Effect Of Brain Histamine On The Development Of Morphine Addiction And Fear Memory After Morphine Withdrawal

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 H₁,H₂ and H₃ 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 H₁ receptor antagonist are addictive.Histamine H₂ 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 H₁/H₂ 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.Partâ… Endogenous histamine inhibits the development of morphine-induced conditioned place preferenceThis 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.Partâ…¡Histidine decarboxylase gene knockout mice potentiates impairment of cued fear extinction induced by morphine withdrawalPrevious 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.