The effect of Gly-Gln [ß-endorphin30-31] on morphine-evoked serotonin and GABA efflux in the nucleus accumbens of conscious rats

•In earlier studies, Gly-Gln inhibited morphine reward and NAc dopamine efflux.•Gly-Gln stimulated serotonin, but not GABA, efflux in the NAc of conscious rats.•Gly-Gln inhibited morphine-evoked serotonin and GABA efflux in the NAc.•Gly-Gln inhibits morphine reward by reducing dopamine, serotonin and GABA efflux.

Glycyl-L-glutamine (Gly-Gln; β-endorphin30-31) is an endogenous dipeptide synthesized through the post-translational processing of β-endorphin1-31. Central Gly-Gln administration inhibits the rewarding properties of morphine and attenuates morphine tolerance, dependence and withdrawal although it does not interfere with morphine analgesia. In an earlier study, we found that Gly-Gln inhibits morphine-induced dopamine efflux in the nucleus accumbens (NAc), consistent with its ability to inhibit morphine reward. To further investigate the mechanism responsible for its central effects we tested whether i.c.v. Gly-Gln administration influences the rise in extracellular serotonin and GABA concentrations evoked by morphine in the NAc. Conscious rats were treated with Gly-Gln (100 nmol/5 μl) or saline i.c.v. followed, 2 min later, by morphine (2.5 mg/kg) or saline i.p. and extracellular serotonin and GABA concentrations were analyzed by microdialysis and HPLC. Morphine administration increased extracellular serotonin and GABA concentrations significantly within 20 min, as shown previously. Unexpectedly, Gly-Gln also increased extracellular serotonin concentrations significantly in control animals. Combined treatment with Gly-Gln + morphine also elevated extracellular serotonin concentrations although the magnitude of the response did not differ significantly from the effect of Gly-Gln or morphine, given alone suggesting that Gly-Gln suppressed morphine induced serotonin efflux. Gly-Gln abolished the morphine-induced rise in extracellular GABA concentrations but had no effect on extracellular GABA when given alone to otherwise untreated animals. These data show that Gly-Gln stimulates NAc serotonin efflux and, together with earlier studies, support the hypothesis that Gly-Gln inhibits the rewarding effects of morphine by modulating morphine induced dopamine, GABA and serotonin efflux in the NAc.