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Dissertation
Chronic treatment with the serotonin 2A antagonist SR 46349B enhances retention and efficiency of rule-guided behavior in mice
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2012
DOI:
https://doi.org/10.17918/00000668
Abstract
The serotonin 2A (5-HT2A) receptor modulates learning and memory processes and thus provides a promising target for cognitive enhancement in humans suffering from neurodegenerative disease and psychiatric disorders. Studies in animal models have established that acute 5-HT2A receptor agonist treatment can enhance learning and memory performance. Long-term agonist treatment results in a decrease in receptor density, however, which might negate these nootropic effects. In the current study, we have characterized 5-HT2A and 5-HT2C densities in the neocortex of the laboratory mouse to use this system to explore the effects of 5-HT2 receptor modulation on cognitive processes and to better compare these findings with those from other species. We found mouse neocortex to have high 5-HT2A receptor density but much lower 5-HT2C density relative to other species. In the second aim, we tested the hypothesis that 5HT2A receptor upregulation would produce cognitive enhancement similar to acute agonist treatment. We administered the 5-HT2A receptor antagonist, SR 46349B (eplivanserin), to mice for 4 days following initial training on a simple rule-based behavior. We then tested their recall of the task, and, subsequently, their ability to adapt to a reversal in reward contingency (reversal learning). For comparison, two other groups were treated with varying doses of the 5-HT2A/2C receptor agonist, DOI, which downregulates the 5-HT2A receptor. SR 46349B improved performance in tests of spatial memory recall but did not affect cognitive flexibility. Moreover, subjects treated with SR 46349B completed trials more quickly and with fewer non-goal-directed movements than either vehicle- or DOI-treated subjects. We then determined the effects of the each drug treatment on 5-HT2A receptor density in brain areas involved in learning and memory using quantitative autoradiography. Chronic DOI treatment significantly downregulated 5-HT2A receptors, but SR 46349B treatment had no effect. Our results suggest that chronic treatment with SR 46349B may be useful in enhancing recall, although further studies are needed to determine the mechanism underlying this effect.
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Details
- Title
- Chronic treatment with the serotonin 2A antagonist SR 46349B enhances retention and efficiency of rule-guided behavior in mice
- Creators
- John Peter Dougherty
- Contributors
- Alessandro Graziano (Advisor)James E. Barrett (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 158 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991014970200304721