Analysis of phencyclidine-induced disruption of acoustic startle in rat

苯环己哌啶诱导的大鼠声惊吓破坏的分析

• 批准号: 10680726
• 负责人: YAMADA Shigeto
• 金额: $ 2.18万
• 依托单位: Kurume University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10680726/
• 关键词: prepulse inhibition; phencyclidine; dopamine; serotonin; neuroleptics; SDA; プレパルス インヒビション; シグマ受容体; prepulse inhibition; phencyclidine; セロトニン2A受容体; ドパミンD_2受容体; ラット

The disruption of prepulse inhibiton of acoustic startle (PPI) is an animal model for some aspects of schizophrenia. Phencyclidine causes psychotomimetic symptoms in human and disrupts PPI in animals, however, the mechanism underlying this disruption remains unclear.In the first experiment, Dopamine and 3,4-dihydroxy phenylacetic acid (DOPAC) levels in discrete regions and apomorphine- or (-)-sulpiride- induced changes in electrically evoked dopamine release from nucleus accumbens slices were assessed after testing prepulse inhibition of acoustic startle (PPI) in rats. Dopamine and DOPAC levels in the nucleus accumbens, but not in the striatum, correlated well with PPI (r=-0.64 for dopamine, r=-0.48 for DOPAC). Evoked dopamine release from the nucleus accumbens did not differ between high-PPI (more than 60 %) and low-PPI (less than 40 %) group. When slices were superfused with 1 mM apomorphine, the S2/S1 ratio in rats showing high PPI was 0.77±0.02 (mean±SEM, 66% of control), significa … More ntly smaller than in the low-PPI group (S2/S1 ratio=0.97±0.08, 94% of control, P<0.05). Moreover, (-)-sulpiride-induced increase in evoked dopamine release from the nucleus accumbens in the high-PPI group was inclined to be greater than in the low-PPI group. The results suggest that PPI differences between individuals may reflect the sensitivity of release-modulating dopamine autoreceptors in the nucleus accumbens.In the second experiment, we tested the hypothesis that serotonin 2A receptor blocking property of drugs reverses the phencyclidine-induced PPI disruption. The ED50 value of spiperone, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, seroquel, pipamperone, mianserin or desipramine to reverse the phencyclidine- or apomorphine-induced PPI disruption in rat was determined. Then the correlation between the ED50 value and the affinity for the serotonin 2A, 2C, dopamine D2, or a-1 receptor of each drug was examined.The ED50 value of the drugs to reverse the phencyclidine- induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D2, serotonin 2C or a- 1 receptor of each drug. In contrast, the ED50 value of the drugs to reverse the apomorphine- induced PPI disruption was significantly correlated with the affinity for the dopamine D2 receptor, but not for the serotonin 2A receptor. These data indicate that an activation of serotonin 2A receptors would mediate the phencyclidine-induced PPI disruption.All the data taken in the present project indicate that PCP-induced disruption would be caused by the stimulation of serotonergic system which was independent to dopaminergic system and be a suseful tool for investigating the pathophysiology of non-dopamine psychosis. Less

声惊（PPI）脉冲前抑制的破坏是精神分裂症某些方面的动物模型。苯环利定引起人的类精神症状，并破坏动物的PPI，然而，这种破坏的机制尚不清楚。在第一个实验中，通过对大鼠的脉冲前声惊吓（PPI）抑制测试，评估了离散区域多巴胺和3,4-二羟基苯乙酸（DOPAC）水平以及阿吗啡或(-)-舒匹利诱导的伏隔核切片电诱发多巴胺释放的变化。伏隔核的多巴胺和DOPAC水平与PPI相关（多巴胺r=-0.64, DOPAC r=-0.48），纹状体中则没有。诱发的伏隔核多巴胺释放在高ppi组（超过60%）和低ppi组（低于40%）之间没有差异。高PPI组大鼠的S2/S1比值为0.77±0.02（平均±SEM，为对照组的66%），显著小于低PPI组（S2/S1比值为0.97±0.08，为对照组的94%，P<0.05）。此外，(-)-舒匹林诱导的高ppi组伏隔核诱发多巴胺释放增加倾向于大于低ppi组。结果表明个体间PPI差异可能反映了伏隔核释放调节多巴胺自身受体的敏感性。在第二个实验中，我们验证了药物的5 -羟色胺2A受体阻断特性逆转苯环利定诱导的PPI破坏的假设。测定哌替龙、氟哌啶醇、氯丙嗪、氯氮平、利培酮、奥氮平、思瑞康、哌替龙、米安色林、地西帕明对苯环利定或阿波吗啡所致大鼠PPI破坏的ED50值。然后检测ED50值与每种药物对血清素2A、2C、多巴胺D2或a-1受体的亲和力之间的相关性。逆转苯环利定诱导的PPI破坏的药物的ED50值与对5 -羟色胺2A受体的亲和力显著相关，但与每种药物的多巴胺D2、5 -羟色胺2C或a- 1受体的亲和力无关。相反，逆转阿波啡诱导的PPI破坏的药物的ED50值与多巴胺D2受体的亲和力显著相关，而与5 -羟色胺2A受体的亲和力无关。这些数据表明5 -羟色胺2A受体的激活可以介导苯环利定诱导的PPI破坏。本项目所获得的数据表明，pcp诱导的破坏可能是由独立于多巴胺能系统的5 -羟色胺能系统的刺激引起的，为研究非多巴胺精神病的病理生理提供了有益的工具。少

项目成果

Yamada S et al: "Effects of shigma-1 receptor ligand, MS-377 on apomorphine- or phencyclidine-induced disruption of prepulse inhibition of acoustic startle in rats"Eur J Pharmacol. 402. 251-254 (2000)

Yamada S 等人：“shigma-1 受体配体 MS-377 对阿扑吗啡或苯环己哌啶诱导的大鼠声惊吓前脉冲抑制破坏的影响”Eur J Pharmacol。

Yamada S et al: "Dopamine autoreceptors in rat nucleus accumbens modulate prepulse inhibition of acoustic startle."Pharmacol Blochem Behav. 60. 803-808 (1998)

Yamada S 等人：“大鼠伏隔核中的多巴胺自身受体调节声惊吓的前脉冲抑制。”Pharmacol Blochem Behav。

Yamada S: "Disruption of prepuls inhibition of acoustic startle as an animal model for schizophrenia. (in japanese)"Jpn J Neuropsychopharmacol. 20. 131-139 (2000)

Yamada S：“作为精神分裂症动物模型，破坏声惊吓的前脉冲抑制。（日语）”Jpn J Neuropsychopharmacol。

S.Yamada,M.Harano,N.Anno M.Tanaka: "Involvement of serotonin 2A receptorsin phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats"Bilogical Psychiatry. 46(6). 832-838 (1999)

S.Yamada、M.Harano、N.Anno M.Tanaka：“苯环己哌啶诱导的大鼠声惊吓前脉冲抑制破坏中血清素 2A 受体的参与”生物精神病学。

Yamada S et al: "Dopamine autoreceptors in rat nucleus accumbens modulate prepulse inhibition of acoustic startle."Pharmacol Biochem Behav. 60. 803-808 (1998)

Yamada S 等人：“大鼠伏隔核中的多巴胺自身受体调节声惊吓的前脉冲抑制。”Pharmacol Biochem Behav。