Modulation of amphetamine-stimulated (transporter mediated) dopamine release in vitro by σ2 receptor agonists and antagonists

Some sigma receptor ligands have been shown to bind with low affinity to the dopamine transporter and to inhibit [H-3]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 [H-3]dopamine release were examined in slices prepared from rat caudate putamen. In the absence of exogenous Ca2+, both (+)-pentazocine and (-)-pentazocine potentiated amphetamine-stimulated [H-3]dopamine release at concentrations consistent with their affinities for sigma(2) receptors. In contrast, BD737 (1S,2R-(-)-cis-N-{2-(3,4-dichlorophenyl)ethyl}-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine), a sigma(1) receptor agonist, had no effect on amphetamine-stimulated release. Neither isomer of pentazocine alone had any effect on basal [H-3]dopamine release under these conditions. Three antagonists at sigma receptors, one of which is non-selective for subtypes, and two of which are sigma(2)-selective, ail blocked the enhancement of stimulated release produced by (+)-pentazocine. Enhancement of stimulated release by (-)-pentazocine was similarly blocked by sigma(2) receptor antagonists. Our data support the contention that it is possible to regulate transporter-mediated events with drugs that act at a subpopulation of a receptors pharmacologically identified as the sigma(2) subtype. (C) 1998 Elsevier Science B.V.