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.
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