112) Individual difference in prepulse inhibition expression predicts the magnitude of amphetamine behavioural sensitization effect in C57BL/6 mice.

PELEG-RAIBSTEIN, D. ; HAUSER, J. ; LLANO LOPEZ, L. ; GARGIULO, P.A. ; FELDON, J. ; YEE B.K.

Florencia. Italia

Conferencia; Schizophrenia International Research Society Conference. April 10-14. 2010.-; 2010

Schizophrenia International Research Society.

112) 2010. Peleg-Raibstein, D.; Hauser, J.; Llano Lopez, L.; Gargiulo, P.A.; Feldon, J.; Yee, B.K. Individual difference in prepulse inhibition expression predicts the magnitude of amphetamine behavioural sensitization effect in C57BL/6 mice. Schizophrenia International Research Society Conference. April 10-14. 2010.- Individual difference in prepulse inhibition expression predicts the magnitude of amphetamine behavioural sensitization effect in C57BL/6 mice Daria Peleg-Raibstein Joram Feldon Benjamin K. Yee Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich CH-8063, Schwerzenbach, Switzerland. Laboratorio de Neurociencias y Psicología Experimental, Instituto de Medicina y Biología Experimental de Cuyo (IMBECU), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina. Mail to: pelegd@behav.biol.ethz.ch. Prepulse inhibition (PPI) is demonstrated when the startle reflex in response to a sudden intense acoustic stimulus is attenuated by a weak prepulse stimulus presented shortly before. PPI is commonly considered as an operational measure of sensory gating whereby perception of the prepulse inhibits the processing of the succeeding pulse stimulus. PPI deficiency is considered to be an endophenotype of schizophrenia and a behavioural trait associated with schizotypy personality. PPI is readily disrupted by dopamine receptor agonists, suggestive of dopaminergic modulation over sensory gating. Repeated prior exposures to amphetamine are also sufficient to produce PPI deficiency even though the drug is no longer present in the subjects during test ? an effect attributable to the development of a sensitized dopamine system. However, the causal link between dopaminergic sensitization and PPI deficiency remains debatable because of controversy over the precise amphetamine exposures regime necessary to induce such an effect. Here, we examined this link within a two-hit model of schizophrenia. Wild type mice were segregated into two subgroups based on their baseline PPI magnitude, and their propensity to develop behavioural sensitization following one single exposure to amphetamine five days ago was evaluated in the open field. It was predicted that intrinsic low-PPI trait confers vulnerability to the development of dopaminergic sensitization, which might underlie the pathophysiology of psychotic symptoms according to the endogenous sensitization hypothesis of schizophrenia. Methods: cohort of 22 male adult C57BL/6 mice were screened using a standard PPI procedure, and was split according to individual?s average PPI magnitude into high-PPI and low-PPI subgroups (n=11). Next, their motor response to systemic amphetamine challenge (2.5mg/kg, i.p.) was evaluated in an open field twice separated by five days. Each test followed a within-subject design comprising a pre-injection phase (30 min), a saline phase (30 min), and finally a drug phase lasting for 120 min. Locomotor activity was indexed by distance moved in 5-min bins by a video tracking system. Enhanced motor response to the drug in the second test relative to the first test constitutes the behavioural sensitization. The outcome confirmed our prediction that low-PPI groups exhibited a stronger behavioural sensitization effect compared to the high-PPI subjects. The two groups did not differ in terms of their motor response in the first exposure to amphetamine. Conclusions: Previous experiments examining the impact of a sensitized dopaminergic system induced by repeated amphetamine exposures on the expression of PPI have suggested that the former can lead to PPI disruption. Here, our results provided evidence for a possible link in the opposite direction: intrinsic low PPI levels might predict the propensity to develop dopaminergic sensitization following a single exposure to amphetamine. This finding suggests that individuals marked by low PPI expression are at greater risk of developing schizophrenia because their dopaminergic system is susceptible to be sensitized. Considering the diverse environmental factors, such as stress, that can shape the development of dopaminergic sensitization, the present finding bears resemblance to a two-hit model of schizophrenia. Schizophrenia International Research Society Conference.