外侧隔GABA_A受体在帕金森病模型大鼠焦虑样行为中的作用
|
摘要
目的:研究外侧隔(lateral septum,LS)GABAA受体在帕金森病(Parkinson's disease,PD)模型大鼠焦虑样行为中的作用。方法:将167只大鼠随机分为假手术组(n=85)和单侧内侧前脑束(medial forebrain bundle,MFB)损毁组(n=82)。采用旷场试验和高架十字迷宫实验观察LS局部给予不同剂量的GABA_A受体激动剂muscimol或拮抗剂picrotoxin对两组大鼠焦虑样行为的影响;采用高效液相色谱-电化学检测法观察焦虑相关脑区单胺类神经递质含量的变化。结果:与假手术组比较,MFB损毁组大鼠产生焦虑样行为,且LS、杏仁核、腹侧海马(ventral hippocampus,v Hip)中多巴胺(DA)水平均明显下降。与溶媒组相比,LS中局部注射muscimol后,在两组大鼠中分别诱发或加重焦虑样行为,且LS、杏仁核和v Hip DA、5-羟色胺(5-HT)水平均下降;LS中局部注射picrotoxin后,在两组大鼠中均改善焦虑样行为,且LS、杏仁核和v Hip的5-HT水平及杏仁核和v Hip的DA水平升高;所不同的是产生以上行为学改变所需剂量,MFB损毁组均高于假手术组。结论:LS中GABAA受体调节大鼠焦虑样行为,其机制与边缘相关脑区DA和5-HT递质含量变化有关。
AIM:To investigate the role of GABAAreceptors in the lateral septum(LS) in the regulation of anxiety-like behaviors in hemiparkinsonian rats.METHODS:A total of 167 rats were randomly divided into sham-operated group(n = 85)and medial forebrain bundle(MFB) lesioned group(n = 82).The open field and elevated plus maze(EPM) test were performed to study the influence of MFB lesion and intra-LS injection of GABA_A agonist muscimol(0.2,0.4 or 0.8 μg/rat) and antagonist picrotoxin(0.1,0.2 or 0.4 μg/rat) on anxiety-like behaviors.Changes of monoamine levels in limbic related brain regions were observed by high performance liquid chromatography with electrochemical detection.RESULTS:Compared with sham-operated group,the MFB lesioned group induced anxiety-like behaviors.The dopamine(DA) levels in LS,amygdala and ventral hippocampus(v Hip) were significantly decreased compared with sham-opreated group.Compared with the rats treated with vehicle in the same group,the intra-injection of muscimol in LS induced or aggravated the anxiety-like behaviors in two groups,and decreased DA and 5-hydroxytryptamine(5-HT) levels in three brain regions.In contrast,the administration of picrotoxin improved anxiety-like behaviors,and increased 5-HT in three brain regions and DA in amygdala and v Hip.However,the doses producing the behavioral effects in the lesioned rats were higher than those in sham-operated rats.CONCLUSION:GABAAreceptors in the LS are involved in the regulation of anxiety-like behaveiors,which is attributable to changes in dopamine,5-HT levels in the limbic-related brain regions after activation and blockade of GABAAreceptors.
AIM:To investigate the role of GABAAreceptors in the lateral septum(LS) in the regulation of anxiety-like behaviors in hemiparkinsonian rats.METHODS:A total of 167 rats were randomly divided into sham-operated group(n = 85)and medial forebrain bundle(MFB) lesioned group(n = 82).The open field and elevated plus maze(EPM) test were performed to study the influence of MFB lesion and intra-LS injection of GABA_A agonist muscimol(0.2,0.4 or 0.8 μg/rat) and antagonist picrotoxin(0.1,0.2 or 0.4 μg/rat) on anxiety-like behaviors.Changes of monoamine levels in limbic related brain regions were observed by high performance liquid chromatography with electrochemical detection.RESULTS:Compared with sham-operated group,the MFB lesioned group induced anxiety-like behaviors.The dopamine(DA) levels in LS,amygdala and ventral hippocampus(v Hip) were significantly decreased compared with sham-opreated group.Compared with the rats treated with vehicle in the same group,the intra-injection of muscimol in LS induced or aggravated the anxiety-like behaviors in two groups,and decreased DA and 5-hydroxytryptamine(5-HT) levels in three brain regions.In contrast,the administration of picrotoxin improved anxiety-like behaviors,and increased 5-HT in three brain regions and DA in amygdala and v Hip.However,the doses producing the behavioral effects in the lesioned rats were higher than those in sham-operated rats.CONCLUSION:GABAAreceptors in the LS are involved in the regulation of anxiety-like behaveiors,which is attributable to changes in dopamine,5-HT levels in the limbic-related brain regions after activation and blockade of GABAAreceptors.
引文
[1]Mongeau R,Miller GA,Chiang E,et al.Neural correlates of competing fear behaviors evoked by an innately aversive stimulus[J].J Neurosci,2003,23(9):3855-3868.
[2]Salome N,Salchner P,Viltart O,et al.Neurobiological correlates of high(HAB)versus low anxiety-related behavior(LAB):differential Fos expression in HAB and LAB rats[J].Biol Psychiatry,2004,55(7):715-723.
[3]Singewald N,Salchner P,Sharp T.Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs[J].Biol Psychiatry,2003,53:275-283.
[4]Yadin E,Thomas E,Grishkat HL,et al.The role of the lateral septum in anxiolysis[J].Physiol Behav,1993,53(4):1077-1083.
[5]Menard J,Treit D.Lateral and medial septal lesions reduce anxiety in the plus-maze and probe-burying tests[J].Physiol Behav,1996,60(3):845-853.
[6]Degroot A,Kashluba S,Treit D.Septal GABAergic and hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests[J].Pharmacol Biochem Behav,2001,69(3/4):391-399.
[7]Sheehan TP,Chambers RA,Russell DS.Regulation of affect by the lateral septum:implications for neuropsychiatry[J].Brain Res Brain Res Rev,2004,46(1):71-117.
[8]Luscher B,Shen Q,Sahir N.The GABAergic deficit hypothesis of major depressive disorder[J].Mol Psychiatry,2011,16(4):383-406.
[9]Shulman LM,Taback RL,Bean J,et al.Comorbidity of the nonmotor symptoms of Parkinson's disease[J].Mov Disord,2001,16(3):507-510.
[10]Segovia J,Armstrong DM,Benzing WC,et al.Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation:densitometric analysis[J].Neurosci Lett,1991,122(2):252-256.
[11]Soghomonian JJ,Laprade N.Glutamate decarboxylase(GAD67 and GAD65)gene expression is increased in a subpopulation of neurons in the putamen of Parkinsonian monkeys[J].Synapse,1997,27(2):122-132.
[12]Emir UE,Tuite PJ,Oz G.Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS[J].Plos One,2012,7(1):e30918.
[13]Calon F,Goulet M,Blanchet PJ,et al.Levodopa or D2 agonist induced dyskinesia in MPTP monkeys:correlation with changes in dopamine and GABAAreceptors in the striatopallidal complex[J].Brain Res,1995,680(1/2):43-52.
[14]Bueno CH,Zangrossi H,Jr.Nogueira RL,et al.Panicolytic-like effect induced by the stimulation of GABAAand GABABreceptors in the dorsal periaqueductal grey of rats[J].Eur J Pharmacol,2005,516(3):239-246.
[15]Shin R,Ikemoto S.Administration of the GABAAreceptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures.Supramammillary picrotoxin and c-Fos expression[J].BMC neuroscience,2010,11:101.
[16]Paxinos G,Watson C.The rat brain in stereotaxic coordinates[M].San Diego:Academic Press,1998.
[17]Tadaiesky MT,Dombrowski PA,Figueiredo CP,et al.Emotional,cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease[J].Neuroscience,2008,156(4):830-840.
[18]Estanislau C,Ramos AC,Ferraresi PD,et al.Individual differences in the elevated plus-maze and the forced swim test[J].Behav Processes,2011,86(1):46-51.
[19]Gui ZH,Zhang QJ,Liu J,et al.Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat[J].Neurochem Int,2011,59(5):618-627.
[20]Zhang YM,Zhang L,Wang Y,et al.Activation and blockade of prelimbic 5-HT6 receptors produce different effects on depressive-like behaviors in unilateral 6-hydroxydopamine-induced Parkinson's rats[J].Neuropharmacol,2016,110(pt A):25-36.
[21]Eskow Jaunarajs KL,George JA,Bishop C.L-DOPAinduced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson's disease[J].Neuroscience,2012,218:243-256.
[22]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.
[23]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.
[24]Zhang T,Chen T,Chen P,et al.MPTP-induced dopamine depletion in basolateral amygdala via decrease of D2R activation suppresses GABAAreceptors expression and LTD induction leading to anxiety-like behaviors[J].Front Mol Neurosci,2017,10:247.
[25]Vega-Quiroga I,Yarur HE,Gysling K.Lateral septum stimulation disinhibits dopaminergic neurons in the antero-ventral region of the ventral tegmental area:Role of GABAAalpha 1 receptors[J].Neuropharmacol,2018,128:76-85.
[26]Thomas E,Dewolfe M,Sancar F,et al.Electrophysiological analysis of the interaction between the lateral septum and the central nucleus of the amygdala[J].Neurosci Lett,2012,524(2):79-83.
[27]Luo XM,Yuan SN,Guan XT,et al.Juvenile stress affects anxiety-like behavior and limbic monoamines in adult rats[J].Physiol Behav,2014,135:7-16.
[28]Ressler KJ,Nemeroff CB.Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders[J].Depress Anxiety,2000,12(Suppl 1):2-19.
[2]Salome N,Salchner P,Viltart O,et al.Neurobiological correlates of high(HAB)versus low anxiety-related behavior(LAB):differential Fos expression in HAB and LAB rats[J].Biol Psychiatry,2004,55(7):715-723.
[3]Singewald N,Salchner P,Sharp T.Induction of c-Fos expression in specific areas of the fear circuitry in rat forebrain by anxiogenic drugs[J].Biol Psychiatry,2003,53:275-283.
[4]Yadin E,Thomas E,Grishkat HL,et al.The role of the lateral septum in anxiolysis[J].Physiol Behav,1993,53(4):1077-1083.
[5]Menard J,Treit D.Lateral and medial septal lesions reduce anxiety in the plus-maze and probe-burying tests[J].Physiol Behav,1996,60(3):845-853.
[6]Degroot A,Kashluba S,Treit D.Septal GABAergic and hippocampal cholinergic systems modulate anxiety in the plus-maze and shock-probe tests[J].Pharmacol Biochem Behav,2001,69(3/4):391-399.
[7]Sheehan TP,Chambers RA,Russell DS.Regulation of affect by the lateral septum:implications for neuropsychiatry[J].Brain Res Brain Res Rev,2004,46(1):71-117.
[8]Luscher B,Shen Q,Sahir N.The GABAergic deficit hypothesis of major depressive disorder[J].Mol Psychiatry,2011,16(4):383-406.
[9]Shulman LM,Taback RL,Bean J,et al.Comorbidity of the nonmotor symptoms of Parkinson's disease[J].Mov Disord,2001,16(3):507-510.
[10]Segovia J,Armstrong DM,Benzing WC,et al.Striatal glutamic acid decarboxylase immunoreactivity is increased after dopaminergic deafferentation:densitometric analysis[J].Neurosci Lett,1991,122(2):252-256.
[11]Soghomonian JJ,Laprade N.Glutamate decarboxylase(GAD67 and GAD65)gene expression is increased in a subpopulation of neurons in the putamen of Parkinsonian monkeys[J].Synapse,1997,27(2):122-132.
[12]Emir UE,Tuite PJ,Oz G.Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 tesla proton MRS[J].Plos One,2012,7(1):e30918.
[13]Calon F,Goulet M,Blanchet PJ,et al.Levodopa or D2 agonist induced dyskinesia in MPTP monkeys:correlation with changes in dopamine and GABAAreceptors in the striatopallidal complex[J].Brain Res,1995,680(1/2):43-52.
[14]Bueno CH,Zangrossi H,Jr.Nogueira RL,et al.Panicolytic-like effect induced by the stimulation of GABAAand GABABreceptors in the dorsal periaqueductal grey of rats[J].Eur J Pharmacol,2005,516(3):239-246.
[15]Shin R,Ikemoto S.Administration of the GABAAreceptor antagonist picrotoxin into rat supramammillary nucleus induces c-Fos in reward-related brain structures.Supramammillary picrotoxin and c-Fos expression[J].BMC neuroscience,2010,11:101.
[16]Paxinos G,Watson C.The rat brain in stereotaxic coordinates[M].San Diego:Academic Press,1998.
[17]Tadaiesky MT,Dombrowski PA,Figueiredo CP,et al.Emotional,cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease[J].Neuroscience,2008,156(4):830-840.
[18]Estanislau C,Ramos AC,Ferraresi PD,et al.Individual differences in the elevated plus-maze and the forced swim test[J].Behav Processes,2011,86(1):46-51.
[19]Gui ZH,Zhang QJ,Liu J,et al.Unilateral lesion of the nigrostriatal pathway decreases the response of fast-spiking interneurons in the medial prefrontal cortex to 5-HT1A receptor agonist and expression of the receptor in parvalbumin-positive neurons in the rat[J].Neurochem Int,2011,59(5):618-627.
[20]Zhang YM,Zhang L,Wang Y,et al.Activation and blockade of prelimbic 5-HT6 receptors produce different effects on depressive-like behaviors in unilateral 6-hydroxydopamine-induced Parkinson's rats[J].Neuropharmacol,2016,110(pt A):25-36.
[21]Eskow Jaunarajs KL,George JA,Bishop C.L-DOPAinduced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson's disease[J].Neuroscience,2012,218:243-256.
[22]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.
[23]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.
[24]Zhang T,Chen T,Chen P,et al.MPTP-induced dopamine depletion in basolateral amygdala via decrease of D2R activation suppresses GABAAreceptors expression and LTD induction leading to anxiety-like behaviors[J].Front Mol Neurosci,2017,10:247.
[25]Vega-Quiroga I,Yarur HE,Gysling K.Lateral septum stimulation disinhibits dopaminergic neurons in the antero-ventral region of the ventral tegmental area:Role of GABAAalpha 1 receptors[J].Neuropharmacol,2018,128:76-85.
[26]Thomas E,Dewolfe M,Sancar F,et al.Electrophysiological analysis of the interaction between the lateral septum and the central nucleus of the amygdala[J].Neurosci Lett,2012,524(2):79-83.
[27]Luo XM,Yuan SN,Guan XT,et al.Juvenile stress affects anxiety-like behavior and limbic monoamines in adult rats[J].Physiol Behav,2014,135:7-16.
[28]Ressler KJ,Nemeroff CB.Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders[J].Depress Anxiety,2000,12(Suppl 1):2-19.