中枢组胺对吗啡成瘾的形成和戒断后恐惧记忆作用
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摘要
如今吸毒已成为一个全球性的社会问题,毒品滥用已遍及全球200多个国家和地区。毒品种类繁多,但在我国仍以阿片类药物滥用为主。吗啡是阿片类药物的主要代表药物,吗啡最大缺点是极易成瘾,能很快发展成为依赖且不易戒断,即使戒断后复吸率也高。目前国内外均没有理想的治疗手段,所以迫切希望探索其神经生物学机制及治疗靶点,并寻找一些安全、有效、低成本的理想药物来治疗阿片(吗啡)成瘾。
目前认为脑内多种神经递质和神经调质系统参与阿片(吗啡)成瘾,除内源性阿片系统外,还有多巴胺(DA)系统、兴奋性氨基酸系统等。研究者试图解析这些非阿片靶受体系统在毒品成瘾中的作用机制并寻求相关治疗药物。脑内DA神经系统是阿片类引起精神依赖作用的轴心部位。
组胺能神经的胞体唯一位于下丘脑结节乳头核,组胺能神经元在脑内有着广泛而弥散的投射。作为脑内一种重要的神经递质或调质,通过H_1、H_2、H_3受体发挥着多种神经调节作用,如参与调节睡眠—觉醒活动、学习和记忆、情绪等生理作用。最近有报道组胺也参与调节药物成瘾的机制,如口服的止咳药(含可待因和H_1受体拮抗药)具有成瘾性。组胺H_2受体拮抗药zolantidine能提高吗啡诱导的奖赏作用,并且加速DA的代谢。H_1/H_2受体双基因敲除小鼠和组氨酸脱羧酶基因敲除(histidine decarboxylase gene knockout,HDCKO)小鼠促进甲基苯丙胺成瘾。这些研究都提示中枢组胺可能在药物成瘾中发挥着抑制作用,但是迄今尚不清楚中枢组胺在吗啡成瘾形成过程中的作用。
此外,药物成瘾表现为不顾后果的强迫性用药和失去控制的觅药行为。药物成瘾是一种记忆性疾病,成瘾过程伴随着在特定的神经环路中以特殊的方式形成突触可塑性改变,这些部位包括海马、杏仁核、皮层。成瘾记忆是一种畸形记忆,其主要特点是顽固存在,有的甚至持续一生,而且药物成瘾者常伴有认知功能的损伤如学习记忆能力下降,注意力不集中,焦虑。而这些认知损伤反过来是成瘾药物的复吸的重要原因之一,这提示可以通过利用改变认知功能来调节药物成瘾的进程。另一方面,组胺能神经系统参与调节神经元的突触可塑性和神经元兴奋性。在离体细胞和脑片电生理的研究发现,组胺可能直接作用于NMDA受体的多胺位点并增强NMDA受体依赖的长时程增强。脑室内注射组胺,或腹腔内给予组氨酸都可以改善动物在多种动物模型中的认知功能障碍,而且脑内组胺水平与学习记忆的能力有着密切的相关性。以上的结果均提示,组胺可通过调节认知功能来抑制吗啡诱导的成瘾以及复吸。但是目前尚无中枢组胺对吗啡成瘾以及学习记忆等三者关联的报告,所以很有必要研究在吗啡成瘾和戒断过程中认知功能的改变以及组胺的作用。
因此,在本研究中,利用整体行为学、免疫组化、生化等实验方法探讨脑内内源性组胺对吗啡诱导的条件性位置偏爱形成过程的作用,并探讨吗啡戒断过程认知功能的改变以及组胺能神经系统在其中的作用。
第一部分内源性组胺抑制吗啡诱导的条件性位置偏爱的形成过程
为了探讨内源性组胺在吗啡诱导的奖赏性觅药行为中的作用,本研究采用条件性位置偏爱(conditioned place preference,CPP)模型来评价吗啡奖赏作用,同时利用高效液相结合电化学技术检测脑内多巴胺(DA)、3,4-二羟苯乙酸(DOPAC)、组胺、谷氨酸、γ-氨基丁酸(GABA),使用免疫组化技术用来观察组胺能神经元的形态学改变。我们发现腹腔内分别注射2、5、10 mg/kg吗啡能剂量依赖性地诱导大鼠的CPP的形成。我们还进一步发现10 mg/kg吗啡多次注射后能显著性降低腹侧被盖核(VTA)和伏隔核(NAc)中组胺的含量,同时升高两个脑区的DOPAC/DA比率;并且观察到位于结节乳头核(TM)的组胺能神经元的胞体萎缩变小,数目也减少。腹腔内注射组氨酸(50,100 0r 200 mg/kg)能升高脑内组胺含量,同时剂量依赖性地抑制了10 mg/kg吗啡所诱导的CPP形成。电毁损双侧TM能降低脑内VTA和NAc区内的组胺含量,但不影响谷氨酸酸和GABA水平;电毁损双侧TM还增强1 mg/kg吗啡(单独给药没有明显作用)所诱导的CPP形成,同时升高VTA和NAc区内的DOPAC/DA比率。而组氨酸能逆转TM毁损对组胺含量、DOPAC/DA比率和CPP形成的作用。我们还利用组氨酸脱羧酶基因敲除小鼠(histidine decarboxylase gene knockout,HDCKO)小鼠进一步发现,HDCKO小鼠比野生型(wild-type,WT)小鼠对吗啡诱导CPP更敏感,同时VTA和NAc区内的DOPAC/DA比率更高。这些结果都提示中枢组胺能够抑制吗啡诱导的CPP形成,该作用可能是通过调节DA的活性来实现的。
第二部分组氨脱羧酶基因敲除小鼠增强吗啡戒断对线索恐惧记忆消除的损害
以前研究已表明吗啡成瘾能降低学习记忆,产生负性情感,而组胺在许多的学习记忆及吗啡成瘾中具有调节作用,但组胺在对吗啡戒断后的学习记忆损伤中的作用未见报道。因此,在本研究中我们采用条件性恐惧性记忆和恐惧记忆消除模型,前者是神经生物学上主要研究关联性情绪记忆的模型,后者是人类焦虑性疾病暴露治疗的临床前模型。实验中给予组氨酸脱羧酶基因敲除小鼠(histididedecarboxylase gene knockout,HDCKO)和野生型(wild-type,WT)小鼠皮下注射吗啡或生理盐水,每天两次,连续5 d,吗啡注射剂量每天递增,从开始的10mg/kg提高到最后一天的50 mg/kg。戒断7 d后小鼠分别接受线索恐惧训练或背景恐惧训练,然后在随后的4 d内每天接受一个线索或背景恐惧记忆的消除,用Western blot技术检测杏仁核、内侧前额叶皮层(mPFC)、海马的细胞外信号调节激酶(ERK)的磷酸化水平。实验发现吗啡戒断对线索和背景恐惧记忆的获得没有影响,对背景恐惧记忆的消除也无作用,但能抑制线索恐惧记忆的消除。HDCKO小鼠提高线索和背景恐惧记忆的获得,但对线索和背景恐惧记忆的消除没有作用。但HDCKO小鼠增强了吗啡戒断对线索恐惧记忆消除的抑制作用,与行为学实验结果相一致是,,吗啡戒断能明显降低WT和HDCKO小鼠在线索恐惧记忆消除第4次训练后杏仁核和mPFC脑区的ERK磷酸化水平,但对海马脑区的ERK磷酸化没有作用;HDCKO小鼠在线索恐惧记忆消除训练的第4次训练后杏仁核、mPFC脑区的ERK蛋白没有明显磷酸化激活。这些结果提示:吗啡戒断能选择性抑制恐惧记忆的消除,此作用是通过抑制杏仁核和mPFC脑区内ERK蛋白磷酸化来实现的;组胺缺乏能增强线索和背景恐惧记忆的获得以及增强吗啡戒断对线索恐惧记忆消除的抑制作用。
Drug addiction has become a global social problem.Drug abuse has spread to more than 200 countries and areas around the world.In china,opioids dominate in many abused drugs.Morphine is a representative substance among opioids.It is easy to develop into morphine tolerance and addiction.Morphine addiction is difficult to withdrawal;and even after withdrawal from morphine addiction,there is a high rate of relapse.At present,there are no satisfactory treatments at home and abroad. Therefore,it is urgent to explore the neurobiological mechanisms underlying the opioids addiction,and thereby find therapeutic targets and develop safe,effective, low-cost drugs.
Now,many studies showed that many neurotransmitters and neuromodulators are involved in opioids(morphine)addiction.Apart from endogenous opioidergic system,opioids addiction recruits dopaminergic and some other excitatory amino acid systems.The researchers study the role of non-opioidergic system involved in drug addiction and try to find new drugs to treat opioids(morphine)addiction.It is considered that dopaminergic system play an important role in psychical dependence of opioids.
The tuberomamillary(TM)nucleus of the hypothalamus was the sole site of histaminergic neurons whose efferent fibers project to almost the entire brain. Histamine plays an important role as both neurotransmitter and neuromodulator in the brain.Through its H_1,H_2 and H_3 receptors,histamine participates in various physiological and behavioral functions including the sleep-wake cycle,learning and memory,emotion.Recently,it has been reported that histamine is involved in modulating drug addiction.For example,oral antitussives including codeine and H_1 receptor antagonist are addictive.Histamine H_2 receptor antagonist,zolantidine, promotes morphine-induced reward and accelerates the metabolism of dopamine,but histamine can inhibit morphine - induced reward by decreasing the dopamine release. The histidine decarboxylase gene knockout mice(HDCKO)and H_1/H_2 receptor gene double knockout mice are more sensitive to methamphetamine action.These findings suggest that histamine may play an inhibitory role in morphine addiction.However,it is unclear what is the role of endogenous histamine in development of morphine addiction.
In addition,drug addiction is defined as compulsive drug use and loss of control over drug-seeking behavior despite negative consequences.Drug addiction is a memory disorder that is associated with aberrant formation of synaptic plasticity in certain neural circuit including the hippocampus,amygdala,and prefrontal cortex. Addiction memory is an aberrant memory which has an important characteristic of stubborn persistence,even maintained one's whole life.Drug addiction is usually associated with impairment of cognitive function including learning,memory,anxiety and attention.Conversely,cognitive impairments may contribute to drug relapse. Therefore,improving the cognitive function could be used to regulate the process of drug addiction.On the other hand,histaminergic system is involved in synaptic plasticity and neuronal excitability.Histamine can activate polyamine site of NMDA receptor and enhance NMDA-dependent Long-Term Potentiation in vitro. Intracerebroventricularly(i.c.v.)administered histamine or intraperitoneal injection (i.p.)of histidine can alleviate cognitive dysfunction in many animal models. Furthermore,the level of brain histamine is closely related with learning and memory. These results suggest that histamine may inhibit addiction and relapse by modulating cognitive impairments induced by morphine addiction.However,as yet there is no report related to endogenous histamine,morphine addiction,learning and memory. Therefore,it is necessary to investigate the effect of endogenous histamine on morphine addiction and cognitive impairments after morphine addiction.
Therefore,in this study,behavioral animal model,immunohistochemistry technique and biochemical detection method will be used to investigat the effect of endogenous histamine on the development of morphine-induced conditioned place preference and the role of the histaminergic system in the change of cognition after morphine withdrawal.
PartⅠEndogenous histamine inhibits the development of morphine-induced conditioned place preference
This study is designed to investigate the effects of brain histamine on the processes leading to morphine-induced reward-seeking behavior.The model of conditioned place preference(CPP)was used to assess the rewarding effect of morphine.The levels of histamine,glutamate,gamma-aminobutyric acid(GABA), dopamine(DA)and 3,4 - dihydroxyphenylacetic acid(DOPAC)were measured with high-performance liquid chromatography.Immunohistochemistry technique was used to observe the morphological changes of neurons.We found that intraperitoneal injection of morphine(2,5 or 10 mg/kg)induced the development of CPP in a dose-dependent manner.In addition,repeated morphine administrations(10 mg/kg) decreased the histamine content and in the ventral tegmental area(VTA)and nucleus accumbens(NAc)and reduced number and size of histaminergic neurons in the tuberomammillary nucleus(TM).It also markedly increased the DOPAC/DA ratios in the VTA and NAc.Intraperitoneal injection of histidine(50,100 or 200 mg/kg) dose-dependently inhibited the development of morphine-induced CPP.Bilateral lesions of the TM,which decreased the histamine levels of the VTA and NAc, potentiated the development of CPP induced by morphine(1 mg/kg,a dose producing no appreciable effect when given alone).It increased the DOPAC/DA ratios in the VTA and NAc,but did not change the glutamate or GABA levels in these nuclei. Histidine reversed the effects of TM lesions.Furthermore,histidine decarboxylase gene knockout(HDCKO)mice were more sensitive to morphine-induced CPP than wild-type(WT)mice,and the DOPAC/DA ratio in VTA and NAc of HDCKO mice is higher than that of WT mice.Therefore,these results indicate that brain histamine plays an important role in inhibiting the development of morphine-induced reward-seeking behavior,and this inhibitiory function may works by modulating dopaminergic activity.
PartⅡHistidine decarboxylase gene knockout mice potentiates impairment of cued fear extinction induced by morphine withdrawal
Previous studies have shown that morphine addiction impairs learning and memory and produces negative emotion.Histamine plays an important modulation on morphine addiction,learning,memory and emotion.However,little is known about the effect of histamine on impairment of learning and memory after morphine withdrawal.In the present study,we use fear conditioning and fear extinction,fear conditioning has long been an important model of associative learning and fear extinction is an important preclinical model for exposure therapy of human anxiety disorders.Histidine decarboxylase gene knockout(HDCKO)and wild - type(WT) mice were administrated subcutaneously morphine hydrochlodde or saline twice per day for continuous 5 days.The dose was 10 mg/kg on the first day,and gradually increased to 50 mg/kg on the fifth day.The mice received an cued or contextual fear conditioning session 7 days after the last morphine injection.During subsequent days, rats received four cued or contextual extinction sessions(one session per day). Western blot was used to detect the extracellular signal-regulated kinase(ERK) phosphorylation in amygdala,medial prefrontal cortex(mPFC)and hippocampus. Morphine withdrawal did not affect the acquisition of cued or contextual fear memory, but it produced impairment in cued but not contextual fear extinction.Histamine deficiency markedly potentiated the acquisition of learning in cued and contextual fear conditioning in the HDCKO mice,but had no effect on cued and contextual fear extinction.However,histamine deficiency potentiated the inhibitory role of morphine withdrawal in cued fear extinction.Consistent with the behavioral results,morphine withdrawal decreased ERK phosphorylation in the amygdala and mPFC but not in the hippocampus of WT and HDCKO mice,and ERK might not be phosphorylad in the amygdale and mPFC of HDCKO mice after the 4th training of cued fear extinction. These results suggest that morphine withdrawal selectively impairs the cued fear extinction through inhibiting the ERK phosphorylation in the amygdale and mPFC. Histamine deficiency not only enhances acquisition the cued and contextual fear conditioning and but also potentiates the impairment of extinction of cued fear memory.
目前认为脑内多种神经递质和神经调质系统参与阿片(吗啡)成瘾,除内源性阿片系统外,还有多巴胺(DA)系统、兴奋性氨基酸系统等。研究者试图解析这些非阿片靶受体系统在毒品成瘾中的作用机制并寻求相关治疗药物。脑内DA神经系统是阿片类引起精神依赖作用的轴心部位。
组胺能神经的胞体唯一位于下丘脑结节乳头核,组胺能神经元在脑内有着广泛而弥散的投射。作为脑内一种重要的神经递质或调质,通过H_1、H_2、H_3受体发挥着多种神经调节作用,如参与调节睡眠—觉醒活动、学习和记忆、情绪等生理作用。最近有报道组胺也参与调节药物成瘾的机制,如口服的止咳药(含可待因和H_1受体拮抗药)具有成瘾性。组胺H_2受体拮抗药zolantidine能提高吗啡诱导的奖赏作用,并且加速DA的代谢。H_1/H_2受体双基因敲除小鼠和组氨酸脱羧酶基因敲除(histidine decarboxylase gene knockout,HDCKO)小鼠促进甲基苯丙胺成瘾。这些研究都提示中枢组胺可能在药物成瘾中发挥着抑制作用,但是迄今尚不清楚中枢组胺在吗啡成瘾形成过程中的作用。
此外,药物成瘾表现为不顾后果的强迫性用药和失去控制的觅药行为。药物成瘾是一种记忆性疾病,成瘾过程伴随着在特定的神经环路中以特殊的方式形成突触可塑性改变,这些部位包括海马、杏仁核、皮层。成瘾记忆是一种畸形记忆,其主要特点是顽固存在,有的甚至持续一生,而且药物成瘾者常伴有认知功能的损伤如学习记忆能力下降,注意力不集中,焦虑。而这些认知损伤反过来是成瘾药物的复吸的重要原因之一,这提示可以通过利用改变认知功能来调节药物成瘾的进程。另一方面,组胺能神经系统参与调节神经元的突触可塑性和神经元兴奋性。在离体细胞和脑片电生理的研究发现,组胺可能直接作用于NMDA受体的多胺位点并增强NMDA受体依赖的长时程增强。脑室内注射组胺,或腹腔内给予组氨酸都可以改善动物在多种动物模型中的认知功能障碍,而且脑内组胺水平与学习记忆的能力有着密切的相关性。以上的结果均提示,组胺可通过调节认知功能来抑制吗啡诱导的成瘾以及复吸。但是目前尚无中枢组胺对吗啡成瘾以及学习记忆等三者关联的报告,所以很有必要研究在吗啡成瘾和戒断过程中认知功能的改变以及组胺的作用。
因此,在本研究中,利用整体行为学、免疫组化、生化等实验方法探讨脑内内源性组胺对吗啡诱导的条件性位置偏爱形成过程的作用,并探讨吗啡戒断过程认知功能的改变以及组胺能神经系统在其中的作用。
第一部分内源性组胺抑制吗啡诱导的条件性位置偏爱的形成过程
为了探讨内源性组胺在吗啡诱导的奖赏性觅药行为中的作用,本研究采用条件性位置偏爱(conditioned place preference,CPP)模型来评价吗啡奖赏作用,同时利用高效液相结合电化学技术检测脑内多巴胺(DA)、3,4-二羟苯乙酸(DOPAC)、组胺、谷氨酸、γ-氨基丁酸(GABA),使用免疫组化技术用来观察组胺能神经元的形态学改变。我们发现腹腔内分别注射2、5、10 mg/kg吗啡能剂量依赖性地诱导大鼠的CPP的形成。我们还进一步发现10 mg/kg吗啡多次注射后能显著性降低腹侧被盖核(VTA)和伏隔核(NAc)中组胺的含量,同时升高两个脑区的DOPAC/DA比率;并且观察到位于结节乳头核(TM)的组胺能神经元的胞体萎缩变小,数目也减少。腹腔内注射组氨酸(50,100 0r 200 mg/kg)能升高脑内组胺含量,同时剂量依赖性地抑制了10 mg/kg吗啡所诱导的CPP形成。电毁损双侧TM能降低脑内VTA和NAc区内的组胺含量,但不影响谷氨酸酸和GABA水平;电毁损双侧TM还增强1 mg/kg吗啡(单独给药没有明显作用)所诱导的CPP形成,同时升高VTA和NAc区内的DOPAC/DA比率。而组氨酸能逆转TM毁损对组胺含量、DOPAC/DA比率和CPP形成的作用。我们还利用组氨酸脱羧酶基因敲除小鼠(histidine decarboxylase gene knockout,HDCKO)小鼠进一步发现,HDCKO小鼠比野生型(wild-type,WT)小鼠对吗啡诱导CPP更敏感,同时VTA和NAc区内的DOPAC/DA比率更高。这些结果都提示中枢组胺能够抑制吗啡诱导的CPP形成,该作用可能是通过调节DA的活性来实现的。
第二部分组氨脱羧酶基因敲除小鼠增强吗啡戒断对线索恐惧记忆消除的损害
以前研究已表明吗啡成瘾能降低学习记忆,产生负性情感,而组胺在许多的学习记忆及吗啡成瘾中具有调节作用,但组胺在对吗啡戒断后的学习记忆损伤中的作用未见报道。因此,在本研究中我们采用条件性恐惧性记忆和恐惧记忆消除模型,前者是神经生物学上主要研究关联性情绪记忆的模型,后者是人类焦虑性疾病暴露治疗的临床前模型。实验中给予组氨酸脱羧酶基因敲除小鼠(histididedecarboxylase gene knockout,HDCKO)和野生型(wild-type,WT)小鼠皮下注射吗啡或生理盐水,每天两次,连续5 d,吗啡注射剂量每天递增,从开始的10mg/kg提高到最后一天的50 mg/kg。戒断7 d后小鼠分别接受线索恐惧训练或背景恐惧训练,然后在随后的4 d内每天接受一个线索或背景恐惧记忆的消除,用Western blot技术检测杏仁核、内侧前额叶皮层(mPFC)、海马的细胞外信号调节激酶(ERK)的磷酸化水平。实验发现吗啡戒断对线索和背景恐惧记忆的获得没有影响,对背景恐惧记忆的消除也无作用,但能抑制线索恐惧记忆的消除。HDCKO小鼠提高线索和背景恐惧记忆的获得,但对线索和背景恐惧记忆的消除没有作用。但HDCKO小鼠增强了吗啡戒断对线索恐惧记忆消除的抑制作用,与行为学实验结果相一致是,,吗啡戒断能明显降低WT和HDCKO小鼠在线索恐惧记忆消除第4次训练后杏仁核和mPFC脑区的ERK磷酸化水平,但对海马脑区的ERK磷酸化没有作用;HDCKO小鼠在线索恐惧记忆消除训练的第4次训练后杏仁核、mPFC脑区的ERK蛋白没有明显磷酸化激活。这些结果提示:吗啡戒断能选择性抑制恐惧记忆的消除,此作用是通过抑制杏仁核和mPFC脑区内ERK蛋白磷酸化来实现的;组胺缺乏能增强线索和背景恐惧记忆的获得以及增强吗啡戒断对线索恐惧记忆消除的抑制作用。
Drug addiction has become a global social problem.Drug abuse has spread to more than 200 countries and areas around the world.In china,opioids dominate in many abused drugs.Morphine is a representative substance among opioids.It is easy to develop into morphine tolerance and addiction.Morphine addiction is difficult to withdrawal;and even after withdrawal from morphine addiction,there is a high rate of relapse.At present,there are no satisfactory treatments at home and abroad. Therefore,it is urgent to explore the neurobiological mechanisms underlying the opioids addiction,and thereby find therapeutic targets and develop safe,effective, low-cost drugs.
Now,many studies showed that many neurotransmitters and neuromodulators are involved in opioids(morphine)addiction.Apart from endogenous opioidergic system,opioids addiction recruits dopaminergic and some other excitatory amino acid systems.The researchers study the role of non-opioidergic system involved in drug addiction and try to find new drugs to treat opioids(morphine)addiction.It is considered that dopaminergic system play an important role in psychical dependence of opioids.
The tuberomamillary(TM)nucleus of the hypothalamus was the sole site of histaminergic neurons whose efferent fibers project to almost the entire brain. Histamine plays an important role as both neurotransmitter and neuromodulator in the brain.Through its H_1,H_2 and H_3 receptors,histamine participates in various physiological and behavioral functions including the sleep-wake cycle,learning and memory,emotion.Recently,it has been reported that histamine is involved in modulating drug addiction.For example,oral antitussives including codeine and H_1 receptor antagonist are addictive.Histamine H_2 receptor antagonist,zolantidine, promotes morphine-induced reward and accelerates the metabolism of dopamine,but histamine can inhibit morphine - induced reward by decreasing the dopamine release. The histidine decarboxylase gene knockout mice(HDCKO)and H_1/H_2 receptor gene double knockout mice are more sensitive to methamphetamine action.These findings suggest that histamine may play an inhibitory role in morphine addiction.However,it is unclear what is the role of endogenous histamine in development of morphine addiction.
In addition,drug addiction is defined as compulsive drug use and loss of control over drug-seeking behavior despite negative consequences.Drug addiction is a memory disorder that is associated with aberrant formation of synaptic plasticity in certain neural circuit including the hippocampus,amygdala,and prefrontal cortex. Addiction memory is an aberrant memory which has an important characteristic of stubborn persistence,even maintained one's whole life.Drug addiction is usually associated with impairment of cognitive function including learning,memory,anxiety and attention.Conversely,cognitive impairments may contribute to drug relapse. Therefore,improving the cognitive function could be used to regulate the process of drug addiction.On the other hand,histaminergic system is involved in synaptic plasticity and neuronal excitability.Histamine can activate polyamine site of NMDA receptor and enhance NMDA-dependent Long-Term Potentiation in vitro. Intracerebroventricularly(i.c.v.)administered histamine or intraperitoneal injection (i.p.)of histidine can alleviate cognitive dysfunction in many animal models. Furthermore,the level of brain histamine is closely related with learning and memory. These results suggest that histamine may inhibit addiction and relapse by modulating cognitive impairments induced by morphine addiction.However,as yet there is no report related to endogenous histamine,morphine addiction,learning and memory. Therefore,it is necessary to investigate the effect of endogenous histamine on morphine addiction and cognitive impairments after morphine addiction.
Therefore,in this study,behavioral animal model,immunohistochemistry technique and biochemical detection method will be used to investigat the effect of endogenous histamine on the development of morphine-induced conditioned place preference and the role of the histaminergic system in the change of cognition after morphine withdrawal.
PartⅠEndogenous histamine inhibits the development of morphine-induced conditioned place preference
This study is designed to investigate the effects of brain histamine on the processes leading to morphine-induced reward-seeking behavior.The model of conditioned place preference(CPP)was used to assess the rewarding effect of morphine.The levels of histamine,glutamate,gamma-aminobutyric acid(GABA), dopamine(DA)and 3,4 - dihydroxyphenylacetic acid(DOPAC)were measured with high-performance liquid chromatography.Immunohistochemistry technique was used to observe the morphological changes of neurons.We found that intraperitoneal injection of morphine(2,5 or 10 mg/kg)induced the development of CPP in a dose-dependent manner.In addition,repeated morphine administrations(10 mg/kg) decreased the histamine content and in the ventral tegmental area(VTA)and nucleus accumbens(NAc)and reduced number and size of histaminergic neurons in the tuberomammillary nucleus(TM).It also markedly increased the DOPAC/DA ratios in the VTA and NAc.Intraperitoneal injection of histidine(50,100 or 200 mg/kg) dose-dependently inhibited the development of morphine-induced CPP.Bilateral lesions of the TM,which decreased the histamine levels of the VTA and NAc, potentiated the development of CPP induced by morphine(1 mg/kg,a dose producing no appreciable effect when given alone).It increased the DOPAC/DA ratios in the VTA and NAc,but did not change the glutamate or GABA levels in these nuclei. Histidine reversed the effects of TM lesions.Furthermore,histidine decarboxylase gene knockout(HDCKO)mice were more sensitive to morphine-induced CPP than wild-type(WT)mice,and the DOPAC/DA ratio in VTA and NAc of HDCKO mice is higher than that of WT mice.Therefore,these results indicate that brain histamine plays an important role in inhibiting the development of morphine-induced reward-seeking behavior,and this inhibitiory function may works by modulating dopaminergic activity.
PartⅡHistidine decarboxylase gene knockout mice potentiates impairment of cued fear extinction induced by morphine withdrawal
Previous studies have shown that morphine addiction impairs learning and memory and produces negative emotion.Histamine plays an important modulation on morphine addiction,learning,memory and emotion.However,little is known about the effect of histamine on impairment of learning and memory after morphine withdrawal.In the present study,we use fear conditioning and fear extinction,fear conditioning has long been an important model of associative learning and fear extinction is an important preclinical model for exposure therapy of human anxiety disorders.Histidine decarboxylase gene knockout(HDCKO)and wild - type(WT) mice were administrated subcutaneously morphine hydrochlodde or saline twice per day for continuous 5 days.The dose was 10 mg/kg on the first day,and gradually increased to 50 mg/kg on the fifth day.The mice received an cued or contextual fear conditioning session 7 days after the last morphine injection.During subsequent days, rats received four cued or contextual extinction sessions(one session per day). Western blot was used to detect the extracellular signal-regulated kinase(ERK) phosphorylation in amygdala,medial prefrontal cortex(mPFC)and hippocampus. Morphine withdrawal did not affect the acquisition of cued or contextual fear memory, but it produced impairment in cued but not contextual fear extinction.Histamine deficiency markedly potentiated the acquisition of learning in cued and contextual fear conditioning in the HDCKO mice,but had no effect on cued and contextual fear extinction.However,histamine deficiency potentiated the inhibitory role of morphine withdrawal in cued fear extinction.Consistent with the behavioral results,morphine withdrawal decreased ERK phosphorylation in the amygdala and mPFC but not in the hippocampus of WT and HDCKO mice,and ERK might not be phosphorylad in the amygdale and mPFC of HDCKO mice after the 4th training of cued fear extinction. These results suggest that morphine withdrawal selectively impairs the cued fear extinction through inhibiting the ERK phosphorylation in the amygdale and mPFC. Histamine deficiency not only enhances acquisition the cued and contextual fear conditioning and but also potentiates the impairment of extinction of cued fear memory.
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