The Role Of Geranylgeranylacetone In Attenuating Reinstatement After Extinction Induced By Morphine

Drug relapse is one of the main characters of drug addiction, also is the main problem for the treatment of drug addiction. Drug relapse usually refers to the drug abuse after stopping to use addictive drugs after period of time of withdrawal under one or more factors stimulatting. These factors can trigger the relapse, environment stimulate and hints related with abuse drugs, exposure to stress. It has been known that the mesocorticolimbic dopamine systems, including prefrontal cortex, ventral tegmental area and nucleus accumbens, are the anatomical and functional base of drug addiction, are important neural circuits of compulsive drug and relapse. The circuits are related with enhancement effect, compulsive drug conditional response of drug-associated cues, withdrawal syndromes of anxieties and fear accompanied by cessation of drug taking. The activation of learning and memory circuits, including ventral tegmental area(VTA), nucleus accumbens(NAc) and hippocampus, play an important role in morphine addiction and relapse. Addiction drugs regulate a series of molecular associated with learning and memory, such as dopamine Dl receptor, cAMP responsive element binding protein(CREB), finally caused a series of changes in synaptic plasticity, the structure reconstruction of the nervous system.Morphine is a kind of alkaloid of poppy extract, because of its powerful analgesic and sedation, it is widely used in all kinds of clinical acute or chronic pain, cancerous pain and postoperative pain. Because of wide application of morphine addiction, the damages to the nervous system are also gradually revealed, morphine can cause neuron apoptosis, inhibition of neuron growth and generation of oxidative stress and so on, however, morphine addiction has become a worldwide problem, its addiction and relapse mechanisms are still unclear. Studies have shown that morphine can cause changes of cell signaling molecules, such as N-methyl-D-aspartate receptors(NMDARs), CREB, Cyclin-dependent kinase 5(Cdk5). NR2B is a subunit of the NMDA receptor which plays important roles in synaptic plasticity and learning and memory processes. It was proved that the overexpression of NR2B transgenic mice performed better than the wild-type littermates in learning and memory aspects. Morphine relapse is an abnormal learning and memory process. Thus, NR2B is associated with addiction and relapse of abuse. Cdk5 belongs to the cyclin-dependent kinase family and phosphorylates the delta receptor of morphine in the morphine addiction, relieves morphine tolerance. In addition, Cdk5 also participates in the regulation of dopamine signaling in the process of addiction. CREB is an important nuclear transcription factor, it can regulate gene transcription, cell growth and survival, addiction, depression, learning and memory. CREB is one of the most in-depth studied addiction-related molecules so far and plays an important role in drug addiction. The opioids can induce the generation of p-CREB and the formation of drug dependence. Thioredoxin-1 (Trx-1) is a small molecular weight protein and involved in many physiological processes in the body, inhibits apoptosis, anti oxidative stress, and promotes cell proliferation and regulates gene transcription. Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid and widely used as an anti-ulcer drug in clinic. Many studies suggest that GGA up-regulates Trx-1 expression in various cells. GGA can exert cytoprotective effects against oxidative stresses in the gastric mucosa, liver and heart.The treatment on the drug addiction and relapse has side effects, low practical using. Thus, in present study, we explore the role of the Trx-1 inducer GGA in reinstatement of conditioned place preference after extinction by morphine. The results of this study are as followings:By using morphine induced reinstatement after conditioned place preference extinction mouse model, first of GGA (800 mg/kg, orally, for 16 days) pretreatment was given in mice, on ninth day morphine (20 mg/kg, intraperitoneally injection on every other day, for 8 days) to cause the formation of CPP, then extinction of CPP and reinstatement. We also detected the relative proteins expressions in the regions of PFC, VTA, NAc and hippocampus, demonstrated GGA pretreatment could attenuate reinstatement after extinction of CPP and mice weight loss induced by morphine. At the molecular levels, GGA suppressed chronic morphine induced increases of Cdk5 in NAc and hippocampus in reinstatement after extinction of CPP. Also increases of NR2B in PFC, VTA and hippocampus, as well as suppressed the increases of p-CREB in VTA and NAc.Conclusion:GGA can resist attenuate reinstatement after extinction of CPP and mice weight loss. which are related with GGA inducing expressions of Trx-1 and NR2B. Accordingly Trx-1 inducer GGA resists the morphine relapse, which is related to NR2B expression induced by GGA.