The non-peptidic delta opioid receptor agonist TAN-67 enhances dopamine efflux in the nucleus accumbens of freely moving rats via a mechanism that involves both glutamate and free radicals

Abstract

The activation of the δ-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal dopamine efflux. (±)-TAN-67 (2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydro-quinolino[2,3,3,-g]isoquinoline) is a centrally acting non-peptidic δ opioid receptor agent which has recently become available. Interestingly, the (+) enantiomer of TAN-67 induces hyperalgesia in contrast to the (−) enantiomer of TAN-67 that produces profound antinociceptive effects in mice; the latter effects are mediated through δ-1 receptor stimulation. Using the microdialysis technique, the ability of the enantiomers of TAN-67 to alter the release of accumbal dopamine in vivo was analyzed. Like the 25-min infusion of the selective δ-1 opioid receptor agonist ( d-[Pen 2,5]-enkephalin) DPDPE (50 nM) and the δ-2 opioid receptor agonist deltorphin II (50 nM), the 25-min infusion of both (−)-TAN-67 (25 and 50 nM) and (+)-TAN-67 (25 and 50 nM) into the nucleus accumbens produced a similar transient dose-dependent increase in the accumbal extracellular dopamine level. Naloxone (1 mg/kg i.p., given 25 min prior to the drugs), namely a treatment that is known to inhibit the increase of dopamine induced by DPDPE and deltorphin II, did not affect the transient increase in the accumbal dopamine level produced by infusion of the enantiomers of TAN-67. The DPDPE and deltorphin II-induced increase in accumbal dopamine level, but not that of (−)-TAN-67 and (+)-TAN-67, was eliminated by subsequently perfused tetrodotoxin (2 μM) into the nucleus accumbens. The increase in accumbal dopamine level produced by an infusion of (−)-TAN-67 and (+)-TAN-67 was not altered by a Ca 2+-free Ringer's solution. The (−)-TAN-67 and (+)-TAN-67-induced accumbal dopamine efflux was strongly prevented by reserpine (5 mg/kg i.p., given 24 h earlier) or α-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of the enantiomers of TAN-67 on the accumbal dopamine were nullified by combined treatment with reserpine and α-methyl-para-tyrosine. The (−)-TAN-induced dopamine efflux was significantly reduced by the N-methyl- d-aspartate (NMDA) receptor antagonists ifenprodil (20 mg/kg i.p., 20 min before) and MK-801 (0.5 mg/kg i.p., 20 min before), respectively. The effects of (−)-TAN-67 on the dopamine efflux were also inhibited by the free radical scavenger N-2-mercaptopropionyl glycine (100 mg/kg i.p., 20 min before). These results show that both enantiomers of TAN-67 enhance the release of reserpine sensitive, vesicular dopamine and α-methyl- p-tyrosine sensitive, cytosolic dopamine from dopaminergic nerve terminals in the nucleus accumbens in a way that is independent of neural activity; activation of δ opioid receptors plays no role in these events. All together, the results suggest that (−)-TAN-67 can generate a burst of free radicals that in turn trigger a release of glutamate that ultimately via activation of NMDA receptors enhances the release of dopamine from dopaminergic nerve terminals in the nucleus accumbens.