Effects Of Cocaine On DNA Methyltransferases In Related Brain Nuclei

Drug addiction is a chronic and palindromic brain disease. Some adaptivechanges are induced in central nervous system by repeated drug administration,and tolerance and addiction can be produced. Relapse forms afterdiscontinuation. The midbrain limbic dopaminergic system is the centralanatomical basis of drug effects. The dependence producing drug activates thereward system then induces dopamine increasing and cheerful feeling andreward effectscome true. The dopaminergic projection from ventral tegmentumarea ventral tegmental area (VTA) to nucleus accumbens (NAc) is an importantcenter to participate drug addiction, and resultes in the changes of behavior.The nerve fiber from lateral habenula (LHb) and hippocampus (Hip) projectesinto the VTA and can influence the release of dopamine. They are alsoimportant brain nuclei related addiction.In recent years, researches on epigenetics provide a reasonable explanationfor genetic changes from induced by environmental factors. It refers to thechange of gene function under the premise of no DNA sequential variation.Mechanisms of Epigenetics include DNA methylation and histonemodification, et al. Major experiments have reported the effects of the histonemodification on drug addiction, while DNA methylation is involved sparsely.DNA methylation is mainly regulated by DNA Methyltransferases (DNMTs).There is evidence showing that DNMTs is rich expression in brain but little isknown the function of DNA methylation in brain. Researches show thatcocaine and heroin can change the DNMT gene expression in NAc and dorsalhippocampus. It plays an important role in drug addiction. LHb is a newlynoticed brain nucleus related addiction. There is no report on the DNA methylation in this brain area. The aim of this experiment is to examine thatcocaine influences DNMTs expression in NAc, Hip and LHb of the rats so as toprove the important role of changes in DNA methylation on drug addictionExperimental results:1. In NAc, the expression of the DNMTs mRNA were altered distinctivelyby cocaine treatment.(1)DNMT1: The expression of the DNMT1mRNA in NAc was increasedsignificantly by cocaine administration after4h compared with control group(P<0.05), and it was decreased statistically after24h compared with cocaine4hgroup (P<0.05) but no statistical difference compared with control group(P>0.05), showing that expression of DNMT1in NAc nearly recovered24hafter cocaine.(2)DNMT3a: The expression of the DNMT3a mRNA in NAcwas increased significantly by cocaine administration after4h compared withcontrol group(P<0.05), and it was obviously lower than control group after24h(P<0.05), which showed that DNMT3a expression in NAc was regulatedbiphasically by cocaine.(3)DNMT3b: The expression of the DNMT3b mRNAin NAc was larger after cocaine administration4h (P<0.05), and no statisticaldifference after24h (P>0.05), displaying that DNMT3b in NAc was recoveredbasically24h after cocaine treatment.2. In Hip, the DNMTs mRNA expressions was altered electively bycocaine treatment.(1)DNMT1: The expression of the DNMT1mRNA was decreasedsignificantly by cocaine administration after4h compared with control group (P<0.05), and it was decreased slightly after24h compared with control group(P>0.05).(2)DNMT3a: The expression of the DNMT3a mRNA was decreasedslightly by cocaine administration after4h and was increased slightly bycocaine administration after24h, but were all no statistical difference comparedwith control group (P>0.05), showing that expression of DNMT1in NAc was not changed by cocaine.(3)DNMT3b: The expression of the DNMT3b mRNAwas increased significantly by cocaine administration after4h and24hcompared with control group (P<0.05). That was to say that cocaine couldincrease the expression of DNMT3b continually.3. In LHb, the DNMTs mRNA expressions was altered electively bycocaine treatment.(1)DNMT1: The expression of the DNMT1mRNA was decreasedsignificantly by cocaine administration after4h compared with control group(P<0.05), and it was increased statistically after24h compared with cocaine4hgroup (P<0.05) but no statistical difference compared with control group(P>0.05), showing that expression of DNMT1in LHb nearly recovered24hafter cocaine.(2)DNMT3a: The expression of the DNMT3a mRNA wasdecreased statistically by cocaine administration after4h compared with controlgroup (P<0.05), and was decreased slightly by cocaine administration after24h, but was no statistical difference compared with control group (P>0.05),showing that expression of DNMT3b in LHb nearly recovered24h aftercocaine.(3)DNMT3b: The expression of the DNMT3b mRNA was increasedslightly by cocaine administration after4h compared with control group butwas no statistical difference（P>0.05）, and it was no obvious change after24h（P>0.05）.It was thus clear that cocaine addiction involved in changes of DNMTsexpression and DNMTs expression was altered distinctively by cocaine indifferent brain regions. We could come to the following conclusions:1. The expression of DNMT3a in NAc was regulated bilaterally bycocaine, suggesting that DNMT3a may be relevant to the drug addiction anddrug seeking behaviors.2.The expression of DNMT3b mRNA in Hip was increased persistently bycocaine, suggesting that DNMT3b may play an important role in maintaining the addicted state or memory of addiction.3.The influence of cocaine on the expression of DNMTs mRNA wastransient in LHb, suggesting that this may be relevant to behaviors afteraddiction but independent from addiction memory.