Type of Document Dissertation Author Frederick, Aliya Latisha Author's Email Address firstname.lastname@example.org URN etd-04112013-203459 Title Genetic dissection of the behavioral effects of the dopamine receptor agonist SKF83959 does not support the D1/D2 receptor heteromer model Degree PhD Department Neuroscience Advisory Committee
Advisor Name Title Danny Winder Committee Chair Alissa Weaver Committee Member Gregg Stanwood Committee Member Heidi Hamm Committee Member Roger Colbran Committee Member Keywords
- Dopamine receptors; Behavior; Agonist
Date of Defense 2012-07-27 Availability unrestricted AbstractSKF83959 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.
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