Illicit psychostimulant addiction remains a significant problem worldwide, despite decades of research into the neural underpinnings and various treatment approaches. The purpose of this review is to provide a succinct overview of the neurocircuitry involved in drug addiction, as well as the acute and chronic effects of cocaine and amphetamines within this circuitry in humans. Investigational pharmacological treatments for illicit psychostimulant addiction are also reviewed. Our current knowledge base clearly demonstrates that illicit psychostimulants produce lasting adaptive neural and behavioral changes that contribute to the progression and maintenance of addiction. However, attempts at generating pharmacological treatments for psychostimulant addiction have historically focused on intervening at the level of the acute effects of these drugs. The lack of approved pharmacological treatments for psychostimulant addiction highlights the need for new treatment strategies, especially those that prevent or ameliorate the adaptive neural, cognitive, and behavioral changes caused by chronic use of this class of illicit drugs.

This thesis attempts to use psychoneuroimmunology (PNI) as a lens for examining different immune and autoimmune disorders, as well as psychological function and dysfunction. Through this examination, it is hypothesized that PNI could point to an accurate theoretical framework for describing the mind-body relation, or at the very least gain a deeper respect for showing the complexity of consciousness and health. Conversely, an appropriate view of the mind-body relation should provide a sound theoretical framework for PNI research.

Chronic pain, or reoccurring pain lasting longer than three months, is frequently co- morbid with other chronic conditions. Physiological health problems such as overall general health, immune function, inflammation, stress, and sleep, as well as psychological problems like depression and anxiety are all associated with chronic pain. Previous studies have also shown evidence for the heritability of chronic pain, indicating a genetic factor for chronic pain in children. However, few studies have investigated potential epigenetic processes involved in childhood chronic pain. DNA methylation and other epigenetic processes are highly susceptible to changes during crucial developmental periods in children, and they are heavily influenced by psychosocial factors and environmental factors. During an immune response, various cytokines such as TNFα, IL-6, and CRP are released. Cytokines are involved in the production of pain through their pro-inflammatory properties. Additionally, there is evidence to believe they increase pain sensitivity acutely by acting directly on nociceptors. Previous studies have shown that higher levels of inflammatory cytokines are associated with more pain because the inflammatory response from our immune cells activates pain pathways. A constant or prolonged activation of the immune response may consequently result in chronic pain. In many cases of chronic pain, there is an increase in the circulating pro-inflammatory cytokines in the blood that also leads to hypersensitivity.

For my thesis, I conducted a study on a healthy pediatric cohort to investigate how DNA methylation of genes related to myelin may predict total white matter volume in a healthy pediatric cohort. The relatively new field of neuroimaging epigenetics investigates how methylation of genes in peripheral tissue samples is related to certain structural or functional features of the brain, as measured by neuroimaging data. Research has already demonstrated that methylation of genes in peripheral tissues is related to a variety of brain disorders. We hypothesized that methylation of myelin-related genes as measured in saliva samples would predict total white matter volume in a healthy pediatric cohort. After processing DNA methylation data from saliva samples from participants, multiple linear regressions were ran to determine if DNA methylation of myelin related genes was related to total white matter volume, as measured by data from structural MRIs. Results showed that these genes, which included MOG, MBP, and MYRF, significantly predicted total white matter volume. Two genes that were significant in our results have been previously shown to produce proteins that are essential to the structure of myelin.

The maternal separation (MS) paradigm is an animal model of early life stress. Animals subjected to MS during the first 2 weeks of life display altered behavioral and neuroendocrinological stress responses as adults. MS also produces altered responsiveness to and self-administration (SA) of various drugs of abuse including cocaine, ethanol, and amphetamine. However, no studies have yet examined the effects of MS on methamphetamine (METH) SA. This study was performed to examine the effects of MS on the acquisition of METH SA, extinction, and reinstatement of METH-seeking behavior in adulthood. Given the known influence of early life stress and drug exposure on epigenetic processes, we also investigated group differences in levels of the epigenetic marker methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) core. Long–Evans pups and dams were separated on postnatal days (PND) 2–14 for either 180 (MS180) or 15 min (MS15). Male offspring were allowed to acquire METH SA (0.05 mg/kg/infusion) in 15 2-h daily sessions starting at PND67, followed by extinction training and cue-induced reinstatement of METH-seeking behavior. Rats were then assessed for MeCP2 levels in the NAc core by immunohistochemistry. The MS180 group self-administered significantly more METH and acquired SA earlier than the MS15 group. No group differences in extinction or cue-induced reinstatement were observed. MS15 rats had significantly elevated MeCP2-immunoreactive cells in the NAc core as compared to MS180 rats. Together, these data suggest that MS has lasting influences on METH SA as well as epigenetic processes in the brain reward circuitry.