[Altered behavioral response to centrally acting drugs in mice lacking PACAP].
Mice lacking PACAP (PACAP-KO) exhibits altered psychomotor behaviors, including impaired habituation to a novel environment and perseverative jumping, with a slightly reduced levels of the serotonin metabolite, 5-HIAA, in the brain. We have recently demonstrated that PACAP-KO exhibits abnormalities in sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle. In the present study, behavioral responses to centrally acting drugs (amphetamine, haloperidol, risperidone, fluoxetine, and 8-OH-DPAT) were examined in PACAP-KO. Surprisingly, a psychostimulant amphetamine effectively normalized the deficit in PPI as well as hyperactivity and jumping behavior. These results implied phenotypic and pharmacological similarity between PACAP-KO and attention deficit hyperactivity disorder (ADHD). Although a potent dopamine D2-like receptor antagonist, haloperidol, ameliorated the hyperactivity and jumping behavior, it had no effect on the deficit in PPI. In contrast, a prototype of serotonin-dopamine antagonist (SDA), risperidone, effectively normalized the deficit in PPI as well as hyperactivity, and jumping behavior. A selective serotonin reuptake inhibitor (SSRI), fluoxetine, also suppressed the hyperactivity and jumping behavior. A 5-HT1A receptor agonist, 8-OH-DPAT, significantly lowered rectal temperature in wild-type mice, while it had only a small effect in PACAP-KO. These results suggest the involvement of dopaminergic and serotonergic dysfunction in phenotypic changes observed in PACAP-KO.
Shintani
Norihito
N
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Tanaka
Kazuhiro
K
Hashimoto
Hitoshi
H
Baba
Akemichi
A
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000502:physiology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018967:Risperidone / Q000494:pharmacology
C495402:Adcyap1 protein, mouse; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D005473:Fluoxetine; D000661:Amphetamine; D006220:Haloperidol; D018967:Risperidone