Potential Roles Of The Medial Prefrontal Cortex And The Dorsal Hippocampus In Methamphetamine-Induced Psychological Dependence And The Potential Anti-Addictive Mechanism Of Oxytocin

Since the mid1990s, methamphetamine (MAP) production and abuse have become a major public health and criminal justice problem in this world. The psychological dependence has been considered to be a very important reason for its abuse, and currently the effect of mesocoticolimbic system on the psychological dependence has become a hot spot. Previous literatures demonstrate that oxytocin (OT), a neurohypophyseal neuropeptide, plays a key role in the reaction of addictive drugs-induced abuse. In this present study, the role of the extracellular amino acid level in the medial prefrontal cortex (mPFC) and the dorsal hippocampus (DHC) and the glutamatergic mechanism of the mesocoticolimbic system were firstly examined in the MAP-induced psychological dependence, moreover, the potential roles of OT in cue-induced drug craving and stress-induced reinstatement were investigatedFirstly, a brain microdialysis technique combined with the high-performance liquid chromatography (HPLC) with fluorescence detection system was used to investigate the change of the mPFC and the DHC extracellular glutamate (Glu) and GABA levels in MAP-induced conditioned place preference procedure in mice. The results showed that the mPFC extracellular Glu levels were significant increased in the acquisition and expression, and gradually decreased in the extinction, finally increased with a low dose MAP-induced reinstatement of CPP. And the DHC extracellular glutamate level was firstly increased in the acquisition, but significantly decreased in the expression, and then the Glu level was decreased after a low dose of MAP in the reinstatement of CPP. Moreover, the mPFC and the DHC extracellular Glu/GABA ratio were significantly increased and decreased in the expression, repectively. These results suggested that the neuroadaptive mechanism of glutamatergic system in the mPFC and DHC existed in MAP-induced psychological dependence.Secondly, the effect of excitotoxic kainic acid (KA) or N-methyl-D-aspartic acid (NMDA) lesions of mPFC or DHC on the expression and reinstatement of MAP-induced CPP was examined. The data showed that a KA lesion of mPFC inhibited the CPP expression and reinstatement. A NMDA lesions of mPFC also inhibited CPP expression. Then, a KA lesion of DHC could significantly decrease CPP expression, and a NMDA lesion of DHC inhibited MAP-priming reinstatement. These data suggest that the mPFC and DHC glutamatergic system are critical to MAP-induced psychological dependence, and different types of glutamate receptors may play different roles in the MAP-induced CPP procedures.Thirdly, a KA or NMDA lesions of mPFC or DHC combined with brain microdialysis was used to investigate the effect of DHC or mPFC extracellular Glu and GABA level on MAP-induced hyperactivity in mice. It was found that a KA or NMDA lesion of mPFC could significantly enhance MAP-induced hyperactivity. NMDA lesions of DHC reduced the inacrease of extracellular Glu and the decrease of GABA in the mPFC. Moreover, NMDA lesions of DHC could significantly enhance vesicular glutamate transporter Ⅱ (VGLUT2) expression in the PFC1h after administration with MAP, suggested that the mPFC extracellular Glu and GABA were regulated by DHC NMDAR in MAP-induced hyperactivity, especially via the VGLUT2expression.The research of cue-induced drug craving has been studied in recent years, since intermittent conditioned stimuli elicit strong drug relapse and relate to the spatial learning and memory. In this present study, we firstly used CPP procedure to establish the model of cue-induced MAP craving, and determined the effect of intracerebroventricular OT on the glutamate transporter and signal pathway protein, such as glutamate transporter1, VGLUT2, NMDAR2B, extracellular regulated protein kinases1/2(ERK1/2), Calcium/calmodulin-dependent protein kinase type II (CaMKII) and cAMP-response element-binding (CREB) expression in the PFC and hippocampal regions. The results showed that after the CPP expression, the mice, when the place preference was extinguished in the home cage for6days and recieved a CPP stimulus again, showed a significant CPP once again. Moreover, the spatial learning and memory were increased undergo a cue-induced MAP craving training. The expression levels of GLT1, VGLUT2, pERK1/2and pCREB in the PFC and VGLUT2, CaMKII and pCREB in the hippocampus were respectively increased and decreased during cue-induced MAP craving after1h. Intracerebroventricular OT could significantly inhibit the increased of GLT1, VGLUT2, pERK1/2and pCREB in the PFC and the VGLUT2, CaMKII and pCREB in the hippocampus via OT receptor. The results suggest that the conditioned cue-induced MAP craving could enhance the spatial learning and memory. Moreover, OT could inhibit the stimulation of the glutamtatergic system in the mesocoticolimbic induced by MAP, through the relulation of glutamatergic transporter and downstream signal pathway via OT receptor.Previous study has demonstrated that OT could inhibit stress-priming CPP reinstatement. In this present study, the role of microinjection with OT into the mPFC or the DHC in the restraint stress-priming reinstatement was studied. Microinjection with OT into the mPFC or the DHC could significantly inhibit the stress-priming reinstatement. And OT could inhibit the increasing of the GLT1、VGLUT2、NR2B、 CaMKII and pCREB levels in the PFC and the decreased of the expression levels of VGLUT2、pERK1/2and pCREB in the hippocampus via OT receptor. The data suggested that OT has a neuroprotective effect on the stress-induced reinstatement, especially via the glutatamatergic neurotransmission in the mesocorticolimbic system.In conclusion, the mesocoticolimbic glutamatergic neurotransmission regulates MAP-induced psychological dependence. OT has a neuroprotective role in MAP-induced drug craving and relapse through the mesocoticolimbic glutamatergic system.