A two-hit model: behavioural investigation of the effect of combined neonatal MK-801 administration and isolation rearing in the rat

作者：Lim Ann Li^*; Taylor David Alan; Malone Daniel Thomas

来源：Journal of Psychopharmacology, 2012, 26(9): 1252-1264.

DOI：10.1177/0269881111430751

• Clozapine
• isolation rearing
• locomotor activity
• neonatal MK-801
• novel object recognition
• prepulse inhibition
• schizophrenia

This study combined two neurodevelopmental manipulations, neonatal MK-801 treatment and isolation rearing, to produce a %26apos;two-hit%26apos; model and determine whether two hits induce a more robust behavioural phenotype of an animal model of aspects of schizophrenia compared with individual manipulations alone. The effect of clozapine was also assessed. Male Sprague-Dawley rats received 0.2 mg/kg MK-801 or saline intraperitoneally (i.p.) once daily on postnatal days (PNDs) 7-10 and were assigned to group or isolation rearing at weaning (PND 21). From PND 77, they received a vehicle or 5 mg/kg clozapine (i.p.) treatment regimen and were subjected to three prepulse inhibition (PPI) tests, a locomotor activity assessment and a novel object recognition task. MK-801-treated rats reared in isolation displayed robust PPI disruptions which were consistently manifested in all three tests. PPI deficits were also detected in saline-treated rats reared in isolation but not in all tests. Only the two-hit rats demonstrated hyperlocomotion and impaired object recognition memory. Clozapine restored PPI anomalies in the two-hit rats. The two-hit model showed greater psychotic-like effects than either neonatal MK-801 or isolation rearing alone. The preliminary predictive validity shown with clozapine suggests this model may be useful for predicting the efficacy of putative antipsychotics.

• 出版日期2012-9