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

J Psychopharmacol. 2012 Sep;26(9):1252-64. doi: 10.1177/0269881111430751. Epub 2012 Feb 23.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Akathisia, Drug-Induced / etiology
  • Akathisia, Drug-Induced / prevention & control
  • Animals
  • Animals, Newborn
  • Antipsychotic Agents / therapeutic use
  • Behavior, Animal / drug effects
  • Clozapine / therapeutic use
  • Disease Models, Animal*
  • Dizocilpine Maleate / administration & dosage
  • Dizocilpine Maleate / toxicity*
  • Excitatory Amino Acid Antagonists / administration & dosage
  • Excitatory Amino Acid Antagonists / toxicity*
  • Exploratory Behavior / drug effects
  • Injections, Intraperitoneal
  • Male
  • Maternal Deprivation*
  • Memory Disorders / etiology
  • Memory Disorders / prevention & control
  • Neural Inhibition / drug effects
  • Neurotoxicity Syndromes / drug therapy
  • Neurotoxicity Syndromes / physiopathology
  • Neurotoxicity Syndromes / psychology*
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Schizophrenia / chemically induced*
  • Schizophrenia / drug therapy
  • Schizophrenia / physiopathology


  • Antipsychotic Agents
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Dizocilpine Maleate
  • Clozapine