Effects Of Oxytocin In Psychological Dependence Induced By Methamphetamine And The Underlying Mechanisms

Methamphetamine (MAP), a psychostimulant, is abused in all of the world, which remains a major social problem. MAP-induced psychological dependence is the main reason of its abuse. Accumulated data have shown the neuroactive properties of oxytocin (OT), a neurohypophyseal neuropeptide, and its capable of reducing the abuse potential of drugs. The present study investigated the effects of OT on MAP-induced behavioral changes in mice and its possible mechanisms of action.First of all, locomotor activity (LA), behavioral sensitization (BS) and conditioned place preference (CPP) models were used to investigate the effects of OT on the behavioral changes induced by MAP in mice. The results showed that intracerebroventricular administration of OT had no effect on locomotor activity in naive mice, but inhibited, in a dose-dependent manner, the hyperactivity induced by acute administration of MAP. OT inhibited the acquisition, facilitated the extinction of MAP-induced CPP and abolished the reinstatement of CPP induced by restraint stress significantly. Moreover, OT blocked the transfer and expression of BS. However, OT had no effect on the development of BS, the expression and the reinstatement of CPP induced by MAP challenge. These effects of OT could be attenuated by atosiban (Ato), a selective OT receptor antagonist, which suggests that OT inhibits drug-seeking behaviors induced by MAP via its receptor.As well known, the mesocorticolimbic dopaminergic system plays a key role in MAP dependence. The high-performance liquid chromatography (HPLC) with electronic detection system was employed in the study to determine the dopamine (DA) and serotonin (5-HT) turnover ratios in prefrontal cortex (PFC), hippocampus, striatum and nucleus accumbens (NAc) of mice. The results showed that OT significantly inhibited the DA turnover ratios in striatum and NAc in acute or chronic MAP-treated mice. These results suggest that OT inhibits the MAP-induced alteration of DA turnover in mesolimbic region of mice.In addition to the mesocorticolimbic dopaminergic system, glutamate (Glu)-mediated synaptic transmission also involves in the psychostimulant abuse. PCF is the origin of the glutamatergic efferents. In the present study, the extracellular Glu levels in the medial prefrontal cortex (mPFC) were determined by using microdialysis coupled to a HPLC with fluorescence detection system. The results indicated OT markedly inhibited the increase of extracellular Glu levels in mPFC of mice induced by acute administration of MAP and restraint stress in CPP mice, but not that induced by MAP priming. Furthermore, OT increased the taurine (Tau) and gamma-aminobutyric acid (GABA) levels in mPFC of naive mice, which suggested that mPFC was in the inhibitory status after OT administration.Previous studies have suggested that glutamatergic receptors (NMDAR1 subunit) and transporters (GLT1 subunit) are mainly involved in the addiction of drug abused. The present studies by using Western blotting method detected the expression of NMDAR1 and GLT1 in PFC and hippocampus after acute and chronic MAP administration. The results showed that OT significantly inhibited the increased NMDAR1 levels in PFC induced by acute MAP and MAP-challenging relapse and markedly attenuated the decreased NMDAR1 levels in PFC induced by MAP withdrawal. Moreover, OT increased the elevated GLT1 levels in hippocampus after acute and chronic MAP administration. No significant differences of NMDAR1 and GLT1 expression in hippocampus and PFC of mice were observed after treated with OT alone. The results indicate that OT attenuates the changes of glutamatergic neurotransmission induced by MAP partially via NMDAR1 and GLT1.In conclusion, although the mechanisms underlying the OT effect are not clear enough, it appears that the ability of OT to modulate MAP-induced psychological dependent behavior is closely related to the effects of the neuropeptide on dopaminergic neurotransmission in the mesolimbic regions and the glutamatergic neurotransmission of the brain. In addition, the present results implicated that OT might be a potential candidate for the prevention and treatment of the neurological disorders induced by amphetamine-like compounds.