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Striatal Dopamine Receptors, Inhibitory Control and Methamphetamine Use Disorder

Abstract

Inhibitory control is a neurocognitive construct that describes the capacity to exert control over behaviors, thoughts, actions and emotions. It is essential to everyday life and is an important component of executive function necessary for goal directed behavior. However, deficits in inhibitory control are manifested across several neuropsychiatric disorders, especially substance use disorders. Although the neurobiological mechanisms that underlie human inhibitory control are not completely clear, neuroimaging studies have advanced our understanding of the underlying circuitry of inhibitory control and pharmacological studies have highlighted an essential role for dopaminergic neurotransmission. However, there remains much to be understood about how different striatal dopaminergic receptor systems influence inhibitory control capacity. Therefore, the research in this dissertation aims to increase our understanding of how striatal dopaminergic signaling at different dopamine receptor subtypes (D1- and D2-type) contributes to individual levels of impulsivity and inhibitory control.

Dopaminergic deficiencies in stimulant use disorder are linked to several clinically relevant indices, including treatment retention and outcomes. Dopamine markers are associated with behaviors and cognitive functions important to the development and maintenance of addiction, including inhibitory control, risk-taking and delay of gratification. Therefore, augmenting dopaminergic function is an attractive therapeutic target in the treatment of stimulant use disorders. However, the lack of approved pharmacological agents for this purpose has spurred an interest in alternative approaches to augmenting the dopaminergic signaling in stimulant users. On the basis of a large animal literature, aerobic exercise has been suggested as a mechanism to increase dopamine system function in stimulant use disorder. Research in this dissertation aims to determine the effects of exercise on the dopamine system in individuals with methamphetamine use disorder.

Determining the relevance of individual variation in dopaminergic markers on human behavior will improve our understanding of the molecular basis of inhibitory control and its dysregulation in substance use disorders. Furthermore, investigating methods to improve dopamine function in individuals with methamphetamine use disorder represents an important step for improving addiction treatment.

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