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A pharmacodynamic model of the role of 5-HT2A and GABAA receptors in the delay in the onset of action of SSRIS

Author

Patrick G. Chan, University of the Pacific

Date of Award

2009

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

James Uchizono

First Committee Member

Donald Floriddia

Second Committee Member

Denis Meerdink

Third Committee Member

Robert Halliwell

Fourth Committee Member

Emil Samara

Abstract

Depression is a common neuropsychiatric illness with a lifetime prevalence of 17% in the United States. The disease can severely impact the daily living and quality of life in patients. The monoamine hypothesis of depression implicates the neurotransmitter serotonin as mediating the pathophysiology. Selective serotonin reuptake inhibitors (SSRIs), a popular and efficacious class of antidepressants, increase serotonin concentrations in the brain. However, full clinical benefit may not be obtained for four to six weeks. This period of waiting for SSRIs to work becomes quite daunting for patients. Research has focused on delineating the control mechanisms surrounding the dorsal raphé nucleus (DRN), the serotonergic control center located in the midbrain. Much evidence points to changes in several receptor systems as the underlying cause of the delay. One particular serotonin receptor, 5-HT 1A , has been established to play a role in affecting the time course of clinical effect. We have targeted another receptor as a possible contributor to the delay: the stimulatory 5-HT 2A heteroreceptors located on GABAergic interneurons of the DRN. The 5-HT 2A receptors of the GABAergic interneurons receive stimulatory input from serotonergic collaterals branching off the DRN serotonergic neurons. The resultant stimulation causes GABA release and inhibition of the serotonergic neurons via GABA A receptors of the DRN, completing a feedback loop. We hypothesize that the 5-HT 2A receptors desensitize under constant stimulation, as in the case with SSRI administration, and as a result contribute to the time delay in the onset of action of SSRIs. Using the microdialysis technique, various receptor agonists and antagonists were administered to examine receptor changes and its influence on serotonin release in male Wistar rats. Our results demonstrate that GABA A receptors exert a large inhibitory influence on serotonergic neurotransmission. Local GABA release results from 5-HT 2A receptor stimulation. Furthermore, serotonin appears to trend back towards basal levels, suggesting a possible desensitization process occurring under constant agonism of 5-HT 2A receptors. The development of our pharmacodynamic model quantitatively shows a slow desensitization process, which may also contribute to the time delay observed with the onset of action of SSRIs.

Pages

235

ISBN

9781109074840

Recommended Citation

Chan, Patrick G.. (2009). A pharmacodynamic model of the role of 5-HT2A and GABAA receptors in the delay in the onset of action of SSRIS. University of the Pacific, Dissertation - Pacific Access Restricted. https://scholarlycommons.pacific.edu/uop_etds/2396