Date of Completion
John D. Salamone
Physiology and Neurobiology
Second Honors Major
Animal Experimentation and Research | Behavioral Neurobiology | Experimental Analysis of Behavior
Depression is a debilitating disorder that can cause motivational deficits such as psychomotor retardation, anergia, apathy, and fatigue. Recent research indicates that these motivational deficits, and potential pathways of therapeutic intervention, can be studied in animal models involving rats and mice. Treatments with the VMAT-2 inhibitor tetrabenazine (TBZ) and cytokine interleukin-1ß (IL-1ß) can create a low-effort bias and impair effort-related motivation (Nunes et al. 2013, 2014). A number of high-affinity DA transport inhibitors such as d-amphetamine, methylphenidate, and cocaine can restore extracellular DA, albeit with the cost of undesirable effects such as high abuse liability. These observations have led researchers to identify a number of molecules that fit the profile of “atypical” dopamine binding, which leads to a longer duration of extracellular DA and minimizes side effects. In this review, the binding affinities and dose-response behavioral outputs for respective FR5/Chow and PROG/Chow feeding procedures have been compiled for eight DAT blockers: bupropion, GBR12909, lisdexamfetamine, PRX-14040, modafinil, (S)-CE-123, (S, S)-CE-158, and methylphenidate. Regression analyses between measures of DAT affinity and minimum significant dose in behavioral studies suggests a strong linear relationship between binding affinity and potency in terms of the ability of drugs to reverse the effects of TBZ the FR5/chow procedure. However, there was a variable relationship in terms of the ability of drugs to enhance lever pressing in rats tested on the PROG/choice procedure.
Desibhatla, Mukund, "The Development and Evaluation of Novel DA Transport Inhibitors and their Effects on Effort-Related Motivation: A Review" (2021). Honors Scholar Theses. 787.