Psychostimulant-induced attenuation of hyperactivity and prepulse inhibition deficits in Adcyap1-deficient mice.

Abstract

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.

• Authors: Kazuhiro Tanaka, Norihito Shintani, Hitoshi Hashimoto, Naofumi Kawagishi, Yukio Ago, Toshio Matsuda, Ryota Hashimoto, Hiroshi Kunugi, Akiko Yamamoto, Chihiro Kawaguchi, Takeshi Shimada, Akemichi Baba
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 26 Issue 19 Pg. 5091-7 (May 10 2006) ISSN: 1529-2401 [Electronic] United States
• PMID: 16687500 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adcyap1 protein, mouse
• Central Nervous System Stimulants
• Pituitary Adenylate Cyclase-Activating Polypeptide
• Amphetamine

Topics

• Acoustic Stimulation (methods)
• Amphetamine (administration & dosage)
• Animals
• Central Nervous System Stimulants (administration & dosage)
• Hyperkinesis (drug therapy, physiopathology)
• Mice
• Pituitary Adenylate Cyclase-Activating Polypeptide (deficiency, metabolism)
• Reaction Time (drug effects)
• Reflex, Startle (drug effects)