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Date of Award

12-2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Medical Sciences

Supervisor

Dr. L. Trevor Young MD PhD

Abstract

Biochemical and structural abnormalities have been reported in postmortem brain tissue from patients with mood disorders. Studies of the molecular pharmacology of drugs used in the treatment of mood disorders have led to a reinterpretation of earlier models of neuropathology in these diseases. Noradrenergic and serotonergic hypotheses have been expanded to include postsynaptic intracellular signal transduction pathways, regulation of gene expression, and synaptic plasticity. Because much of this evidence was obtained from postmortem brain, the experiments in this study also used postmortem tissue to examine the neuropathology of mood disorders. Human postmortem brain tissue was obtained from the Stanley Consortium Neuropathology Foundation and consisted of pieces of temporal and occipital cortex, and slices of prefrontal cortex and hippocampus from patients with bipolar affective disorder (BD), major depressive disorder (MDD), schizophrenia (SCZ) and controls (N = 15 per group). Components of the cAMP system were examined, as were potential target transcription and neurotrophic factors. Morphological consequences arising from altered cAMP signalling such as sprouting and DNA fragmentation were also investigated. There was a trend towards blunted temporal cortex adenylyl cyclase activity in subjects with mood disorders, and decreased occipital cortex Gas in lithium-treated BD subjects. Temporal cortex CREB level~ were decreased in antidepressant-untreated MDD subjects compared to controls, and normal in those subjects treated by antidepressants at the time of death. Temporal cortex CREB levels were decreased in BD patients treated with anticonvulsants relative to those not treated by anticonvulsants at the time of death. When assessing the effect of suicide on cAMP signalling, subjects who died as a result of suicide had lower temporal cortex CREB levels and CRE-binding than subjects who died of other causes. This effect was most evident in the MDD group. In hippocampus, BDNF levels were increased in subjects treated by antidepressants compared to subjects not treated by these medications at the time of death. This finding was more pronounced in the MDD group. Hippocampal studies also showed that BD subjects had increased mossy fibre staining relative to controls and other diagnoses, suggesting increased sprouting of the dentate gyrus axons. These postmortem findings are consistent with recent animal and cell models of antidepressant and mood stabilizer pharmacology. The changes in post-receptor signalling and hippocampal sprouting are also consistent with current conceptualizations of the neurobiology of mood disorders. These studies support the use of postmortem brain tissue as a clinically relevant research model, and add to the growing literature elucidating the pathophysiology of mood disorders and the molecular pharmacology of their treatments.

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