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- HT1A) 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- HT1A 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- HT1A- mediated pathways are important determinants of the psychostimulant- elicited, rate- dependent effects that are in a negative function of the baseline rate of activity.