Effect Of Histaminergic-related Compounds On Morphine-induced Conditioned Place Preference In Rats

Drug addiction is one kind of chronic relapse nature brain disease,which is characterized by compulsive,out-of-control drug taking and emergence of a negative emotional state.Psychoactive Substance,such as morphine,can cause to physical dependence and psychological dependence,which is the reason of the high rate replasing.Due to the complicated mechanisms,it is not yet found an effective anti-addictive drug and interventions.Thus,it is of great importance to develop pharmacological interventions for morphine dependence.Histamine,a biogenic amine,is an important neurotransmiter or neuromodulator in the mammalian central nervous system.Brain histarninergic system seems to be involved in various physiological and behavioral functions including sleep-wake cycles,appetite control,neuroendocrine,learning and memory through its specific receptors.The tuberomammillary nucleus(TM)is the only source of histaminergic neurons,which project to various parts of the brain including the nucleus accumbens (NAc)and the ventral tegmental area(VTA),regions known to be involved in reward mechanisms.A role for brain histamine in regulating reward mechanisms has been recently documented in several studies.For example,histamine injected into the lateral ventricle immediately raises the reinforcement threshold,which can be prevented by the application of histaminergic antagonists.Histidine,a histamine precursor,attenuates the thresholdlowering effects of pentazocine.H1 receptor antagonists act as rewards in combination with opioids and even when given alone. Recently,our group further found that histidine inhibits the development of morphine-induced CPP,and bilateral lesions in the tuberomammilary nucleus (damaging histaminergic neurons)potentiate the development of morphine-induced CPP,histidine decarboxylase knock out(HDC,KO)mice showed enhanced place preference,and this enhancement extincted more slowly.Therefore,these studies suggest that histamine plays an inhibitory role in drug addiction,including morphine dependence and withdrawal,and histaminergic system may be closely related to drug addiction.1.Carnosine on the effect of morphine-induced conditioned place preference and locomotor sensitization in ratsCarnosine(β-alanyl-l-histidine),a natural occurring dipeptide,is present at high concentrations in mammalian muscle and brain.It has been characterized as a putative neurotransmitter in olfactory receptor neurons,and acts as an anti-inflammatory,free radical scavenger.It also serves as a reservoir for histidine and can be metabolically transformed into histamine through the carnosine-histidine-histamine pathway. Lately,our group also found carnosine prevents both pentyleneterazole kindling seizures and amygdaloid kinding seizures through carnosine-histidine-histamine pathway;in addition,carnosine protects against NMDA-induced neurotoxicity and necrotic cell death in PC12 cells through the carnosine-histidine-histamine pathway and H1/H3 receptors,these results suggest carnosine also can be transformed into histamine to inhibit morphine dependence.In the present study,our study was designed to investigate the effect of carnosine on the development of morphine-induced CPP and locomotor sensitization and its possible underlying mechanism in Sprague-Dawley rats.We expect to elucidate the relations between carnosine and morphine dependence in the two addiction models.In conclusion,our study provides more evidences that carnosine inhibts the development of morphine-induced CPP.The objectives of this study were to determine the effects of carnosine on the development of morphine-induced conditioned place preference(CPP)and locomotor sensitization,at the same time,investigate its possible mechanism of action in Sprague-Dawley rats.Rats were given i.p.morphine(10 mg/kg)or saline(1 ml/kg), and carnosine(200,500,1000 mg/kg)or saline(1 ml/kg)was given 1 h prior to saline or morphine treatment.Intraperitioneal injection of carnosine(200,500,1000 mg/kg) significantly inhibited the development of morphine-induced CPP in a dose-dependent manner.Although carnosine had no appreciable effect on the levels of histamine in the ventral tegmental area(VTA),nucleus accumbens(NAc)and prefrontal cortex(PFC), it significantly decreased glutamate level in the VTA,dopamine levels in the NAc and PFC,and 3,4-dihydroxy-phenylacetic acid(DOPAC)level in the NAc of morphine-treated rats.In addition,intraperitioneal injection of carnosine(500 mg/kg) partly inhibits the expression of morphine induced locomotor sensitization in a time-dependent manner.These results indicate that carnosine inhibits morphine-induced CPP in rats,and its action may be due to modulation of dopaminergic and glutaminergic activity,but carnosine has no significant effect on morphine-induced hyperlocomotion,which suggest that the effect of carnosine on conditioned rewarding and psycho-motor exists disassociation and different neuromechanisms.The study suggests that camosine has potential as a new anti-addictive drug.2.Clobenpropit and histidine on the effect of a priming drug-induced reinstatement of morphine-induced conditioned place preferenceThe objectives of this study were to determine the effects of clobenpropit and histidine on a drug-induced reinstatement of a morphine-induced conditioned place preference in rats.In the present experiments,we established the persistence, extinction,and reinstatement of a morphine-induced CPP.Rats were given i.p. morphine(1 mg/kg)and histidine(100,200,500 mg/kg)was given 1 h prior to morphine treatment.Three different doses of clobenpropit(2,5 and 10μg/rat,i.c.v.) co-administered with morphine(1 mg/kg,i.p.)was injected 15 min before testing.The CPP was reinstated by priming injection of 1 mg/kg morphine.Histidine(100,200, 500 mg/kg)significantly inhibited the reinstatement in a dose-dependent manner; Clobenpropit(5,10μg/rat)can significantly inhabits the reinstatement by a priming dose of morphine-induced CPP compared with the morphine control group. Clobenpropit and histidine inhibited the revival of morphine-induced CPP in a dose dependent manner,the study suggests that they may be inhibit relapse of morphine to some extent.