Theses and Dissertations
This collection includes both ASU Theses and Dissertations, submitted by graduate students, and the Barrett, Honors College theses submitted by undergraduate students.
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- All Subjects: Dopamine
Description
Intermittent social defeat stress induces cross-sensitization to psychostimulants and escalation of drug self-administration. These behaviors could result from the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. Brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is persistently elevated after social defeat stress, and may contribute to the stress-induced neuroadaptation in the mesocorticolimbic dopamine circuit. BDNF modulates synaptic plasticity, and facilitates stress- and drug-induced neuroadaptations in the mesocorticolimbic system. The present research examined the role of mesolimbic BDNF signaling in social defeat stress-induced cross-sensitization to psychostimulants and the escalation of cocaine self-administration in rats. We measured drug taking behavior with the acquisition, progressive ratio, and binge paradigms during self-administration. With BDNF overexpression in the ventral tegmental area (VTA), single social defeat stress-induced cross-sensitization to amphetamine (AMPH) was significantly potentiated. VTA-BDNF overexpression also facilitates acquisition of cocaine self-administration, and a positive correlation between the level of VTA BDNF and drug intake during 12 hour binge was observed. We also found significant increase of DeltaFosB expression in the nucleus accumbens (NAc), the projection area of the VTA, in rats received intra-VTA BDNF overexpression. We therefore examined whether BDNF signaling in the NAc is important for social defeat stress-induced cross-sensitization by knockdown of the receptor of BDNF (neurotrophin tyrosine kinase receptor type 2, TrkB) there. NAc TrkB knockdown prevented social defeat stress-induced cross-sensitization to psychostimulant. Also social defeat stress-induced increase of DeltaFosB in the NAc was prevented by TrkB knockdown. Several other factors up-regulated by stress, such as the GluA1 subunit of Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and BDNF in the VTA were also prevented. We conclude that BDNF signaling in the VTA increases social defeat stress-induced vulnerability to psychostimulants, manifested as potentiated cross-sensitization/sensitization to AMPH and escalation of cocaine self-administration. Also BDNF signaling in the NAc is necessary for the stress-induced neuroadaptation and behavioral sensitization to psychostimulants. Therefore, TrkB in the NAc could be a therapeutic target to prevent stress-induced vulnerability to drugs of abuse in the future. DeltaFosB in the NAc shell could be a neural substrate underlying persistent cross-sensitization and augmented cocaine self-administration induced by social defeat stress.
ContributorsWang, Junshi (Author) / Hammer, Ronald (Thesis advisor) / Feuerstein, Burt (Committee member) / Nikulina, Ella (Committee member) / Neisewander, Janet (Committee member) / Arizona State University (Publisher)
Created2013
Description
Fibromyalgia (FM) is a chronic musculoskeletal disorder characterized by widespread pain, fatigue, and a variety of other comorbid physiological and psychological characteristics, including a deficit of positive affect. Recently, the focus of research on the pathophysiology of FM has considered the role of a number of genomic variants. In the current manuscript, case-control analyses did not support the hypothesis that FM patients would differ from other chronic pain groups in catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genotype. However, evidence is provided in support of the hypothesis that functional single nucleotide polymorphisms on the COMT and OPRM1 genes would be associated with risk and resilience, respectively, in a dual processing model of pain-related positive affective regulation in FM. Forty-six female patients with a physician-confirmed diagnosis of FM completed an electronic diary that included once-daily assessments of positive affect and soft tissue pain. Multilevel modeling yielded a significant gene X environment interaction, such that individuals with met/met genotype on COMT experienced a greater decline in positive affect as daily pain increased than did either val/met or val/val individuals. A gene X environment interaction for OPRM1 also emerged, indicating that individuals with at least one asp allele were more resilient to elevations in daily pain than those homozygous for the asn allele. In sum, the findings offer researchers ample reason to further investigate the contribution of the catecholamine and opioid systems, and their associated genomic variants, to the still poorly understood experience of FM.
ContributorsFinan, Patrick Hamilton (Author) / Zautra, Alex (Thesis advisor) / Davis, Mary (Committee member) / Lemery-Chalfant, Kathryn (Committee member) / Presson, Clark (Committee member) / Arizona State University (Publisher)
Created2011