Vigor-inducing effects of dopamine transport (DAT) blockers: studies using different types of behavioral activation and effort-based decision-making tasks in rodents.

Abstract

Dopamine transporter (DAT) blockers increase dopamine (DA) availability by inhibiting reuptake, enhancing dopaminergic activity, and are being explored as treatments for motivational deficits in psychiatric and neurological conditions. The mesolimbic DA system, particularly the ventral tegmental area to nucleus accumbens pathway, regulates motivation and effort-based decision-making. Dysfunction in this pathway is linked to symptoms like anergia and fatigue, common in depression, which often resist treatment. This thesis focuses on developing and validating mice models to study effort-related behaviors and test novel DAT blockers. Chapter 1 explores decision-making under varying reinforcer and effort conditions, adapting rat paradigms for mice. Chapter 2 validates these models using bupropion and examines the role of CDNF in motivation. Chapter 3 assesses new DAT inhibitors (CE-123, CE-158, MK-26) compared to modafinil and cocaine, analyzing their effects on anxiety and locomotion. These findings demonstrate the therapeutic potential of DAT blockers for addressing motivational dysfunctions.