title: A two-hit model: behavioural investigation of the effect of combined neonatal MK-801 administration and isolation rearing in the rat.
abstract: This study combined two neurodevelopmental manipulations, neonatal MK-801 treatment and isolation rearing, to produce a 'two-hit' 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.
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia. ann.lim@monash.edu
authors.forename: Ann Li
authors.initials: AL
authors.lastname: Lim
authors.forename: David Alan
authors.initials: DA
authors.lastname: Taylor
authors.forename: Daniel Thomas
authors.initials: DT
authors.lastname: Malone
mesh_terms: D017109:Akathisia, Drug-Induced / Q000209:etiology / Q000517:prevention & control; D000818:Animals; D000831:Animals, Newborn; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000627:therapeutic use; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D005106:Exploratory Behavior / Q000187:drug effects; D007274:Injections, Intraperitoneal; D008297:Male; D008426:Maternal Deprivation; D008569:Memory Disorders / Q000209:etiology / Q000517:prevention & control; D009433:Neural Inhibition / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D003024:Clozapine