边缘前皮质α_1肾上腺素受体调节帕金森病模型大鼠的焦虑样行为
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摘要
目的观察帕金森病(Parkinson’s disease,PD)模型大鼠的焦虑样行为,以及激活或阻断边缘前皮质(prelimbic cortex,Pr L)的α_1肾上腺素受体对大鼠焦虑样行为的影响。方法将成年、雄性SD大鼠156只随机分为假手术组和PD模型组,每组78只。采用6-羟基多巴胺(6-hydroxydopamine,6-OHDA)单侧损毁内侧前脑束(medial forbrain bundle,MFB)建立PD大鼠模型;利用高架十字迷宫(elevated plus maze,EPM)实验检测大鼠的焦虑样行为; Pr L内注射α_1肾上腺素受体激动剂或拮抗剂后,观察大鼠焦虑样行为的变化。结果与假手术组比较,模型组大鼠在开放臂停留时间百分比、开放臂进入次数百分比和探头次数均明显降低(均P <0. 001),而前伸次数显著增加(P <0. 001)。与注射生理盐水比较,Pr L内注射苯肾上腺素显著降低了假手术大鼠在开放臂停留时间百分比、开放臂进入次数百分比和探头次数(均P <0. 001),且明显增加大鼠前伸次数(P <0. 01);而Pr L内注射苯那沙坦后模型组大鼠在开放臂停留时间百分比(P <0. 05)、开放臂进入次数百分比(P <0. 01)和探头次数(P <0. 001)均显著增加,而前伸次数明显减少(P <0. 05)。与注射生理盐水比较,Pr L内注射苯肾上腺素后模型组大鼠探头次数显著减少(P <0. 05)而前伸次数明显增加(P <0. 001); Pr L内注射苯那沙坦后模型组大鼠探头次数显著增加(P <0. 05)而前伸次数明显减少(P <0. 01)。结论 6-OHDA损毁MFB后诱发大鼠产生焦虑样行为,Pr L内α_1肾上腺素受体参与PD大鼠焦虑样行为的调节。
Objective To observe the anxiety-like behaviors in a rat model of Parkinson's disease and explore the effects of activation or blockade of the prelimbic( Pr L) α_1-adrenoceptors on anxiety-like behaviors in rats. Methods A total of 156 healthy adult male Sprague-Dawley rats were randomly divided into sham-operated group( n = 78) and PD group( n = 78). The rat model of Parkinson's disease( PD) was established by unilateral 6-hydroxydopamine( 6-OHDA) lesion of the medial forbrain bundle( MFB). Then the anxiety-like behaviors of rats were detected by the elevated plus maze( EPM) test. In addition,the changes of anxiety-like behaviors in sham-operated and PD rats were also observed after local injection of the selective α_1-adrenoceptor agonist or antagonist into the Pr L by guided cannula. Results Compared with sham-operated group,the percentage of open arm retention time,the number of open arm entries and the number of head-dippings significantly decreased in PD group( all P < 0. 001),but the number of stretched-forwards was significantly increased( P < 0. 001). Compared with rats treated with saline,intra-PrL injection of phenylephrine significantly decreased the percentage of open arm retention time,the number of open arm entries and the number of head-dippings in sham-operated group( all P < 0. 001),while increased the number of stretched-forwards( P < 0. 01),however,intra-PrL injection of benoxathian increased the percentage of open arm retention time( P < 0. 05),the number of open arm entries( P < 0. 01) and the number of head-dippings( P <0. 001) while decreased the number of stretched-forwards( P < 0. 05). In addition,compared with rats treated with saline,intra-PrL injection of phenylephrine significantly decreased the number of head-dippings in PD group( P < 0. 05),while increased the number of stretched-forwards( P < 0. 001),however,intra-PrL injection of benoxathian increased the number of head-dippings( P < 0. 05),while decreased the number of stretched-forwards( P < 0. 01). Conclusion Unilateral 6-OHDA lesions of the MFB in rats can induce anxiety-like behaviors,and the Pr L α_1-adrenoceptors may be involved in the regulation of anxiety-like behaviors in PD.
Objective To observe the anxiety-like behaviors in a rat model of Parkinson's disease and explore the effects of activation or blockade of the prelimbic( Pr L) α_1-adrenoceptors on anxiety-like behaviors in rats. Methods A total of 156 healthy adult male Sprague-Dawley rats were randomly divided into sham-operated group( n = 78) and PD group( n = 78). The rat model of Parkinson's disease( PD) was established by unilateral 6-hydroxydopamine( 6-OHDA) lesion of the medial forbrain bundle( MFB). Then the anxiety-like behaviors of rats were detected by the elevated plus maze( EPM) test. In addition,the changes of anxiety-like behaviors in sham-operated and PD rats were also observed after local injection of the selective α_1-adrenoceptor agonist or antagonist into the Pr L by guided cannula. Results Compared with sham-operated group,the percentage of open arm retention time,the number of open arm entries and the number of head-dippings significantly decreased in PD group( all P < 0. 001),but the number of stretched-forwards was significantly increased( P < 0. 001). Compared with rats treated with saline,intra-PrL injection of phenylephrine significantly decreased the percentage of open arm retention time,the number of open arm entries and the number of head-dippings in sham-operated group( all P < 0. 001),while increased the number of stretched-forwards( P < 0. 01),however,intra-PrL injection of benoxathian increased the percentage of open arm retention time( P < 0. 05),the number of open arm entries( P < 0. 01) and the number of head-dippings( P <0. 001) while decreased the number of stretched-forwards( P < 0. 05). In addition,compared with rats treated with saline,intra-PrL injection of phenylephrine significantly decreased the number of head-dippings in PD group( P < 0. 05),while increased the number of stretched-forwards( P < 0. 001),however,intra-PrL injection of benoxathian increased the number of head-dippings( P < 0. 05),while decreased the number of stretched-forwards( P < 0. 01). Conclusion Unilateral 6-OHDA lesions of the MFB in rats can induce anxiety-like behaviors,and the Pr L α_1-adrenoceptors may be involved in the regulation of anxiety-like behaviors in PD.
引文
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[2]Du CX,Guo Y,Zhang QJ,et al.Involvement of prelimbic 5-HT7 receptors in the regulation of anxiety-like behaviors in hemiparkinsonian rats[J].Behav Neurosci,2018,40(10):847-855.
[3]Day HE,Campeau S,Watson SJ,et al.Distribution of alpha1a-,alpha 1b-and alpha 1d-adrenergic receptor m RNA in the rat brain and spinal cord[J].J Chem Neuroanat,1997,13(2):115-139.
[4]Singh A,Subhashini N,Sharma S,et al.Involvement of theα1-adrenoceptor in sleep-waking and sleep loss-induced anxiety behavior in zebrafish[J].Neuroscience,2013,245:136-147.
[5]Takamura N,Masuda T,Inoue T,et al.The effects of the coadministration of the alpha(1)-adrenoreceptor antagonist prazosin on the anxiolytic effect of citalopram in conditioned fear stress in the rat[J].Prog Neuropsychopharmacol Biol Psychiatry,2012,39(1):107-111.
[6]Komaki A,Abdollahzadeh F,Sarihi A,et al.Interaction between antagonist of cannabinoid receptor and antagonist of adrenergic receptor on anxiety in male rat[J].Basic Clin Neurosci,2014,5(3):218-224.
[7]Khoo TK,Yarnall AJ,Duncan GW,et al.The spectrum of nonmotor symptoms in early Parkinson disease[J].Neurology,2013,80(3):276-281.
[8]Duncan GW,Khoo TK,Yarnall AJ,et al.Health-related quality of life in early Parkinson’s disease:the impact of nonmotor symptoms[J].Mov Disord,2014,29(2):195-202.
[9]Marsh L.Neuropsychiatric aspects of Parkinson's disease[J].Psychosomatics,2000,41(1):15-23.
[10]Paxinos G,Watson C.The rat brain in stereotaxic coordinates 4th ed[M].San Diego:Academic Press,1998.
[11]Breit S,Bouali-Benazzouz R,Benabid AL,et al.Unilateral lesion of the nigrostriatal pathway induces an increase of neuronal activity of the pedunculopontine nucleus,which is reversed by the lesion of the subthalamic nucleus in the rat[J].Eur J Neurosci,2001,14(11):1833-1842.
[12]Cecchi M,Khoshbouei H,Morilak DA.Modulatory effects of norepinephrine,acting on alpha 1 receptors in the central nucleus of the amygdala,on behavioral and neuroendocrine responses to acute immobilization stress[J].Neuropharmacology,2002,43(7):1139-1147.
[13]Kochenborger L,Zanatta D,Berretta LM,et al.Modulation of fear/anxiety responses,but not food intake,following alpha-adrenoceptor agonist microinjections in the nucleus accumbens shell of free-feeding rats[J].Neuropharmacology,2012,62(1):427-435.
[14]Han LN,Zhang L,Li LB,et al.Activation of serotonin(2C)receptors in the lateral habenular nucleus increases the expression of depression-related behaviors in the hemiparkinsonian rat[J].Neuropharmacology,2015,93:68-79.
[15]Wu ZH,Zhang QJ,Du CX,et al.Prelimbic alpha1-adrenoceptors are involved in the regulation of depressive-like behaviors in the hemiparkinsonian rats[J].Brain Res Bull,2017,134:99-108.
[16]Hui YP,Zhang QJ,Zhang L,et al.Activation of prelimbic 5-HT1A receptors produces antidepressant-like effects in a unilateral rat model of Parkinson’s disease[J].Neuroscience,2014,268:265-275.
[17]Zhang QJ,Du CX,Tan HH,et al.Activation and blockade of serotonin 7 receptors in the prelimbic cortex regulate depressivelike behaviors in a 6-hydroxydopamine-induced Parkinson’s disease rat model[J].Neuroscience,2015,311:45-55.
[18]Eskow Jaunarajs KL,Dupre KB,Ostock CY,et al.Behavioral and neurochemical effects of chronic L-DOPA treatment on nonmotor sequelae in the hemiparkinsonian rat[J].Behav Pharmacol,2010,21(7):627-637.
[19]Jungnickel J,Kalve I,Reimers L,et al.Topology of intrastriatal dopaminergic grafts determines functional and emotional outcome in neurotoxin-lesioned rats[J].Behav Brain Res,2011,216(1):129-135.
[20]Carvalho MM,Campos FL,Coimbra B,et al.Behavioral characterization of the 6-hydroxidopamine model of Parkinson’s disease and pharmacological rescuing of non-motor deficits[J].Mol Neurodegener,2013,8(14):1-11.
[21]Delaville C,Chetrit J,Abdallah K,et al.Emerging dysfunctions consequent to combined monoaminergic depletions in Parkinsonism[J].Neurobiol Dis,2012,45(2):763-773.
[22]Zhang YM,Zhang L,Wang Y,et al.Activation and blockade of prelimbic 5-HT6 receptors produce different effects on depressivelike behaviors in unilateral 6-hydroxydopamine-induced Parkinson’s rats[J].Neuropharmacology,2016,110(Pt A):25-36.
[23]Gonzalez LE,Rujano M,Tucci S,et al.Medial prefrontal transection enhances social interaction.Ⅰ:behavioral studies[J].Brain Res,2000,887(1):7-15.
[24]Stern CA,Do Monte FH,Gazarini L,et al.Activity in prelimbic cortex is required for adjusting the anxiety response level during the elevated plus-maze test[J].Neuroscience,2010,170(1):214-222.
[25]Bremner JD,Licinio J,Darnell A,et al.Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder[J].Am J Psychiatry,1997,154(5):624-629.
[26]Drevets WC,Price JL,Simpson JR,et al.Subgenual prefrontal cortex abnormalities in mood disorders[J].Nature,1997,386(6627):824-827.
[27]Jett JD,Morilak DA.Too much of a good thing:blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition[J].Neuropsychopharmacology,2013,38(4):585-595.
[28]Pieribone VA,Nicholas AP,Dagerlind A,et al.Distribution of alpha 1 adrenoceptors in rat brain revealed by in situ hybridization experiments utilizing subtype-specific probes[J].J Neurosci,1994,14(7):4252-4268.
[29]Santana N,Mengod G,Artigas F.Expression of alpha(1)-adrenergic receptors in rat prefrontal cortex:cellular co-localization with 5-HT(2A)receptors[J].Int J Neuropsychopharmacol,2013,16(5):1139-1151.