Post-weaning social isolation and subchronic NMDA glutamate receptor blockade: effects on locomotor activity and GABA signaling in the rat suggest independent mechanisms |
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Authors: | Hickey Andrea J Reynolds James N Beninger Richard J |
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Affiliation: | a Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada K7L 3N6b Department of Psychology, Queen's University, Kingston, Ontario, Canada K7L 3N6c Department of Psychiatryy, Queen's University, Kingston, Ontario, Canada K7L 3N6d Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada K7L 3N6 |
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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 GABAA receptor expression in the frontal cortex and hippocampus. SI resulted in increased locomotor activity, GAT-1 activity in frontal cortex and hippocampus and GABAA receptor expression in the frontal cortex; MK-801 increased GABAA receptor expression in the hippocampus. Activity changes were correlated with changes in hippocampal GAT-1 and frontocortical GABAA 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 GABAA 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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Keywords: | Gamma-amino-butyric-acid (GABA) NMDA receptor MK-801 Sprague-Dawley rat Schizophrenia |
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