Date of Award

1-1-2021

Language

English

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

College/School/Department

Department of Psychology

Program

Behavioral Neuroscience

Content Description

1 online resource (vii, 189 pages) : illustrations (some color)

Dissertation/Thesis Chair

Damian G Zuloaga

Committee Members

Christine K Wagner, Andrew M Poulos

Keywords

Corticosterone, HPA axis, Methamphetamine, Psychostimulant, Sex differences, Stress, Methamphetamine abuse, Stress (Physiology), Stress (Psychology), Anxiety, Brain

Subject Categories

Biological Psychology | Psychology | Social and Behavioral Sciences

Abstract

Methamphetamine (MA) is a psychostimulant drug of addiction that induces a wide range ofeffects. Among its many side effects is the potentiation of cellular, physiological, and behavioral changes in the stress response system. Upon exposure, the hypothalamic-pituitary-adrenal (HPA) axis is initiated. This process entails many factors. Receiving input from other brain regions, the paraventricular nucleus (PVN) of the hypothalamus secretes corticotropin-releasing factor (CRF) and arginine vasopressin into the anterior pituitary gland. These together stimulate the synthesis and release of adrenocorticotropic hormone, which circulates via the blood stream to cause the release of glucocortoicoids, the stress hormone (CORT). Binding of glucocorticoids to glucocorticoid receptors (GR) in the brain positively and negatively modulates stress, which in turn modulates stress-related behaviors. In MA abusers, elevated stress due to exposure may have significant implications for risk of future use, as well as lasting alterations to the stress response system. Existing literature has shown that subjects undergoing withdrawal from MA exhibit higher levels of anxiety and depression, disorders that are associated with stress. Further, acute stress is capable of increasing one’s vulnerability to drug reinstatement. Sex differences in patterns of MA abuse have been found, indicating women possess greater addiction-like behaviors. For example, women begin using MA at an earlier age, are more committed to MA, and become addicted faster. This disparity has been reflected in rodent models in which females demonstrate greater MA self-administration, escalation of MA intake, and reinstatement to MA self-administration during withdrawal. The underlying cause of these observations is not clear, but is thought to be due to differences between male and female stress response systems. To explore this possibility, the following experiments examined the effects of MA exposure in males and females on the neuroendocrine stress response, as well as anxiety/depression-related behaviors. By studying cell activation patterns in stress-associated brain regions, we assessed how different cell phenotypes are affected by acute and chronic MA exposure. Upon re-exposure to MA following withdrawal from chronic administration, attenuated activation was found in several limbic brain regions, and in some areas this observation persisted long after MA cessation. With regard to mechanisms underlying sex differences in patterns of MA addiction, an observed sensitization of activity in the nucleus accumbens core only in females may be a contributing factor. Reduced activity was also found in response to nondrug stress during early withdrawal, suggesting a weakening of HPA axis associated brain regions by chronic MA emerges early and is long lasting. Impaired nest building by females withdrawing from chronic MA suggest a sex-specific affective impairment. We then examined levels of stress hormones to compare levels of limbic activity and overall HPA axis output. Gonadal hormones have been suggested to play a role in sex differences to drug exposure. Therefore, we determined the contributions of androgens and estrogens in the HPA axis response to acute MA exposure. In the absence of circulating sex steroids, only males demonstrated less efficient HPA axis negative feedback evidenced by protracted elevation of acute MA-induced CORT. This was accompanied by hormone-dependent alterations of regional GR cell activity, suggesting gonadal hormones modulate the brain’s regulation of MA-induced HPA axis activity. Because androgens appeared to mitigate these effects, we examined their role in withdrawal from chronic MA exposure. However, behavioral measures of depression during early withdrawal were not affected by the absence of androgens. Although gonadal hormones appear to modulate the effects of acute MA, they may play a lesser role in withdrawal-related depression. A deeper understanding of sex-specific effects of MA will aid in formulating more effective therapies. A strong modulator of limbic region activity is CRF binding to its receptor 1 (CRFR1) subtype. Using two distinct transgenic mouse reporter lines to visualize both neuropeptide and protein, we assessed the effects of chronic MA on their expression and activation following challenge MA. We found a weakening of CRF/CRFR1 activity in the extended amygdala and PVN. These regions contribute to anxiogenesis, suggesting an overall impairment of function. Because women exhibit greater addiction-like patterns to MA, and often are of childbearing age, there is heightened interest in the effects of prenatal MA exposure. We tested the effects of gestational MA on the development and activation of the male and female HPA axis and behavior in neonatal and adult stages. Because of the known teratogenic effects of prenatal MA, we also examined the brain’s immune response during the neonatal phase. Prenatal MA exposure (PME) produced greater microglial activation in the central amygdala (CeA) in neonates, suggesting some form of injury is occurring. In adulthood, lower restraint-stress induced activation in the central amygdala, as well as altered activity in other amygdala regions, suggests PME exerted permanent damage onto these areas. Moreover, depressive/despair-like behaviors in the tail suspension test were greater in PME offspring. Early-life interventions can have a remarkable impact on children with unfavorable predispositions. Discovering the teratogenic effects of prenatal MA exposure is central to this objective. The experiments described herein illuminate the effects of acute and chronic MA on components of stress and HPA axis output, as well as affective behaviors during MA withdrawal. Overall, regions of the extended amygdala appear to be most consistently affected by MA, whereas sex specific findings in particular regions, such as the nucleus accumbens core, provide interesting targets for future investigation into underlying mechanisms of sex differences in patterns of MA abuse.

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