Abstract

The mesolimbic dopamine (DA) system originates in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NAc) and other areas including the basolateral amygdala (BLA), prefrontal cortex, and the hippocampus. Drug use induces reward and leads to dysregulation in these brain areas and eventually to substance use disorders (SUDs). Chapter 1 introduces the mesolimbic DA system and its relationship to drug use and their relevance to each chapter. Chapter 2 explores opioid effects on BLA circuitry which is known to play a role in the emotional response including anxiety and stress in SUDs. We showed that morphine induced an inhibitory effect on GABAergic lateral paracapsular cells (LPCs). These cells inhibit BLA principal neuron output and are influenced by opioids. Opioid activation in LPCs leads to upregulated BLA output, and activation in the NAc and central amygdala which may have important implications for stress/anxiety response for patients with SUDs. Chapter 3 explores the effect of interleukin-10 on the mesolimbic DA system. Specifically, cell-attached recordings of VTA DA neurons increase their firing rate in the presence of IL-10, and in vivo studies showed increased DA release in the NAc. Interleukin-10 receptors were expressed in VTA DA neurons and signals through the phosphoinositide 3-kinase. Surprisingly, IL-10 induced conditioned place aversion in mice which may be related to depression- and anxiety-like behaviors reported by others. Thus, IL-10 appears to be regulating the mesolimbic DA system and its association with reward which may be important in understanding the relationship between inflammation and SUDs. Chapter 4 explores the DA transporter (DAT) kinetics in the presence of psychostimulants using DA iontophoresis. We showed that iontophoretic DA delivery increased DA concentration and clearance rates compared to evoked release making it an important tool in measuring DAT kinetics. Cocaine was bath applied and slowed DAT reuptake at high concentrations and D2 stimulant quinpirole slowed the reuptake process but did not show any effect on DAT trafficking, and D2 antagonist eticlopride showed no change in reuptake or DAT trafficking. Cocaine-injected mice increased locomotion and reduced anxiety-like behavior, and iontophoresis experiments slowed reuptake with bath-applied cocaine. Thus, DA iontophoresis is useful in studying DAT blocker kinetics but has limitations in studying the effects of DAT trafficking. Chapter 5 discusses the impact these studies have on society, the limitations of each chapter, and future directions for this dissertation. Together these studies explore the reward system and its relationship with SUDs. The overarching aim has been to understand the involvement of DA in motivation and reward in the context of SUDs and the influence of opioids, cytokines, and psychostimulants.

Degree

PhD

College and Department

Life Sciences; Neuroscience

Rights

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