Mechanisms and treatments of drug consumption: A preclinical exploration in harm reducing pharmacotherapies for substance use disorders

Abstract

The loss of control in amounts of drug consumed is a common trait experienced by persons living with drug addiction. The motivation of this dissertation is to further our understanding in the neural mechanisms that mediate consumption of drugs of abuse, to reveal targets for pharmacological intervention to decrease uncontrollable drug use, and ultimately promote harm-reduction. Most contemporary theories of drug abuse posit that adaptations in mesolimbic dopamine signaling are a fundamental mediator in the development, and maintenance of drug addiction. However, the manner and direction of alterations in dopaminergic signaling during drug addiction are heavily debated. Within Chapter 2 of this dissertation we demonstrate that dopaminergic signaling to drug paired stimuli has diametric changes across the addiction cycle that depends on the context in which the cues are presented. We explore how drug-taking history, drug-taking patterns, and abstinence influence alterations observed in nucleus accumbens (NAc) dopamine signaling to stimuli associated with drug-delivery. We further demonstrate causal evidence that differential changes in phasic dopamine transmission can drive drug-taking and drug-seeking behaviors, ultimately revealing that treating people living with addiction will heavily depend on what stage of recovery that person is currently within. Harm reduction is an approach often used to treat drug addiction. One way to accomplish this is to help people decrease drug consumption to more moderate levels. In Chapter 2 we found that replacement of diminished phasic dopamine release within the NAc during a drug-paired cue decreases escalated drug consumption. In Chapter 3 I explore the mechanisms mediating the observed decrement cue evoked dopamine release within the NAc cues. Overall, we find that the endogenous signaling of the kappa opioid receptor ligand, dynorphin is a likely candidate responsible for attenuated dopamine signaling. Altering the ability for dynorphin to act on kappa, with pharmacologic or genetic approaches, prevents the development of escalated cocaine intake and decreases drug consumption. It was previously found that administration of L-DOPA, a precursor of dopamine, replenishes the attenuated cue evoked dopamine in the NAc, and decreases cocaine consumption (Willuhn et al., 2014). In Chapter 4 I present our investigations in the effect L-DOPA has on ethanol and fentanyl consumption. We observed significant decreases in drug consumption of both ethanol and fentanyl following L-DOPA treatment. These results demonstrate that L-DOPA, and FDA approved drug taken by humans, has harm-reducing properties in psychostimulant, alcohol, and opioid use. Another FDA approved drug, finasteride, has shown promise in decreasing gambling disorders in people living with Parkinson’s and decreases ticks in people living with Tourette’s. Because it is known that both of these disease have heavily disrupted dopamine signaling we were interested in how this drug would affect drug-taking behaviors. We found that administering animals with finasteride decreased their intake of hydrocodone, fentanyl (Chapter 5), as well as cocaine (Chapter 6). Interestingly, we also found that finasteride decreases drug-seeking behaviors that are observed after animals experience prolonged abstinence and are shown the stimuli that are paired with imminent drug delivery. Collectively, the results within this dissertation reveal neurobiological mechanisms promoting excessive drug use. Additionally, the data within demonstrate two promising pharmacological therapies to aid in decreasing drug consumption, and such reduce harm in people struggling with drug addiction.