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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 - 20-02-2014

Fingerprint

Pituitary Adenylate Cyclase-Activating Polypeptide
Hallucinogens
adenylate cyclase
polypeptides
drugs
mutants
mice
receptors
Sensory Gating
serotonin
antagonists
Serotonin
Genes
Head
Serotonin 5-HT2 Receptor Agonists
Hypothermia
Ritanserin
Serotonin 5-HT2 Receptor Antagonists
Receptor, Serotonin, 5-HT2A
Serotonin Antagonists

All Science Journal Classification (ASJC) codes

  • 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., ... 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
Hazama, Keisuke ; Hayata-Takano, Atsuko ; Uetsuki, Kazuki ; Kasai, Atsushi ; Encho, Naoki ; Shintani, Norihito ; Nagayasu, Kazuki ; Hashimoto, Ryota ; Reglodi, Dora ; Miyakawa, Tsuyoshi ; Nakazawa, Takanobu ; Baba, Akemichi ; Hashimoto, Hitoshi. / Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. In: PloS one. 2014 ; Vol. 9, No. 2.
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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, vol. 9, no. 2, e89153. https://doi.org/10.1371/journal.pone.0089153

Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. / Hazama, Keisuke; Hayata-Takano, Atsuko; Uetsuki, Kazuki; Kasai, Atsushi; Encho, Naoki; Shintani, Norihito; Nagayasu, Kazuki; Hashimoto, Ryota; Reglodi, Dora; Miyakawa, Tsuyoshi; Nakazawa, Takanobu; Baba, Akemichi; Hashimoto, Hitoshi.

In: PloS one, Vol. 9, No. 2, e89153, 20.02.2014.

Research output: Contribution to journalArticle

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AU - Encho, Naoki

AU - Shintani, Norihito

AU - Nagayasu, Kazuki

AU - Hashimoto, Ryota

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AU - Nakazawa, Takanobu

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AU - Hashimoto, Hitoshi

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Hazama K, Hayata-Takano A, Uetsuki K, Kasai A, Encho N, Shintani N et al. Increased behavioral and neuronal responses to a hallucinogenic drug in PACAP heterozygous mutant mice. PloS one. 2014 Feb 20;9(2). e89153. https://doi.org/10.1371/journal.pone.0089153