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The Journal of Neuroscience, May 10, 2006, 26(19):5091-5097; doi:10.1523/JNEUROSCI.4376-05.2006

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Behavioral/Systems/Cognitive
Psychostimulant-Induced Attenuation of Hyperactivity and Prepulse Inhibition Deficits in Adcyap1-Deficient Mice

Kazuhiro Tanaka,^1 * Norihito Shintani,^1 * Hitoshi Hashimoto,¹ Naofumi Kawagishi,¹ Yukio Ago,^1,2 Toshio Matsuda,² Ryota Hashimoto,³ Hiroshi Kunugi,³ Akiko Yamamoto,¹ Chihiro Kawaguchi,¹ Takeshi Shimada,¹ and Akemichi Baba¹

¹Laboratories of Molecular Neuropharmacology and ²Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka 565-0871, Japan, and ³Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan

Correspondence should be addressed to either of the following: Dr. Hitoshi Hashimoto, Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan, Email: hasimoto{at}phs.osaka-u.ac.jp or Dr. Akemichi Baba, Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan, baba{at}phs.osaka-u.ac.jp

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.

Key words: neuropeptide; knock-out mice; psychostimulant; hyperactivity; prepulse inhibition; serotonin 5-HT_1A receptor

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Received Oct. 13, 2005; revised March 24, 2006; accepted March 24, 2006.

Correspondence should be addressed to either of the following: Dr. Hitoshi Hashimoto, Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan, Email: hasimoto{at}phs.osaka-u.ac.jp or Dr. Akemichi Baba, Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan, baba{at}phs.osaka-u.ac.jp

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