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. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2010-09-01 15:21:58.474
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/6013 |
| Date | 01 September 2010 |
| Creators | Hickey, Andrea |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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