Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice

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

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Abstract

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.

Original languageEnglish
Article numbere89153
JournalPloS one
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 20 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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. (2014). Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. PloS one, 9(2), [e89153]. https://doi.org/10.1371/journal.pone.0089153