Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

12-2002

Committee Chair or Co-Chairs

Paul J. Monaco

Committee Members

Ronald H. Baisden, Michael L. Woodruff, Kenneth E. Ferslew, Ellen M. Rasch, Barney E. Miller

Abstract

Lithium continues to be widely prescribed for the management of bipolar disease, yet cognitive impairment-related side effects promote noncompliance of the treatment regimen. We have introduced a novel animal model, the black molly fish, to study dose-response effects of lithium on short-term (STM) and long-term (LTM) memories. We developed a method utilizing capillary ion analysis (CIA), to measure plasma and brain lithium levels employed in our behavioral studies. We then developed an appropriate testing environment to ascertain learning capacities of these fish. We established that black mollies could adequately perform a forced-choice spontaneous alternation (SA) task used extensively in rodents as an index of spatial STM. Employing this paradigm we designed a dose-response experiment utilizing chronic lithium regimens with a wide range of dosage groups to assess STM in the black molly. Results of the experiment indicated a robust effect in which performances of all dose groups were impaired in different degrees but not dose dependently. Using the same dosing regimen, we tested subjects in a place-learning task to assess dose-response effects of lithium on spatial LTM. A variety of performance measures were analyzed presenting a consistent theme implicating significant impairment with the high dose group. CIA results for the STM and LTM experiments revealed consistent linear relationships between mean plasma and brain lithium levels and lithium dosages. We have immunolocalized a 5-HT1A-like receptor from the caudal midbrain of black mollies, an area structurally homologous to the mammalian raphe nuclei. This autoinhibitory receptor is considered to be involved in the regulation of firing of raphe serotonergic fibers and 5-HT release in terminal projection areas such as the hippocampus and frontal cortex. Downregulation of these receptors initiates excessive serotonin availability that may relieve symptoms of depression yet paradoxically impair cognition. It is unclear whether activity in the presynaptic raphe nuclei or the postsynaptic projection areas is responsible for these phenomena. Because the black molly is not equipped with postsynaptic 5-HT1A receptors it offers a unique opportunity to study the effects of lithium on the presynaptic form of the receptor without compensating effects of the postsynaptic form exhibited in the mammal.

Document Type

Dissertation - unrestricted

Copyright

Copyright by the authors.

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