Melatonin Counteracts Reinstatement Of Cocaine Priming Induced CPP And △FosB/AGS3/TH Expression In Related Brain Regions

IntroductionMajor features of Cocaine addiction contain long-terming, difficulty to extinct and vulnerability to relapse. Given their side effects that neurotoxicity and abnormal in behaviors, those available medicine for addiction still unpopular at present among people taking in drug. It is urgent priority to look for safe and effective medicine for treatment of addiction.Results indicated that melatonin possessed multiple functions within pharmacologic dose without tolerance and dependence in itself. The report that melatonin improved morphine induced-abstinent symptom in rats, which brought it possible that development of melatonin as potential medicine for treatment of disorder induced by psychostimulants. Melatonin receptors, coupled to Gαi, widespread in limbic dopamine system. Also, melatonin may antagonize Ca2+/CaM by binding CaM, and inhibit the activation and autophosphorylation of CaMKII, leading to decrease regulation of CaMKII on neuron. Melatonin was reported to execute negative effects by more than both pathways.It was reported, cocaine affected mainly limbic dopamine system, preventing re-uptake of DAT on dopamine, as well as affecting TH, with dopamine accumulation and receptors mediated-signaling cascade to produce reward. With observing melatonin signaling and cocaine affected signaling pathways, AC, cAMP and Ca2+/CaM were regarded as key molecules in both pathways.Our study try to investigate the effects of melatonin and pinealectomy on reinstatement of cocaine priming induced-CPP andΔFosB/AGS3/TH expression in related brain regions, by adopting CPP assay and establishing animal model, in view of common molecules in both melatonin pathway and cocaine pathway. And new targets for treating effectively cocaine addiction may be found in present study.Methods1. Establishment of animal model(1) Pinealectomy and Sham-operation in rats(2) Conditioning, withdrawal, and priming of CPP in animal model of cocaine addiction2. Effects of melatonin on modulation of cocaine priming inducedΔFosB/AGS3/TH expression is examined by Western blottingΔFosB/AGS3/TH expression is examined by western blotting in PFC, NAc, CPu, AMY and VTA from Saline, Cocaine, Melatonin and cocaine, Pinealectomy, Sham-operation.3.ΔFosB expression is investigated by Confocal microscopyΔFosB expression is examined by confocal microscopy in HIP, CPu and NAc from Saline, Cocaine, and Melatonin and cocaine.Results1. Animal model of cocaine addiction was successfully established, extinguished, and primed.(1) Cocaine group and Melatonin-cocaine group preferred for drug-paired compartment after repeated cocaine administration in CPP assay. The preference of Pinealectomy group was lower than Sham-operation group in CPP assay after repeated cocaine administration.(2) Natural preference was restored after withdrawal followed repeated cocaine administration in each group. (3) Cocaine priming induced CPP reinstatement in Melatonin-cocaine group, which was significantly lower than that of Cocaine.2. Results from Western blotting indicated that the regulation of three targets induced by cocaine priming was counteracted by MT or pinealectomy.(1) Cocaine priming inducedΔFosB accumulation in related brain regions, MT inhibited its expression in most brain regions but NAc. Pinealectomy counteractedΔFosB increase after cocaine priming.(2) Cocaine priming decreased AGS3 expression in PFC and VTA, and increased AGS3 expression in CPu, both the decreasing and the increasing were inhibited by MT.(3) Cocaine priming decreased TH expression in PFC and VTA, and increased TH expression in CPu, both the decreasing and the increasing were inhibited by MT. Pinealectomy counteracted cocaine priming induced-TH increase in AMY.3.ΔFosB expression is investigated by confocal microscppy assayResults indicated that MT inhibitedΔFosB accumulation in HIP, CPu but NAc, which was induced by cocaine priming.ConclusionsMT counteracts the reinstatement of CPP induced by cocaine priming. MT inhibited modulation of cocaine priming onΔFosB/AGS3/TH expression. MT counteracts the reinstatement of cocaine priming induced-CPP, which is mediated possibly by TH/AGS3/ΔFosB.