Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice.
Psychostimulants, including amphetamine, act as antihyperkinetic agents in humans with hyperkinetic disorder such as attention-deficit hyperactivity disorder and are known to be effective in enhancing attention-related processes; however, the underlying mechanisms have not been adequately addressed. Mice lacking the Adcyap1 gene encoding the neuropeptide pituitary adenylate cyclase-activating polypeptide (Adcyap1(-/-)) display psychomotor abnormalities, including increased novelty-seeking behavior and hyperactivity. In this study, Adcyap1(-/-) mice showed sensory-motor gating deficits, measured as deficits in prepulse inhibition (PPI), and showed normal PPI in response to amphetamine. Amphetamine also significantly decreased hyperlocomotion in Adcyap1(-/-) mice, and this paradoxical antihyperkinetic effect depended on serotonin 1A (5-HT(1A)) receptor signaling. c-Fos-positive neurons were increased in the prefrontal cortex in amphetamine-treated Adcyap1(-/-) mice, suggesting increased inhibitory control by prefrontal neurons. Additionally, amphetamine produced an antihyperkinetic effect in wild-type mice that received the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin. These results indicate that Adcyap1(-/-) mice act as a model of hyperlocomotion and PPI deficits and suggest that 5-HT(1A)-mediated pathways are important determinants of the psychostimulant-elicited, rate-dependent effects that are in a negative function of the baseline rate of activity.
Tanaka
Kazuhiro
K
Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan.
Shintani
Norihito
N
Hashimoto
Hitoshi
H
Kawagishi
Naofumi
N
Ago
Yukio
Y
Matsuda
Toshio
T
Hashimoto
Ryota
R
Kunugi
Hiroshi
H
Yamamoto
Akiko
A
Kawaguchi
Chihiro
C
Shimada
Takeshi
T
Baba
Akemichi
A