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

• Published in: PloS one 2014-02, Vol.9 (2), p.e89153
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Abnormalities; Amphetamines - pharmacology; Animals; Antipsychotics; Behavior, Animal - drug effects; Bioaccumulation; Biology; Brain; Brain - cytology; Brain - drug effects; Brain research; c-Fos protein; Channel gating; Child development; Children & youth; Cortex (somatosensory); Corticosterone; Dopamine; Dopamine D2 receptors; Female; Fos protein; Gene Expression Regulation - drug effects; Hallucinogenic drugs; Hallucinogens - pharmacology; Head; Hypothermia; Laboratory animals; Male; Medical research; Medicine; Memory; Mental disorders; Mice; Mothers; Mutation; Nervous system diseases; Neurons; Neurons - drug effects; Neurons - metabolism; Neurophysiology; Pharmaceutical sciences; Pituitary adenylate cyclase-activating polypeptide; Pituitary Adenylate Cyclase-Activating Polypeptide - genetics; Polypeptides; Post traumatic stress disorder; Proto-Oncogene Proteins c-fos - metabolism; Psychopharmacology; Psychosis; Psychotropic drugs; Receptors; Receptors, Serotonin, 5-HT2 - metabolism; Risk factors; Risperidone; Rodents; Schizophrenia; Sensorimotor gating; Serotonin; Serotonin 5-HT2 Receptor Agonists - pharmacology; Serotonin S2 receptors; Somatosensory cortex; Toxicology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089153

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.