Matching Items (3)
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
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
Latino youth have substantially higher rates of obesity and T2D than their white peers. The higher prevalence of obesity and T2D among Latino youth places them at greater risk for cognitive dysfunction, an urgent and serious health threat to the United States. Exercise has been the cornerstone to combat the negative effects of obesity, diabetes and recent research also supports this effects for preventing cognitive dysfunction. A wealth of evidence suggests that a mediating mechanism linking exercise with brain health is BDNF, a cognitive biomarker that increases in the brain with exercise. BDNF is the most abundant neurotrophic factor that supports growth, survival and synaptic plasticity of neurons, all vital for cognitive function and brain health. The present study sought to investigate the effects of a 12-week lifestyle intervention of physical activity and lifestyle education on serum BDNF, in obese pre diabetic Latino youth.
A total of twelve obese pre diabetic Latino youth were selected from a larger RCT sample to be the focus for this analysis. After an overnight fast, a serum concentration was collected from all youth to be used for the BDNF analysis. In addition, the following cardio metabolic measures were also at taken at baseline and post intervention: Submaximal VO2max, medical and family history questionnaire, anthropometric, fasting glucose and a 2-hour oral glucose tolerance test (OGTT). A 12-weeks Lifestyle Intervention that involved a progressive moderate to high intensity exercise component and lifestyle education program did not significantly change serum BDNF levels in obese pre diabetic Latino youth. In conclusion, the variation of our serum BDNF results are highly speculative at this time, therefore the need for future investigations is crucial.
A total of twelve obese pre diabetic Latino youth were selected from a larger RCT sample to be the focus for this analysis. After an overnight fast, a serum concentration was collected from all youth to be used for the BDNF analysis. In addition, the following cardio metabolic measures were also at taken at baseline and post intervention: Submaximal VO2max, medical and family history questionnaire, anthropometric, fasting glucose and a 2-hour oral glucose tolerance test (OGTT). A 12-weeks Lifestyle Intervention that involved a progressive moderate to high intensity exercise component and lifestyle education program did not significantly change serum BDNF levels in obese pre diabetic Latino youth. In conclusion, the variation of our serum BDNF results are highly speculative at this time, therefore the need for future investigations is crucial.
ContributorsBarraza, Estela (Author) / Shaibi, Gabriel Q. (Thesis advisor) / Swan, Pamela (Committee member) / Nanez, Jose E (Committee member) / Arizona State University (Publisher)
Created2016