Post-Weaning Social Isolation and Subchronic NMDA Glutamate Receptor Blockade: Effects on Locomotor Activity and GABA Signalling in the Rat
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The etiology and pathophysiology of schizophrenia are poorly understood, although increasing evidence suggests an important role for altered GABA neurotransmission. Animal models of schizophrenic symptoms include administration of noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, such as dizocilpine (MK-801), and post-weaning social isolation. The present study tested the hypothesis that a “double-hit” model, in which subchronic MK-801 administration and post-weaning social isolation are combined, produces greater behavioural and neurochemical effects than either insult alone. As a secondary objective, the present study also assessed whether the timing of the subchronic MK-801 injections (early adolescence vs. early adulthood) influences these measures. Male Sprague-Dawley rats (N = 74) were obtained at weaning (P21) and were either socially isolated (n = 42) or group housed (n = 32) for the duration of the experiment. Subgroups received subchronic treatment with MK-801 (0.5 mg/kg ip) or saline injections (1.0 ml/kg ip) twice daily for seven days either during early adolescence (P25-P32) or early adulthood (P56-63). At P70, all groups were tested for locomotor activity and subsequently sacrificed to assess the function of the GABA membrane transport protein, GAT-1, and GABAA receptor expression in the frontal cortex and hippocampus. For animals treated in early adulthood, post-weaning social isolation, in comparison to group housing, resulted in an increase in (1) locomotor activity (2) GAT-1 activity in frontal cortex and hippocampus and (3) GABAA receptor expression in the frontal cortex. MK-801 treatment in early adulthood increased GABAA receptor expression in the hippocampus, whereas post-weaning social isolation had no effect on GABAA receptor expression in the hippocampus. Previous studies have demonstrated that increased GAT-1 activity is associated with suppression of GABA-mediated inhibitory synaptic transmission. Furthermore, increased GABAA receptor expression may be a compensatory response to decreased availability of GABA. These data indicated that combined post-weaning social isolation and subchronic MK-801 treatment do not produce additive or synergistic effects on locomotor behaviour or GABA signalling, but rather induced differential effects on GABAA receptor binding.