Date of Completion
Motivation, Depression, Touchscreen chambers, Adenosine
R Holly Fitch
Field of Study
Doctor of Philosophy
The major objective of the present research was to characterize the underlying mechanisms of effort-related aspects of motivation using pharmacological and genetic approaches in rodent subjects. Effort-related decision making tasks have been widely used to assess motivated behavior in human and animals. However, human studies often yield mixed results due to less controllable genetic heterogeneity. Additionally, considering the importance of developing clinical interventions for human psychiatric disorders, there is a need to establish animal models that are useful for understanding the mechanisms of motivational symptoms. This dissertation consists of five sets of experiments which aimed to investigate the roles of dopamine (DA) and adenosine in motivated behavior in rats, and to develop novel touchscreen procedures using transgenic mouse models and pharmacological interventions to assess DA related genes and DA transmission in regulating effort-related decision making. Exp 1 demonstrated that the administration of DA depleting agent tetrabenazine (TBZ) and the DA D2 receptor antagonist haloperidol increased elasticity of demand for food in rats. In addition to DA, Exp 2 showed the ability of the highly selective adenosine A2A receptor antagonist preladenant to reverse the motivation effects induced by TBZ in a rat effort-related choice task. While the neural mechanisms underlying effort-related choice behavior have been widely studied in rats, fewer studies have been performed in mice. Exp 3 established mouse effort-related choice procedures by using Bussay-Sakisda touchscreen chambers, and evaluated the effects of haloperidol on CD1 mice responding on the touchscreen paradigm. Using the developed touchscreen paradigm, Exp 4 indicated that transgenic mice carrying humanized catechol-o-methyltransferase gene valine allele was associated with motivational impairments. Moreover, Exp 5 studied the effects of TBZ on C57BL6 mice tested on the touchscreen procedures, and determined the effects of TBZ on striatal DA levels with a tissue assay and high performance liquid chromatography. This research could lead to a greater understanding of the neurochemical and genetic mechanisms underlying effort-based aspects of motivation, and these models could serve as a platform for assessment of novel strategies for the treatment of motivational dysfunctions in human psychiatric and neurological patients.
Yang, Jen-Hau, "Pharmacological and Genetic Studies of Effort-Related Decision Making Using Rodent Models: Roles of Dopamine in Motivated Behavior" (2019). Doctoral Dissertations. 2333.