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Muscarinic Acetylcholine Receptors in Alcohol Use Disorder

神经药理学报 2019年第Z1期 30-31页

作者： andrew j lawrence Florey Institute of Neuroscience and Mental Health ParkvilleVictoriaFlorey Department of Neuroscience and Mental HealthUniversity of Melbourne

Background:Despite the large socioeconomic burden of alcohol use disorders(AUD),therapeutic treatment options are limited. There is a need to characterise the underlying neurochemistry driving alcohol seeking to identify and evaluate novel targets. AUDs are characterised by a transition to compulsive seeking,which is hypothesized to involve a shift from ventral to dorsal striatum and a medial to lateral dorsal striatal shift in the transition from goaldirected to habitual alcohol-seeking behaviours. Muscarinic acetylcholine receptors(mAChRs) are a potential target for AUD;they are expressed within the mesocorticolimbic reward system,including dense expression in the dorsal striatum,where they modulate dopamine and glutamate release,which may regulate reward processing. Methods:To assess the role of mAChRs in AUD,we first conducted genome-wide RNA sequencing in the caudate/putamen of 10 human alcoholics and 10 healthy controls and concurrently examined muscarinic receptor expression in the corresponding regions in rat(dorsolateral and dorsomedial striatum) following chronic alcohol consumption/withdrawal using qPCR. Next we examined the role of select muscarinic and nicotinic receptor subtypes in alcohol consumption and seeking using selective allosteric modulators. Finally,we probed the role of select muscarinic and nicotinic receptor subtypes in the dorsal striatum in alcohol consumption and seeking. Results:In human alcoholics M4 receptor expression was significantly decreased in the putamen. In line with this,M4 receptor expression was decreased in the rat dorsolateral striatum. Further,administration of VU154(30 mg·kg-1,p.o.) reduced alcohol self-administration and cue-induced relapse,without effects on natural reward consumption or sedation. We also found that a centrally active and selective negative allosteric modulator(NAM) for the rat M5 muscarinic receptor(mAChR),ML375,selectively decreases ethanol self-administration and attenuates cue-induced reinstateme

关键词： AUD Muscarinic Acetylcholine Receptors in Alcohol Use Disorder

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Phosphodiesterase-4 inhibitor rolipram decreases ethanol seeking and consumption in alcohol-preferring fawn-hooded rats

Phosphodiesterase-4 inhibitor rolipram decreases ethanol see...

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中国药理学会第十一次全国学术会议

作者： andrew j lawrence Florey Neuroscience Institutes and Centre for Neuroscience University of MelbourneVictoriaAustralia

OBjECTIVE Since cyclic AMP(cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment *** 4(PDE4),an enzyme that specifically catalyzes the hydrolysis of cAMP,plays a critical role in regulating its intracellular ***,it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and *** Male Fawn-Hooded(FH/Wjd) rats were tested for 5%(V/V) ethanol and 10%(W/V) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram(0.0125,0.025,and 0.05 mg·kg,s.c.);rolipram at higher doses(0.05,0.1,and 0.2 mg·kg,s.c.) was tested to determine its impact on the intake of ethanol,sucrose,or water using the two-botde choice drinking *** open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor *** Acute administration of rolipram dose-dependently reduced operant self-administration of 5%ethanol,but had no effect on 10%sucrose ***-course assessment revealed a significant anti-drinking effect of rolipram(0.1 and 0.2 mg·kg) in continuous-and intermittent-access to ethanol at 5%or 10%,***,chronic rolipram treatment time-dependently decreased 5%ethanol consumption and preference during treatment days and after the termination of rolipram *** at the highest doses(0.1 and 0.2 mg·kg) did decrease locomotor activity,but the effect lasted only 10 and 20 min,respectively,which did not likely alter long-term ethanol *** These results suggest that PDE4 plays a role in alcohol seeking and consumption *** interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.

关键词： cyclic AMP signaling phosphodiesterase-4 rolipram FH/Wjd rat ethanol intake

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Protein synthesis inhibitors disrupt the induction of behavioral sensitization to a single morphine exposure and regulate Hsp70 expression in the mouse nucleus accumbens

Protein synthesis inhibitors disrupt the induction of behavi...

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中国药理学会第十次全国学术会议

作者： andrew j.lawrence Howard Florey Institute and Centre for Neuroscience ParkvilleVictoria 3010 Australia

De novo protein synthesis has been implicated as necessary for long-lasting changes in neuronal *** sensitization to a single exposure to addictive drugs is a form of neuroplasticity,but little is known about the impo...

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Effect of histone deacetylase inhibitor sodium butyrate on behavioral sensitization to a single morphine exposure in C57BL/6 mice

Effect of histone deacetylase inhibitor sodium butyrate on b...

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中国药理学会第十次全国学术会议

作者： andrew j.lawrence Howard Florey Institute and Centre for Neuroscience ParkvilleVictoria 3010Australia

Background and purpose More recently behavioral sensitization induced by a single morphine exposure has been considered as behavioral plasticity associated with drug *** histone acetylation mediating chromatin remodeling plays a critical role in the mechanisms underlying some types of behavioral ***-fore, the present study was designed to investigate whether the HDAC inhibitor SB would alter the establishing processes of behavioral sensitization to a single injection of *** approach Appling a single morphine-induced behavioral sensitization model in male C57BL/6 mice,we chose in this study to multiply treat mice with SB in the phases of induction,transfer,and expression of behavioral sensitization and to measure the distance of horizonal locomotor activity.

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Rolipram,a selective phosphodiesterase-4 inhibitor,decreases ethanol seeking and consumption in alcohol-preferring Fawn Hooded rats

Rolipram,a selective phosphodiesterase-4 inhibitor,decreases...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： andrew j.lawrence Howard Florey Institute and Centre for Neuroscience ParkvilleVictoria 3010Australia

＜正＞Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapy. Since the cyclic AMP（cAMP） signaling cascade has been implicated in mediating the behavioral response to alcohol, it would be of interest to determine whether phosphodiesterase-4（PDE4）,an enzyme that selectively hydrolyzes intracellular cAMP,is involved in the regulation of alcohol ***,the selective PDE4 inhibitor rolipram was used to measure its anti-drinking properties in alcohol-preferring Fawn-Hooded（FH/Wjd） *** showed that acute administration of rolipram（0.05,0.1,and 0.2 mg/kg） selectively and dose-dependently reduced 5%ethanol, but not 10%sucrose,operant self-administration;it also decreased voluntary 5%ethanol intake,but not water consumption,for the initial 30 min in rats showing high stable preference for *** course assessment revealed the significant anti-drinking effect of rolipram（0.1,0.2 mg/kg） lasted for 5 h in both continuous- and intermittentaccess to 5%or 10%***,chronic rolipram treatment decreased 5%ethanol consumption and preference during the drug treatment *** effect lasted even after withdrawal of drug *** locomotor activity was inhibited by rolipram at 0.1 and 0.2 mg/kg,the effect was present only in the initial about 20 min,which did not seem to alter long-term ethanol *** data suggest that PDE4 may play a promising role in ethanol drinking and dependent *** may be a potential treatment target for further development of anti-drinking drugs.

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先天性嗜酒大鼠的饮酒行为特性

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中国药理学与毒理学杂志 2009年第1期23卷 65-69页

作者：景丽张振华王卫平张敏罗娟陈锋 andrew j lawrence 梁建辉北京大学中国药物依赖性研究所北京100083 School of Medical Sciences Royal Melbourne Institute of Technology University Victoria 3083 Australia Howard Florey Institute the University of Melbourne Victoria 3010 Australia

目的系统考察先天性嗜酒(FH/Wjd)大鼠嗜酒的行为特性。方法采用双瓶(5%或10%乙醇和自来水)自由选择的方法,观察FH/Wjd大鼠的饮酒量、饮水量和乙醇偏爱率,并进一步探讨FH/Wjd大鼠饮酒的昼夜差异性;在乙醇剥夺实验中,研究乙醇剥夺24h对FH/... 详细信息

目的系统考察先天性嗜酒(FH/Wjd)大鼠嗜酒的行为特性。方法采用双瓶(5%或10%乙醇和自来水)自由选择的方法,观察FH/Wjd大鼠的饮酒量、饮水量和乙醇偏爱率,并进一步探讨FH/Wjd大鼠饮酒的昼夜差异性;在乙醇剥夺实验中,研究乙醇剥夺24h对FH/Wjd大鼠饮酒量和乙醇偏爱率的影响;选用固定比率(FR1)实验程序,探讨FH/Wjd大鼠操作性自身饮酒的行为特点。结果在双瓶自由选择饮酒实验中,给予5%乙醇,大鼠的饮酒量为(4.3±0.2)g·kg-1·d-1,饮水量为(20.1±2.3)g·kg-1·d-1,乙醇偏爱率为(82.9±2.0)%;给予10%乙醇,大鼠的饮酒量为(6.4±0.2)g·kg-1·d-1,饮水量为(37.2±2.7)g·kg-1·d-1,乙醇偏爱率为(69.2±2.0)%,与5%乙醇相比较,饮酒量和饮水量显著增大,但乙醇偏爱率明显降低。FH/Wjd大鼠的饮酒行为呈明显的昼夜节律,夜间饮酒量和乙醇偏爱率均显著高于白天,夜间饮水量虽呈增加趋势,但差异无显著性。FH/Wjd大鼠乙醇剥夺24h,再次给酒后1h的饮酒量增加37.7%,乙醇偏爱率增加22.1%;再次给酒后24h的饮酒量增加15.6%,乙醇偏爱率存在增高趋势,但差异无显著性。FH/Wjd大鼠操作性自身饮酒行为训练13d后,连续测试3d,操作性饮酒行为的偏爱率为49%～64%。结论FH/Wjd大鼠具有饮酒量大和乙醇偏爱率高的特点,存在明显的乙醇剥夺效应,并可在短期内建立操作性自身饮酒行为,是一种理想的先天嗜酒动物模型。

关键词：大鼠 FH/Wjd 乙醇饮酒行为乙醇剥夺

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胍丁胺对先天嗜酒FH-Wjd大鼠饮酒行为的影响

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中国新药杂志 2009年第3期18卷 243-247页

作者：景丽邱毅张敏王卫平 CHEN Feng andrew j lawrence 李锦梁建辉北京大学中国药物依赖性研究所北京100083 澳大利亚RMIT大学医学院 Victoria 3083 澳大利亚Melbourne大学Howard Florey研究所 Victoria 3010 北京毒物药物研究所北京100850

目的:探讨胍丁胺对嗜酒FH/Wjd大鼠饮酒行为的影响。方法:利用FH/Wjd大鼠先天嗜酒的特点,采用双瓶(5%酒精和自来水)自由选择的方法,观察胍丁胺给药前后以及撤药后对FH/Wjd大鼠饮酒量、饮水量和酒精偏爱率的影响。结果:80和160 ***-1胍丁... 详细信息

目的:探讨胍丁胺对嗜酒FH/Wjd大鼠饮酒行为的影响。方法:利用FH/Wjd大鼠先天嗜酒的特点,采用双瓶(5%酒精和自来水)自由选择的方法,观察胍丁胺给药前后以及撤药后对FH/Wjd大鼠饮酒量、饮水量和酒精偏爱率的影响。结果:80和160 ***-1胍丁胺皮下注射给药可明显抑制大鼠的饮酒量,与给药前(生理氯化钠溶液对照)相比,饮酒量分别下降25.9%和34.7%。进一步研究发现,500 ***-1胍丁胺灌胃给药同样可以降低大鼠的饮酒量,与给药前(生理氯化钠溶液对照)相比,饮酒量下降41.2%。无论皮下注射或灌胃给药,大鼠的酒精偏爱率均呈现明显下降的趋势。给药期间饮水量呈现一定的上升趋势。灌胃给予胍丁胺对大鼠的进食量无明显影响。结论:胍丁胺能够降低嗜酒FH/Wjd大鼠的饮酒量,可能具有治疗酒精依赖的药理活性。

关键词：胍丁胺 FH/Wjd大鼠饮酒行为

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酒精滥用与成瘾中枢神经递质的研究进展

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中国药物依赖性杂志 2007年第1期16卷 5-12页

作者：陈锋 andrew j lawrence 梁建辉 Melbourne大学Howard Florey研究所北京大学中国药物依赖性研究所北京100083

酒精滥用及其成瘾是一种失控且紊乱的饮酒行为，被定义为一种病理状态行为综合征。酒精成瘾患者除了机体出现对酒精产生耐受，中断饮酒后出现戒断症状以及各种并发症外，还突出表现为强迫性觅酒行为，对酒的强烈渴求（craving）和对酒... 详细信息

酒精滥用及其成瘾是一种失控且紊乱的饮酒行为，被定义为一种病理状态行为综合征。酒精成瘾患者除了机体出现对酒精产生耐受，中断饮酒后出现戒断症状以及各种并发症外，还突出表现为强迫性觅酒行为，对酒的强烈渴求（craving）和对酒的反复滥用，并且这些行为特征即使在断酒数年后也可能再次出现。

关键词：酒精滥用酒精成瘾中枢神经递质饮酒行为病理状态戒断症状行为特征综合征

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S2B-2 Comorbidity of Anxiety and Depression Induced by Liang’s Contextual-Stress Box in Mice

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神经药理学报 2018年第4期8卷 44-45页

作者： LIANG jian-hui LIANG hui CHENG tao LIU Xiao-yan Simon M.Y.Lee TANG Ben-qin WANG Xiufen CHEN Feng andrew j.lawrence Department of Molecular and Cellular Pharmacology School of Pharmaceutical SciencesPeking UniversityBeijing100083China Department of Pharmacology School of Basic Medicine SciencesPeking UniversityBeijing100083China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoTaipaMacaoChina The Florey Institute of Neuroscience and Mental Health University of MelbourneParkvilleVictoria3010Australia

Rationale:Comorbidity of depression and anxiety is one of the most common mental disorders in *** experimental procedures,however,have focused on identifying mixed depression-and anxiety-like behaviors in animal ***:To develop a novel testing paradigm,the so-called Liang’s contextual-stress Box(briefly,Liang’s Box),for evaluating depression-and/or anxiety-like behaviors in ***:Liang’s Box consisted of a central area(CA)with three peripheral arms(PA).Mice were placed individually in the end of a peripheral arm facing to the central area and were allowed to travel around Liang’s *** a test period,behavioral parameters were recorded and collected by a video-tracking system named SMART 3.0(Panlab,Spain),including①Latency to CA,②Time spent in CA(CA-time),③Distance traveled in CA(CA-distance),④Distance traveled in PA(PA-distance),⑤Transition number between CA and PA,⑥Global activity,⑦CA-time/cm2,⑧PA-time/cm2,⑨CAdistance/cm2,and⑩PA-distance/*** order to assess the reliability and validity of Liang’s Box and get baseline information,we undertook a series of experiment,including verifying consistency and stability in the various strains of mice(KM,ICR,and C57 BL/6 j mice),imposing high illumination,restraint and tail suspension stress,pre-treating with an anxiolytic(diazepam,buspirone)or antidepressant(desipramine,mianserin).Results:①There were not remarkable differences in all the parameters among KM,ICR,and C57 BL/6 j mice;②High illumination,restraint and tail suspension significantly increased the latency to CA and decreased the CA-time,CA-distance and transition ***,these three types of stresses evoked different effect on global *** illumination increased activity,but restraint stress had no significant *** contrast with high illumination,tail suspension stress markedly reduced activity in mice;③The anxiolytics diazepam(0.25 mg·kg-1 and 0.5 mg·kg-1,i.p.)and buspirone(0.5 mg·kg-1 and 1.0 mg·kg-1,i.p.)

关键词： Depression Anxiety Stress Animal model Comorbidity

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胍丁胺对先天嗜酒FH／Wjd大鼠饮酒行为的影响

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中国药理通讯 2008年第3期25卷 39-40页

作者：景丽邱毅张敏王卫平 CHEN Feng andrew j lawrence 李锦梁建辉北京大学中国药物依赖性研究所北京100191 澳大利亚RMIT大学医学院 Victoria3083 澳大利亚Melbourne大学Howard Florey研究所 Victoria3010 北京毒物药物研究所北京100850

目的：探讨胍丁胺对嗜酒FH／Wjd大鼠饮酒行为的影响。方法：利用FH／Wjd大鼠先天嗜酒的特点，采用双瓶（5％酒精和自来水）自由选择的方法，观察胍丁胺给药前后以及撤药后对FH／Wjd大鼠饮酒量、饮水量、总饮液量和酒精偏爱率的影响。结... 详细信息

目的：探讨胍丁胺对嗜酒FH／Wjd大鼠饮酒行为的影响。方法：利用FH／Wjd大鼠先天嗜酒的特点，采用双瓶（5％酒精和自来水）自由选择的方法，观察胍丁胺给药前后以及撤药后对FH／Wjd大鼠饮酒量、饮水量、总饮液量和酒精偏爱率的影响。结果：80mg／kg和160mg／kg胍丁胺皮下给药可明显抑制大鼠的饮酒量，与给药前（生理盐水对照）相比，饮酒量分别下降26．7％和34．7％。

关键词：饮酒行为胍丁胺生理盐水对照酒精偏爱饮酒量

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