Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice.
Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice.
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DOI：
10.1371/journal.pone.0089153
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Hashimoto H
中科院分区：
文献类型：
--
作者：
Hazama K;Hayata-Takano A;Uetsuki K;Kasai A;Encho N;Shintani N;Nagayasu K;Hashimoto R;Reglodi D;Miyakawa T;Nakazawa T;Baba A;Hashimoto H
来自人类遗传学研究的越来越多的证据表明，垂体腺苷酸环化酶激活多肽（PACAP）基因是精神疾病（包括精神分裂症和应激相关疾病）的危险因素。PACAP基因纯合破坏的小鼠表现出严重的行为和神经异常，这些异常可通过非典型抗精神病药和多巴胺D2和5-羟色胺（5-HT）2拮抗剂利培酮和5-HT 2受体拮抗剂利坦色林得到改善;然而，其潜在机制仍不清楚。在这里，我们研究了行为正常的PACAP杂合突变（PACAP+/−）小鼠是否容易受到厌恶性刺激。PACAP+/−小鼠被给予5-HT 2受体激动剂，（±）-2，5-二甲氧基-4-碘苯丙胺（DOI），一种致幻药物，并将它们的反应与同窝野生型小鼠进行比较。注射DOI后，PACAP+/−小鼠表现出头部抽搐反应增加，而注射生理盐水后其行为正常。DOI诱导感觉运动门控缺陷，通过前脉冲抑制确定，特别是在PACAP+/−小鼠中。然而，其他5-HT 2受体依赖性反应，如皮质酮释放和体温过低，在PACAP+/−和野生型小鼠中也观察到类似的结果。在不同脑区进行的c-Fos表达分析显示，与野生型小鼠相比，DOI诱导的c-Fos阳性细胞数量增加在PACAP+/−小鼠的躯体感觉皮层中的5-HT 2A受体阴性细胞中更为明显。这些结果表明，PACAP+/−小鼠对DOI诱导的皮质感觉功能缺陷表现出特定的脆弱性，例如夸大的头部抽搐反应和感觉运动门控缺陷。我们的研究结果提供了深入了解受损的行为反应，其中5-HT 2受体牵连的神经机制。
Accumulating evidence from human genetic studies implicates the pituitary adenylate cyclase-activating polypeptide (PACAP) gene as a risk factor for psychiatric disorders, including schizophrenia and stress-related diseases. Mice with homozygous disruption of the PACAP gene display profound behavioral and neurological abnormalities that are ameliorated with the atypical antipsychotic and dopamine D2 and serotonin (5-HT)2 antagonist risperidone and the 5-HT2 receptor antagonist ritanserin; however, the underlying mechanisms remain unknown. Here, we investigated if PACAP heterozygous mutant (PACAP+/−) mice, which appear behaviorally normal, are vulnerable to aversive stimuli. PACAP+/− mice were administered a 5-HT2 receptor agonist, (±)-2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug, and their responses were compared with the littermate wild-type mice. After DOI injection, PACAP+/− mice showed increased head-twitch responses, while their behavior was normal after saline. DOI induced deficits in sensorimotor gating, as determined by prepulse inhibition, specifically in PACAP+/− mice. However, other 5-HT2 receptor-dependent responses, such as corticosterone release and hypothermia, were similarly observed in PACAP+/− and wild-type mice. c-Fos expression analysis, performed in various brain regions, revealed that the DOI-induced increase in the number of c-Fos-positive cells was more pronounced in 5-HT2A receptor-negative cells in the somatosensory cortex in PACAP+/− mice compared with wild-type mice. These results indicate that PACAP+/− mice exhibit specific vulnerability to DOI-induced deficits in cortical sensory function, such as exaggerated head-twitch responses and sensorimotor gating deficits. Our findings provide insight into the neural mechanisms underlying impaired behavioral responses in which 5-HT2 receptors are implicated.
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影响因子：
15.9
作者：
Freson, K;Hashimoto, H;Van Geet, C
通讯作者：
Van Geet, C
影响因子：
11
作者：
Hashimoto, R.;Hashimoto, H.;Baba, A.
通讯作者：
Baba, A.
DOI：
10.1523/jneurosci.4230-10.2011
发表时间：
2011-02-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Moreno JL;Kurita M;Holloway T;López J;Cadagan R;Martínez-Sobrido L;García-Sastre A;González-Maeso J
通讯作者：
González-Maeso J
影响因子：
3.3
作者：
Gaszner, B.;Kormos, V.;Helyes, Z.
通讯作者：
Helyes, Z.
DOI：
10.1007/978-3-642-25761-2_4
发表时间：
2012-01-01
期刊：
CURRENT ANTIPSYCHOTICS
影响因子：
--
作者：
Meltzer, Herbert Y.
通讯作者：
Meltzer, Herbert Y.