activate sigma and non-sigma receptors, including phencyclidine receptors, over the broad concentration ranges tested. However, concentrations of (+)pentazocine below about 100 nM appear to act solely through sigma receptors. This phase of inhibition was reversed by the sigma antagonist N-[-2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-[1- pyrimidinyl-1-piperazine butanol and by the sigma1-selective antagonist (1-(cyclopropylmethyl)-4-2'4"-fluorophenyl)-(2'-oxoethyl)piperi din e HBr. Neither of these antagonists affected stimulated release in the absence of (+)pentazocine. The synthetic sigma ligands 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride, 6-[6-(4-hydroxypiperidinyl)-hexoxy]-3-methylflavone hydrochloride and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- piperazine butanol enhanced NMDA-stimulated DA release significantly in the presence of (+)pentazocine. These drugs have affinity at non-sigma receptors as well, and their stimulatory effects may be mediated through these receptors along with nonreceptor mechanisms. Our findings on the regulation of dopamine support earlier assertions that sigma receptors may be important in the regulation of motor function.