Post-weaning social isolation and subchronic NMDA glutamate receptor blockade: effects on locomotor activity and GABA signaling in the rat suggest independent mechanisms

Pharmacol Biochem Behav. 2012 Apr;101(2):231-8. doi: 10.1016/j.pbb.2012.01.015. Epub 2012 Jan 24.


Animal models of schizophrenia symptoms include administration of noncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonists, such as MK-801, and post-weaning social isolation (SI). We tested the hypothesis that a "double-hit" model, in which MK-801 administration during adulthood [post-natal day (P) 56-62] and SI are combined, produces greater behavioral and neurochemical effects than either insult alone. Rats obtained at weaning (P21) were either SI (n=21) or group housed (n=16) for the duration of the experiment. Subgroups received subchronic treatment with MK-801 (0.5 mg/kg i.p., 2 times daily for 7 days) or saline injections from P56-62. At P70, all groups were tested for locomotor activity and subsequently sacrificed to assess GAT-1 activity and GABA(A) receptor expression in the frontal cortex and hippocampus. SI resulted in increased locomotor activity, GAT-1 activity in frontal cortex and hippocampus and GABA(A) receptor expression in the frontal cortex; MK-801 increased GABA(A) receptor expression in the hippocampus. Activity changes were correlated with changes in hippocampal GAT-1 and frontocortical GABA(A) receptor number. There was no evidence that the double-hit produced a greater effect. Increased GAT-1 activity may be associated with suppression of GABA-mediated inhibitory synaptic transmission and increased GABA(A) receptor expression may be a compensatory response to decreased availability of GABA. Results suggest that SI and subchronic MK-801 may act through independent mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dizocilpine Maleate / administration & dosage
  • Excitatory Amino Acid Antagonists / administration & dosage*
  • GABA Plasma Membrane Transport Proteins / metabolism
  • Male
  • Motor Activity / drug effects*
  • Muscimol / pharmacology
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Signal Transduction / drug effects*
  • Social Isolation*
  • Weaning


  • Excitatory Amino Acid Antagonists
  • GABA Plasma Membrane Transport Proteins
  • Receptors, GABA-A
  • Receptors, N-Methyl-D-Aspartate
  • Slc6a1 protein, rat
  • Muscimol
  • Dizocilpine Maleate