嘌呤核苷酸对海洛因成瘾大鼠多巴胺奖赏系统的影响
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摘要
本课题研究补偿嘌呤核苷一磷酸对海洛因依赖大鼠脑中嘌呤核苷酸含量及多巴胺等相关神经递质代谢的影响,探索临床戒毒治疗的新方法。
实验首先建立海洛因依赖及嘌呤核苷酸补偿的大鼠模型,在此基础上测定了脑中多巴胺、去甲肾上腺素、嘌呤类小分子物质含量的改变,相关酶含量以及基因转录物含量的改变,并对相关组织做了形态学的观察。实验结果如下:
1.给海洛因的同时补偿嘌呤核苷酸,可以抑制海洛因成瘾大鼠部分戒断症状。
2.海洛因引起大鼠脑中多巴胺含量降低,去甲肾上腺素含量降低,合成关键酶酪氨酸羟化酶含量和基因表达水平降低而补偿嘌呤核苷酸可在一定程度上抑制上述作用。
3.海洛因成瘾动物体内嘌呤核苷酸分解代谢增强,合成不足,表现为脑中部分嘌呤核苷酸含量降低,而补偿嘌呤核苷酸可部分缓解此现象。
4.海洛因降低大鼠脑中GTP环水化酶基因表达水平,这可能是引起脑神经递质改变的原因之一,补偿嘌呤核苷酸有抑制这种作用的趋势。
5.补偿嘌呤核苷酸可抑制海洛因造成的相关脑区病理改变。
6.细胞水平试验发现,补偿嘌呤核苷酸可减弱海洛因造成的细胞增殖抑制。海洛因给药的PC12细胞内TH基因表达水平增高,GTP环水化酶基因表达水平降低,补偿嘌呤核苷酸有减缓这两种基因表达改变的作用,海洛因组D3受体基因表达水平有下降趋势,补偿嘌呤核苷酸后无明显改变。
综上所述,脑中嘌呤核苷酸分解代谢增强、合成代谢减弱可能是导致多巴胺代谢改变,进而导致了海洛因成瘾形成的原因之一。补偿嘌呤核苷酸明显抑制海洛因的上述作用,可能成为治疗海洛因依赖的有效方法。
Opioid like heroin abuse make the addicts shape psychological dependence and physical dependence to heroin and result in damage to multisystem. There is still no ideal drug for clinical therapy so far. Previous studies in our lab showed that both heroin and morphine promoted purine nucleotide catabolism and inhibited purine nucleotide anabolism in several tissues.
This project is about the study on purine nucleotides in rat brain of heroin addict’s purine nucleotides and the effects of dopamine reward system in order to provide a new treatment for clinical way of thinking.
1. Establishment of heroin addiction model
Adult male Wistar rats were randomly divided into control group (ip normal saline for 9 days), heroin group (ip heroin for 9 days), heroin and nucleotide administration group (ip the mixture of heroin, AMP and GMP for 9 days), heroin and AMP administration group (ip heroin and AMP for 9 days), and heroin and GMP administration group (ip heroin and GMP for 9 days). Abstinence symptom evoked by naloxone was done to test the establishment of heroin addition model.
After 9 days heroin treatment, naloxone treatment evoked abstinent symptoms such as erection, wet dog shake, stretch, tooth chattering, ptosis and diarrhea.
Above-mentioned results showed that rats shaped physical dependence after exposure to heroin for 9 days and the addiction model was successfully established.
Rats treated with heroin had a lower increasing rate of body weight than control ones and nucleotide and heroin administrated rats had a low increasing rate of body weight than control ones but a relative high rate than heroin treated rats.
2. Effects of heroin and purine nucleotide compensation on neurotransmitter in rats’mid brain
Mesolimbic dopaminergic system (MLDS) is the core location of psychological dependence induced by opiate, and it is neurophysiological base of all drug addiction. The synthesis and releasing of many neurotransmitters are changed during the course of opioid addiction and withdrawal, and the changes of dopamine (DA) and norepinephrine (NE) are the base of addiction, dependence, tolerance and relapse. The concentrations of DA and NE were detected in rats’midbrain in purine nucleotides compensation during heroin dependence and withdrawal by fluorospectrophotometry.
Compared with the C group,in H group DA levels decreased (P <0.01). With the H group, HAG group DA levels increased (P <0.05), with the C group, HAG, HA, HG group of DA to reduce the level (P <0.01). With the H group, HA, HG group DA upward trend, but the difference was not significant (P> 0.05). And C compared, H group decreased NE levels (P <0.05). NE levels of HAG, HG higher than the H group (P <0.05), HA with the H group difference was not statistically significant (P> 0.05).
Compared with C, H groups decreased DA levels (P <0.01). Compared with H group, HAG group DA levels increased (P <0.05), and Compared with the C group, HAG, HA, HG group DA levels decreased (P <0.01). Compared with H group, HA, and HG groups DA were increased, but the difference was not statistically significant (P> 0.05). Compared with C group, H group decreased NE levels (P <0.05). NE levels of HAG, HG were higher than H group (P <0.05), HA and the H group showed no significant difference (P> 0.05).
Studies generally agreed that opioids stimulate the nervous system during the early time, so that DA neurotransmitters are released, however, may also hinder the re-uptake of neurotransmitters and inhibit central monoamine oxidase activity, leading to brain neurotransmitter levels relatively increased, and euphoria produced. The long-term role, neuronal activity decreased, addicts, opiate abusers must increase the dosage of opioids to achieve the purpose of the initial euphoria. A large number of drug abuse in long-term process, the DA and other neurotransmitters in neuronal activity gradually decreased until failure.
Compensation purine nucleotides makes the DA, NE content in the past in the control group, indicating that heroin-dependent purine nucleotide to treat symptoms of physical dependence in rats, reducing withdrawal symptoms.
3 Effects of heroin and purine nucleotide to neurotransmitter related enzymes
TH is one rate-limiting enzyme which is involved in the DA and NE synthesis pathway.. Studies have shown that TH levels decreased significantly in the brains that were died of heroin addicts. In this experiment, TH protein and gene expressions were significantly decreased in heroin addiction rats, which was likely to result in DA and NE declined.
Compared with the H group,TH protein and gene expressions were significantly higher in HAG, HA, and HG groups ,indicating compensation for purine nucleotides plays an important role in TH expression.
GTP is the tetrahydrobiopterin’s(BH4)precursor. Under GTPCH,GTP enzyme-catalyzed into BH4.BH4 is an important coenzyme of hydroxylase in vivo, including tyrosine hydroxylation enzyme(TH)which is the key enzyme in dopamine synthesis..
Our results showed that GTP content and GTPCH expression were decreased significantly in heroin addiction group, which may lead to BH4 synthesis reduction,, further leading to hydroxylase TH content and expression decreased, resulting in dopamine and norepinephrine levels reduction.
Compensation with the purine nucleotide GTPCH gene expression tended to increase, but the difference was not significant.
In this study, we first reported that those purine nucleotides can increase TH content in the brain; TH content may increase neurotransmitter DA in the brain, , also improve the drug withdrawal symptoms of heroin addiction rats .
4 Effects of heroin and purine nucleotide to changes of purine nucleotides in brain
HPLC method was used in this study, and measured the content of purine nucleotides in brain tissue. Compared with the control group, AMP and GTP were significantly lower levels in heroin group. In HAG, HA and HG groups, AMP contents were increased. Higher GTP contents were only observed in HA and HG groups. Compared with the control group, GMP content was significantly lower in heroin group, but the content was not changed significantly after the compensation.
GTP in the GTP hydrolase-catalyzed into BH4, BH4 is a coenzyme of the tyrosine hydroxylase (TH), TH is the rate-limiting enzyme of dopamine synthesis. Our experimental results suggested that dopamine reduction caused by long-term opioids abuse may related to purine nucleotides (including the GTP).declined..
The content of GTP was not changed obviously.This phenomenon may be related to energy conversion and signaling pathways.The precise mechanisms are needed to be further elucidated. Purine nucleotide catabolism increased in heroin addiction.Purine nucleotide administration improved this effect. ,Our study provided a new direction for drug addiction treatment.and good prospect for clinical application.
5. Effects of heroin and purine nucleotide compensation on morphology of rat’s brain
Morphological observation showed that control group was normal under electron microscope.
Heroin group neuropil appeared more obvious protuberances cavitation phenomenon, myelinated nerve fibers edema and shedding myelin sheath. Compensation purine nucleotide three groups showed that normal neuropil processes and relatively complete cell structures,.
Immunohistochemistry showed that heroin addiction in rat VTA area lower TH expression and higher GFAP protein levels, indicating heroin damaged brain astrocytes, and the functions of neurons which synthesize TH changed, leading to synthesis of TH reduced. Compensate for reduced expression of purine nucleotide GFAP trends and TH expression tended to increase, indicating that nucleotide may have some protective effects on the brain.
6. Effects of compensative purine nucleotides on cell proliferation and dopamine metabolism key enzyme gene expression PC12 cells
Purine nucleotide is one of basic constituents of cell and essential material of cell proliferation. Heroin caused cell purine nucleotide scant synthesis and over disassociation, so purine nucleotide deficit is induced in heroin long-term user. Purine nucleotides were compensated by exogenous in this test. Cell viability was examined by MTT method in PC12 cells. RealTime-PCR was used to examine the gene transcripts of TH, D3 and GTPCH.
The results showed that, purine nucleotides administration compensated PC12 growth inhibitory effect caused by heroin. A key enzyme in dopamine synthesis -------- content of tyrosine hydroxylase expression increased in heroin group. TH gene expression level decreased in HAG, HA and HG groups compared with heroin group, but increased compared with the control group .
The GTPCH gene expression is dereased in heroin group, but increased in HAG, HA and HG. D3 receptor gene expression was not changed significantly. It suggested that purine nucleotides may have some protective effects on cell function.
In conclusion, long-term repeated stimulation of heroin and norepinephrine dopamine decreased the contents of synthesis key enzyme (TH). The level of TH gene expression reduced, leading to brain dopamine, norepinephrine and other neurotransmitters declined. Purine nucleotide through compensation can partially compensate such damages. Purine nucleotide metabolism treated with heroin in the brain increased,.Some purine nucleotides by exogenous compensation can make a number of nucleotide content increased, but not yet fully recovered. The changes of GTP content may alter GTPCH expression. GTPCH can also indirectly affect BH4 activity. Purine compensation can reduce ultrastructure injury caused by heroin, and also improve increased GFAP protein in astrocytes. Short-term stimulation of heroin increased TH gene expression in PC12 cells, GTPCH gene expression decreased. Purine nucleotide compensation can alleviate growth inhibition and gene expression changes caused by heroin. . These results showed that the purine contents in the brain have an important impact on the dopamine system, and purine nucleotide compensation can partially inhibit this effect.
实验首先建立海洛因依赖及嘌呤核苷酸补偿的大鼠模型,在此基础上测定了脑中多巴胺、去甲肾上腺素、嘌呤类小分子物质含量的改变,相关酶含量以及基因转录物含量的改变,并对相关组织做了形态学的观察。实验结果如下:
1.给海洛因的同时补偿嘌呤核苷酸,可以抑制海洛因成瘾大鼠部分戒断症状。
2.海洛因引起大鼠脑中多巴胺含量降低,去甲肾上腺素含量降低,合成关键酶酪氨酸羟化酶含量和基因表达水平降低而补偿嘌呤核苷酸可在一定程度上抑制上述作用。
3.海洛因成瘾动物体内嘌呤核苷酸分解代谢增强,合成不足,表现为脑中部分嘌呤核苷酸含量降低,而补偿嘌呤核苷酸可部分缓解此现象。
4.海洛因降低大鼠脑中GTP环水化酶基因表达水平,这可能是引起脑神经递质改变的原因之一,补偿嘌呤核苷酸有抑制这种作用的趋势。
5.补偿嘌呤核苷酸可抑制海洛因造成的相关脑区病理改变。
6.细胞水平试验发现,补偿嘌呤核苷酸可减弱海洛因造成的细胞增殖抑制。海洛因给药的PC12细胞内TH基因表达水平增高,GTP环水化酶基因表达水平降低,补偿嘌呤核苷酸有减缓这两种基因表达改变的作用,海洛因组D3受体基因表达水平有下降趋势,补偿嘌呤核苷酸后无明显改变。
综上所述,脑中嘌呤核苷酸分解代谢增强、合成代谢减弱可能是导致多巴胺代谢改变,进而导致了海洛因成瘾形成的原因之一。补偿嘌呤核苷酸明显抑制海洛因的上述作用,可能成为治疗海洛因依赖的有效方法。
Opioid like heroin abuse make the addicts shape psychological dependence and physical dependence to heroin and result in damage to multisystem. There is still no ideal drug for clinical therapy so far. Previous studies in our lab showed that both heroin and morphine promoted purine nucleotide catabolism and inhibited purine nucleotide anabolism in several tissues.
This project is about the study on purine nucleotides in rat brain of heroin addict’s purine nucleotides and the effects of dopamine reward system in order to provide a new treatment for clinical way of thinking.
1. Establishment of heroin addiction model
Adult male Wistar rats were randomly divided into control group (ip normal saline for 9 days), heroin group (ip heroin for 9 days), heroin and nucleotide administration group (ip the mixture of heroin, AMP and GMP for 9 days), heroin and AMP administration group (ip heroin and AMP for 9 days), and heroin and GMP administration group (ip heroin and GMP for 9 days). Abstinence symptom evoked by naloxone was done to test the establishment of heroin addition model.
After 9 days heroin treatment, naloxone treatment evoked abstinent symptoms such as erection, wet dog shake, stretch, tooth chattering, ptosis and diarrhea.
Above-mentioned results showed that rats shaped physical dependence after exposure to heroin for 9 days and the addiction model was successfully established.
Rats treated with heroin had a lower increasing rate of body weight than control ones and nucleotide and heroin administrated rats had a low increasing rate of body weight than control ones but a relative high rate than heroin treated rats.
2. Effects of heroin and purine nucleotide compensation on neurotransmitter in rats’mid brain
Mesolimbic dopaminergic system (MLDS) is the core location of psychological dependence induced by opiate, and it is neurophysiological base of all drug addiction. The synthesis and releasing of many neurotransmitters are changed during the course of opioid addiction and withdrawal, and the changes of dopamine (DA) and norepinephrine (NE) are the base of addiction, dependence, tolerance and relapse. The concentrations of DA and NE were detected in rats’midbrain in purine nucleotides compensation during heroin dependence and withdrawal by fluorospectrophotometry.
Compared with the C group,in H group DA levels decreased (P <0.01). With the H group, HAG group DA levels increased (P <0.05), with the C group, HAG, HA, HG group of DA to reduce the level (P <0.01). With the H group, HA, HG group DA upward trend, but the difference was not significant (P> 0.05). And C compared, H group decreased NE levels (P <0.05). NE levels of HAG, HG higher than the H group (P <0.05), HA with the H group difference was not statistically significant (P> 0.05).
Compared with C, H groups decreased DA levels (P <0.01). Compared with H group, HAG group DA levels increased (P <0.05), and Compared with the C group, HAG, HA, HG group DA levels decreased (P <0.01). Compared with H group, HA, and HG groups DA were increased, but the difference was not statistically significant (P> 0.05). Compared with C group, H group decreased NE levels (P <0.05). NE levels of HAG, HG were higher than H group (P <0.05), HA and the H group showed no significant difference (P> 0.05).
Studies generally agreed that opioids stimulate the nervous system during the early time, so that DA neurotransmitters are released, however, may also hinder the re-uptake of neurotransmitters and inhibit central monoamine oxidase activity, leading to brain neurotransmitter levels relatively increased, and euphoria produced. The long-term role, neuronal activity decreased, addicts, opiate abusers must increase the dosage of opioids to achieve the purpose of the initial euphoria. A large number of drug abuse in long-term process, the DA and other neurotransmitters in neuronal activity gradually decreased until failure.
Compensation purine nucleotides makes the DA, NE content in the past in the control group, indicating that heroin-dependent purine nucleotide to treat symptoms of physical dependence in rats, reducing withdrawal symptoms.
3 Effects of heroin and purine nucleotide to neurotransmitter related enzymes
TH is one rate-limiting enzyme which is involved in the DA and NE synthesis pathway.. Studies have shown that TH levels decreased significantly in the brains that were died of heroin addicts. In this experiment, TH protein and gene expressions were significantly decreased in heroin addiction rats, which was likely to result in DA and NE declined.
Compared with the H group,TH protein and gene expressions were significantly higher in HAG, HA, and HG groups ,indicating compensation for purine nucleotides plays an important role in TH expression.
GTP is the tetrahydrobiopterin’s(BH4)precursor. Under GTPCH,GTP enzyme-catalyzed into BH4.BH4 is an important coenzyme of hydroxylase in vivo, including tyrosine hydroxylation enzyme(TH)which is the key enzyme in dopamine synthesis..
Our results showed that GTP content and GTPCH expression were decreased significantly in heroin addiction group, which may lead to BH4 synthesis reduction,, further leading to hydroxylase TH content and expression decreased, resulting in dopamine and norepinephrine levels reduction.
Compensation with the purine nucleotide GTPCH gene expression tended to increase, but the difference was not significant.
In this study, we first reported that those purine nucleotides can increase TH content in the brain; TH content may increase neurotransmitter DA in the brain, , also improve the drug withdrawal symptoms of heroin addiction rats .
4 Effects of heroin and purine nucleotide to changes of purine nucleotides in brain
HPLC method was used in this study, and measured the content of purine nucleotides in brain tissue. Compared with the control group, AMP and GTP were significantly lower levels in heroin group. In HAG, HA and HG groups, AMP contents were increased. Higher GTP contents were only observed in HA and HG groups. Compared with the control group, GMP content was significantly lower in heroin group, but the content was not changed significantly after the compensation.
GTP in the GTP hydrolase-catalyzed into BH4, BH4 is a coenzyme of the tyrosine hydroxylase (TH), TH is the rate-limiting enzyme of dopamine synthesis. Our experimental results suggested that dopamine reduction caused by long-term opioids abuse may related to purine nucleotides (including the GTP).declined..
The content of GTP was not changed obviously.This phenomenon may be related to energy conversion and signaling pathways.The precise mechanisms are needed to be further elucidated. Purine nucleotide catabolism increased in heroin addiction.Purine nucleotide administration improved this effect. ,Our study provided a new direction for drug addiction treatment.and good prospect for clinical application.
5. Effects of heroin and purine nucleotide compensation on morphology of rat’s brain
Morphological observation showed that control group was normal under electron microscope.
Heroin group neuropil appeared more obvious protuberances cavitation phenomenon, myelinated nerve fibers edema and shedding myelin sheath. Compensation purine nucleotide three groups showed that normal neuropil processes and relatively complete cell structures,.
Immunohistochemistry showed that heroin addiction in rat VTA area lower TH expression and higher GFAP protein levels, indicating heroin damaged brain astrocytes, and the functions of neurons which synthesize TH changed, leading to synthesis of TH reduced. Compensate for reduced expression of purine nucleotide GFAP trends and TH expression tended to increase, indicating that nucleotide may have some protective effects on the brain.
6. Effects of compensative purine nucleotides on cell proliferation and dopamine metabolism key enzyme gene expression PC12 cells
Purine nucleotide is one of basic constituents of cell and essential material of cell proliferation. Heroin caused cell purine nucleotide scant synthesis and over disassociation, so purine nucleotide deficit is induced in heroin long-term user. Purine nucleotides were compensated by exogenous in this test. Cell viability was examined by MTT method in PC12 cells. RealTime-PCR was used to examine the gene transcripts of TH, D3 and GTPCH.
The results showed that, purine nucleotides administration compensated PC12 growth inhibitory effect caused by heroin. A key enzyme in dopamine synthesis -------- content of tyrosine hydroxylase expression increased in heroin group. TH gene expression level decreased in HAG, HA and HG groups compared with heroin group, but increased compared with the control group .
The GTPCH gene expression is dereased in heroin group, but increased in HAG, HA and HG. D3 receptor gene expression was not changed significantly. It suggested that purine nucleotides may have some protective effects on cell function.
In conclusion, long-term repeated stimulation of heroin and norepinephrine dopamine decreased the contents of synthesis key enzyme (TH). The level of TH gene expression reduced, leading to brain dopamine, norepinephrine and other neurotransmitters declined. Purine nucleotide through compensation can partially compensate such damages. Purine nucleotide metabolism treated with heroin in the brain increased,.Some purine nucleotides by exogenous compensation can make a number of nucleotide content increased, but not yet fully recovered. The changes of GTP content may alter GTPCH expression. GTPCH can also indirectly affect BH4 activity. Purine compensation can reduce ultrastructure injury caused by heroin, and also improve increased GFAP protein in astrocytes. Short-term stimulation of heroin increased TH gene expression in PC12 cells, GTPCH gene expression decreased. Purine nucleotide compensation can alleviate growth inhibition and gene expression changes caused by heroin. . These results showed that the purine contents in the brain have an important impact on the dopamine system, and purine nucleotide compensation can partially inhibit this effect.
引文
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