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Neuroendocrine challenge studies of serotonin and gaba function in mania and in the mechanism of action of the mood stabilizer divalproex sodium

University of British Columbia

In this thesis, we report on studies that investigated the roles of serotonin (5- hydroxytryptamine; 5-HT) and y-aminobutyric acid (GABA) in the pathophysiology of mania and in the mechanism of action of the mood stabilizer, divalproex sodium (DVP) using neuroendocrine challenge paradigm. Pharmacological challenges with the 5-HTiA receptor agonist, ipsapirone and the GABAB receptor agonist, baclofen were administered to patients with mania and normal healthy volunteers. Following the administration of challenge agents, hormonal, hypothermic, and/or behavioral responses were measured at regular intervals. We found that 1) manic patients had significantly enhanced ACTH and Cortisol responses to ipsapirone when compared to normal controls, but the hypothermic response to ipsapirone did not differ between the two groups; 2) one-week treatment with DVP significantly attenuated hypothermic response to ipsapirone in healthy controls but this did not modify the ACTH or Cortisol response to ipsapirone; 3) GH response to baclofen was significantly increased in manic patients compared to normal controls; 4) one-week treatment with DVP significantly attenuated the GH response to baclofen in healthy controls. The results of 5-HT neuroendocinre challenge studies suggest that manic patients have an increase in postsynaptic 5-HT]A receptor sensitivity, which may be secondary to diminished 5-HT availability in central 5-HT synapses, and that DVP enhances 5-HT neurotransmission via a subsensitization of 5-HTIA autoreceptors. These appear to support hypotheses that a 5-HT deficit is involved in mania and that enhancement of 5-HT neurotransmission exerts a mood stabilizing effect. The findings of GABA neuroendocrine challenge studies suggest that manic patients also have an up-regulated hypothalamic GABAB receptor function, presumably resulting from a GABA deficit in brain, and that DVP treatment restores this deficit by enhancing GABAergic neurotransmission, thus leading to a down-regulation in hypothalamic GABAB receptor function. These experiments have provided some evidence for the contribution of 5-HT and GABA in mania and in the mechanism of action of DVP. However, it is very likely that other neurotransmitters such as norepinephrine and dopamine and their interaction with 5-HT and GABA also play important roles. More neurobiological studies on manic patients are warranted to enhance our understanding of this illness and its treatment.

Thesis/Dissertation

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2009-07-03

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http://hdl.handle.net/2429/10078

Neuroscience

University of British Columbia

UBCV

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