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 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-HT_2A 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.