TY - JOUR T1 - Modulation of Amphetamine-Stimulated [<sup>3</sup>H]Dopamine Release from Rat Pheochromocytoma (PC12) Cells by ς Type 2 Receptors JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 278 LP - 284 VL - 289 IS - 1 AU - John K. Weatherspoon AU - Linda L. Werling Y1 - 1999/04/01 UR - http://jpet.aspetjournals.org/content/289/1/278.abstract N2 - An important regulatory mechanism of synaptic dopamine (DA) levels is activation of the dopamine transporter (DAT), which is a target for many drugs of abuse, including amphetamine (AMPH). ς receptors are located in dopaminergic brain areas critical to reinforcement. We found previously that agonists at ς2 receptors enhanced the AMPH-stimulated release of [3H]DA from slices of rat caudate-putamen. In the present study, we modeled this response in undifferentiated pheochromocytoma-12 (PC12) cells, which contain both the DAT and ς2 receptors but not neural networks that can complicate investigation of individual neuronal mechanisms. We found that enhancement of AMPH-stimulated [3H]DA release by the ς agonist (+)-pentazocine was blocked by ς2 receptor antagonists. Additionally, the reduction in the effect of (+)-pentazocine by the inclusion of ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid led us to hypothesize that ς2 receptor activation initiated a Ca2+-dependent process that resulted in enhancing the outward flow of DA via the DAT. The source of Ca2+ required for the enhancement of reverse transport did not appear to be via N- or L-type voltage-dependent Ca2+ channels, because it was not affected by nitrendipine or ω-conotoxin. However, two inhibitors of Ca2+/calmodulin-dependent protein kinase II blocked enhancement in AMPH-stimulated release by (+)-pentazocine. Our findings suggest that ς2 receptors are coupled to the DAT via a Ca2+/calmodulin-dependent protein kinase II transduction system in PC12 cells, and that ς2 receptor antagonists might be useful in the treatment of drug abuse by blocking elevation of DA levels via reversal of the DAT. The American Society for Pharmacology and Experimental Therapeutics ER -