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- Creators: Barrett, The Honors College
- Creators: Malone, Shane
Description
Intermittent social defeat stress produces vulnerability to drugs of abuse, a phenomena known as cross-sensitization, which is proceeded by a corresponding upregulation of ventral tegmental area (VTA) mu-opioid receptors (MORs). Since VTA MORs are implicated in the expression of psychostimulant sensitization, they may also mediate social stress-induced vulnerability to drugs of abuse. Social stress and drugs of abuse increase mesolimbic brain-derived neurotrophic factor (BDNF) signaling with its receptor, tropomyosin-related kinase B (TrkB). These studies examined whether VTA MOR signaling is important for the behavioral and cellular consequences of social stress. First, the function of VTA MORs in the behavioral consequences of intermittent social defeat stress was investigated. Lentivirus-mediated knockdown of VTA MORs prevented social stress-induced cross-sensitization, as well as stress-induced social avoidance and weight gain deficits. Next it was examined whether VTA MOR expression is critical for stress-induced alterations in the mesocorticolimbic circuit. At the time cross-sensitization was known to occur, lentivirus-mediated knockdown of VTA MORs prevented stress-induced increases in VTA BDNF and its receptor, TrkB in the nucleus accumbens (NAc), and attenuated NAc expression of delta FosB. There was no effect of either stress or virus on BDNF expression in the prefrontal cortex. Since social stress-induced upregulation of VTA MORs is necessary for consequences of social stress, next activity dependent changes in AKT, a downstream target of MOR stimulation associated with sensitization to psychostimulant drugs, were investigated. Using fluorescent immunohistochemical double labeling for the active form of AKT (pAKT) and markers of either GABA or dopamine neurons in the VTA, it was determined that social stress significantly increased the expression of pAKT in GABA, but not dopamine neurons, and that this effect was dependent on VTA MOR expression. Moreover, intra-VTA inhibition of pAKT during stress prevented stress-induced weight gain deficits, while acute inhibition of VTA pAKT blocked the expression of cross-sensitization in subjects that had previously exhibited sensitized locomotor activity. Together these results suggest that social stress upregulates MORs on VTA GABA neurons, resulting in AKT phosphorylation, and that increased VTA MOR-pAKT signaling may represent a novel therapeutic target for the intervention of substance abuse disorders.
ContributorsJohnston, Caitlin (Author) / Hammer, Ronald P. (Thesis advisor) / Nikulina, Ella M. (Thesis advisor) / Neisewander, Janet L. (Committee member) / Wu, Jie (Committee member) / Olive, Michael F. (Committee member) / Arizona State University (Publisher)
Created2015
Description
The purpose of this study was to evaluate existing data from the Arizona Youth Survey (AYS) to give policymakers and representatives from the Arizona Criminal Justice Commission some insight into the high rates of youth prescription drug abuse. This study examined trends in prescription drug consumption among Pima County, Arizona adolescents, as well as the contexts in which these drugs were used and the numerous consequences resulting from such actions. The results of this research will allow professionals at the Arizona Criminal Justice Commission to inform state officials on the most cost-effective methods of prescription drug abuse prevention and intervention.
ContributorsLewis, Melissa (Author) / Roosa, Mark (Thesis director) / Dumka, Larry (Committee member) / Malone, Shane (Committee member) / Barrett, The Honors College (Contributor)
Created2013-05
Description
Consequences of drug abuse and addiction affect both men and women, but women tend to rapidly progress through drug addiction phases, have higher drug dependency, and have higher relapse rates. Ovarian hormones fluctuate with female reproductive cycles and are thought to cause increased sensitivity to psychostimulants. Additionally, intermittent social defeat stress induces social avoidance, weight loss, and long-lasting cross-sensitization to psychostimulants, which is associated with increased FosB/ΔFosB expression in the nucleus accumbens (NAc) shell. In this study, we examined the estrous cycle in female rats on social defeat stress-induced amphetamine cross-sensitization through FosB/ΔFosB expression in the NAc shell. Every third day for ten days, we induced social defeat stress in rats through short confrontations with a lactating female resident rat and her pups. In parallel, a group of rats were handled for control. Vaginal swabs were taken daily to assess estrous stage. Ten days after the last stress exposure, rats were administered a low dose of amphetamine (0.5 mg/kg, i.p.), which induced cross-sensitization in stressed rats, evidenced by enhanced locomotor activity. Approximately 3-10 days after amphetamine challenge, brain tissue was collected for immunohistochemistry analyses. Stressed female rats had lower body weight gain, higher social avoidance, and increased FosB/ΔFosB expression in the NAc shell. Differences in FosB/ΔFosB expression in the NAc shell was also observed in handled animals in different estrous stages. Furthermore, rats in proestrous/estrous stages displayed enhanced social defeat stress-induced amphetamine cross-sensitization in comparison to rats in metestrous/diestrous stages. Elucidating the effects of the female reproductive cycle on drug use may provide a novel approach to treatments or therapies in preventing women’s stress-induced vulnerability to substance abuse.
ContributorsAzuma, Alyssa (Author) / Neisewander, Janet (Thesis director) / Nikulina, Ella (Thesis director) / Hammer, Ronald (Committee member) / School of Mathematical and Natural Sciences (Contributor) / Watts College of Public Service & Community Solut (Contributor) / Barrett, The Honors College (Contributor)
Created2019-05