Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice.
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 behavior...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089153&type=printable |
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| author | Keisuke Hazama Atsuko Hayata-Takano Kazuki Uetsuki Atsushi Kasai Naoki Encho Norihito Shintani Kazuki Nagayasu Ryota Hashimoto Dora Reglodi Tsuyoshi Miyakawa Takanobu Nakazawa Akemichi Baba Hitoshi Hashimoto |
| author_facet | Keisuke Hazama Atsuko Hayata-Takano Kazuki Uetsuki Atsushi Kasai Naoki Encho Norihito Shintani Kazuki Nagayasu Ryota Hashimoto Dora Reglodi Tsuyoshi Miyakawa Takanobu Nakazawa Akemichi Baba Hitoshi Hashimoto |
| author_sort | Keisuke Hazama |
| collection | DOAJ |
| description | 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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| format | Article |
| id | doaj.art-8881ec411f95400280e26ab6087e5f08 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2025-03-14T16:43:06Z |
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| spelling | doaj.art-8881ec411f95400280e26ab6087e5f082025-02-21T05:38:39ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8915310.1371/journal.pone.0089153Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice.Keisuke HazamaAtsuko Hayata-TakanoKazuki UetsukiAtsushi KasaiNaoki EnchoNorihito ShintaniKazuki NagayasuRyota HashimotoDora ReglodiTsuyoshi MiyakawaTakanobu NakazawaAkemichi BabaHitoshi HashimotoAccumulating 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089153&type=printable |
| spellingShingle | Keisuke Hazama Atsuko Hayata-Takano Kazuki Uetsuki Atsushi Kasai Naoki Encho Norihito Shintani Kazuki Nagayasu Ryota Hashimoto Dora Reglodi Tsuyoshi Miyakawa Takanobu Nakazawa Akemichi Baba Hitoshi Hashimoto Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. PLoS ONE |
| title | Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. |
| title_full | Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. |
| title_fullStr | Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. |
| title_full_unstemmed | Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. |
| title_short | Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. |
| title_sort | increased behavioral and neuronal responses to a hallucinogenic drug in pacap heterozygous mutant mice |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0089153&type=printable |
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