Potential Roles Of The Medial Prefrontal Cortex And The Lateral Orbital Cortex In Morphine Dependence And The Underlying Mechanisms

Opiate abuse remains a major social problem in Asian countries. Opiateslike morphine are commonly used clinically to relieve pain and treat chronicdiarrhea. Repeated administration of morphine produces dependence andaddiction. However, the neurobiological mechanisms of morphine actions arestill not completely understood. A better understanding of the neuralmechanisms underlying morphine addiction could lead to more effectivetreatment strategies for addictive disorders. The prefrontal cortex hasimplicated in drug abuse in recent years. To further understand theneuromechanisms underlying morphine addiction, in the present study weinvestigated the pharmacological, biochemical and molecular alterations in thesubregions of the PFC, the medial prefrontal cortex (mPFC) and theorbofrontal cortex (OFC).Firstly, we employed animal models of addiction coupled with excitotoxicbrain lesion technique to investigate the roles of the mPFC and OFC inmorphine actions. The results showed that both mPFC and OFC lesionsprevented the acquisition of morphine induced conditioned place preference(CPP), but only OFC lesions destroyed drug priming induced reinstatement ofCPP in mice.In the behavioral sensitization tests, lesions of mPFC and OFC blockedthe hyperactivity induced by acute morphine and the induction of behavioralsensitization by repeated morphine. While only OFC lesions prevented theexpression of behavioral sensitization. These results suggested that the mPFCand OFC may involve in the acute morphine action and mediate, at leastpartially, morphine addiction and stress-induced relapse. This was also provedby the further studies using immunohistochemical methods that both acutemorphine treatment and naloxone-precipitated withdrawal significantly increased c-fos expression in mPFC and OFC.With the consideration of learning-based addiction theories, we alsoexamined the effects of mPFC and OFC lesions on the process of learning andmemory using spontaneous Y maze in this study. The results showed mPFClesions impaired the working memory, while OFC lesions has little effect on theworking memory, indicating the involvement of mPFC in morphine addictionpartially by its role in memory process.In addition to the mesocorticolimbic dopaminergic system, glutamate-mediated synaptic transmission also involves in the opiate abuse. The sourceof glutamate is shown to be glutamatergic afferents from the prefrontal cortex.In the present study, we investigated the effect of morphine on the extracellularlevels of glutamate in the mPFC and OFC in freely moving rats by using in vivomicrodialysis coupled with high performance liquid chromatography (HPLC).The results showed that acute morphine decreased the extracellular levels ofglutamate in the mPFC, while increased the extracellular levels of glutamate inthe OFC. Repeated morphine decreased the basal levels of glutamate in bothregions. Naloxone could reverse the decrease induced by repeated morphine,suggesting that the glutamatergic system in the two regions is involved in thecentral actions of morphine.In the present study, we also investigate the effects of Pseudoginsenoside-F11 (PF11) , an ocotillol-type saponin existing in American ginseng, onmorphine induced behavioral sensitivity and alternations in glutamate levels inthe medial prefrontal cortex on the base of our previous studies. As the resultsshown PF11 antagonized morphine-induced behavioral sensitivity anddecrease of glutamate in the mPFC. Therefore, it is demonstrated that PF11may block morphine-induced behavioral sensitivity via its effect, at leastpartially, on the glutamatergic system in the mPFC and also suggest thatnatural products, such as ginseng, might be potential candidates for theprevention and treatment of the neurological disorders induced by morphineabuse. In conclusion, the mPFC and OFC are differentially involved in the acutemorphine action and mediate, at least partially, morphine addiction and relapse.The mediation may relate to the glutamatergic system in these regions. Inaddition, PF11 might be a potential candidate for the prevention and treatmentof the neurological disorders induced by morphine.