title: Post-weaning social isolation and subchronic NMDA glutamate receptor blockade: effects on locomotor activity and GABA signaling in the rat suggest independent mechanisms.
abstract: 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.
authors.affiliation: Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Hickey
authors.forename: James N
authors.initials: JN
authors.lastname: Reynolds
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Beninger
mesh_terms: D000818:Animals; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009118:Muscimol / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D012934:Social Isolation; D014886:Weaning
chemical_list: D018691:Excitatory Amino Acid Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; C493415:Slc6a1 protein, rat; D009118:Muscimol; D016291:Dizocilpine Maleate