SKF83959 is a high affinity dopamine D1 receptor agonist that has been reported to preferentially activate D1 receptors coupled to G(alpha)q. This pathway results in phosphatidylinositol hydrolysis, intracellular calcium mobilization, and potential activation of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIalpha), an important regulator of synaptic transmission. Although the exact mechanism remains unclear, one recent model suggested that SKF83959 activates a D1/D2 receptor heteromer complex coupled to G(alpha)q. Here, we have used genetic models to define the signaling specificity of SKF83959 using behavioral endpoints. Furthermore, we have extended the behavioral characterization of SKF83959 on motor output and additionally defined SKF83959-induced effects on anxiety and depressive-like behaviors.
In wildtype mice, a peripheral injection of SKF83959 (1mg/kg) produced a modest but significant increase in horizontal locomotor activity and orofacial grooming. The SKF83959-induced responses were blocked by the D1-like receptor antagonist SCH23390 and absent in D1 receptor knockout mice, confirming the role of D1 receptors in mediating the effects. SKF83959-induced behaviors were largely intact in D5 receptor and G(alpha)q knockouts, suggesting that these proteins are not necessary for mediating SKF83959-induced actions. There was, however, a significant difference between the response of wildtype and D5 receptor knockouts suggesting that D5 receptors may play some role in the signaling. Additionally, these responses were intact in D2 receptor knockouts and autophosphorylation-deficient CaMKIIalpha-Thr286Ala knockin mice, also negating the necessity of these proteins in SKF83959-mediated actions.
SKF83959 produced no significant effects in an elevated zero maze, a useful task for assessing anxiety in rodent models. There was, however, a reduction in immobility observed in SKF83959-treated mice in the forced swim test, suggesting reduced behavioral despair; an effect that was confirmed in a second measure of behavioral depression, the tail suspension test. Finally, we evaluated chronic SKF83959 exposure (0.5 mg/kg for 21 days) and observed differences between treatment groups in a novelty-induced food suppression test; a paradigm sensitive to chronic antidepressant treatment. Taken together, these studies define the specificity of receptor-G-protein signaling in the effects of SKF83959. Furthermore, our data indicate that SKF83959 may be useful in treating motor dysfunction and could potentially define a novel class of antidepressants targeting the dopamine system.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04112013-203459 |
| Date | 22 April 2013 |
| Creators | Frederick, Aliya Latisha |
| Contributors | Alissa Weaver, Danny Winder, Roger Colbran, Gregg Stanwood, Heidi Hamm |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-04112013-203459/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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