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- Creators: Neisewander, Janet L
- Creators: School of Historical, Philosophical and Religious Studies
Description
Smoking remains the leading cause of preventable death in the United States, and early initiation is associated with greater difficulty quitting. Among adolescent smokers, those with attention-deficit hyperactivity disorder (ADHD), characterized by difficulties associated with impulsivity, hyperactivity, and inattention, smoke at nearly twice the rate of their peers. Although cigarette smoking is highly addictive, nicotine is a relatively weak primary reinforcer, spurring research on other potential targets that may maintain smoking, including the potential benefits of nicotine on attention, inhibition, and reinforcer efficacy. The present study employs the most prevalent rodent model of ADHD, the spontaneously hypertensive rat (SHR) and its control comparison Wistar Kyoto (WKY) to examine the effects of acute and chronic subcutaneous nicotine injections on performance in three operant response inhibition paradigms. Functional activation in select regions of the prefrontal cortex and striatum was also explored. Acute (0.1, 0.3, 0.6 mg/kg) and chronic (0.3 mg/kg) nicotine increased impulsive responding regardless of strain, dose, or operant schedule. Dose-dependent decreases in latency to initiate the task were also observed. SHR receiving daily nicotine injections showed less activation in the nucleus accumbens shell compared to saline controls. Despite close similarities, one of the three operant tasks did not detect response inhibition deficits in SHR relative to WKY. A closer examination of these tasks may highlight critical components involved in the amelioration of response inhibition deficits.
ContributorsMazur, Gabriel Joseph (Author) / Sanabria, Federico (Thesis advisor) / Killeen, Peter R (Committee member) / Neisewander, Janet L (Committee member) / Wynne, Clive DL (Committee member) / Arizona State University (Publisher)
Created2014
Description
Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light. This study examined whether rats acquire nicotine self-administration in the absence of these facilitators. A new mathematical modeling procedure was used to define the criterion for acquisition and to determine dose-dependent differences in rate and asymptote levels of intake. Rats were trained across 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0, 0.015, 0.03, 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined by the best fit of a logistic function (i.e., S-shaped) versus a constant function (i.e., flat line) for reinforcers obtained across sessions using a corrected Akaike information criterion (AICc) as a model selection tool. The results showed an inverted-U shaped function for dose in relation to the percentage of animals that acquired nicotine self-administration, with 46% acquiring at 0.015 mg/kg, 73% at 0.03 mg/kg, and 58% at 0.06 mg/kg. All saline rats failed to acquire as expected. For rats that acquired nicotine self-administration, multiple model comparisons demonstrated that the asymptote (highest number of reinforcers/session) and half learning point (h; session during which half the assymptote had been achieved) were justified as free parameters of the reinforcers/session function, indicating that these parameters vary with nicotine dose. Asymptote exhibited an inverted U-shaped function across doses and half learning point exhibited a negative relationship to dose (i.e., the higher the dose the fewer sessions to reach h). These findings suggest that some rats acquire nicotine self-administration without using procedures that confound measures of acquisition rate. Furthermore, the modeling approach provides a new way of defining acquisition of drug self-administration that takes advantage of using all data generated from individual subjects and is less arbitrary than some criteria that are currently used.
ContributorsCole, Natalie (Author) / Neisewander, Janet L (Thesis advisor) / Sanabria, Federico (Thesis advisor) / Bimonte-Nelson, Heather A. (Committee member) / Olive, Michael F (Committee member) / Arizona State University (Publisher)
Created2011
Description
High fat diets (HFD) are known to cause hepatic non-alcoholic steatosis in rats in as few as four weeks. Accumulation of triglycerides in liver and skeletal muscle is associated with insulin resistance and obesity. However, studies of fat accumulation in cardiac muscle are not as prevalent. Therefore, the first hypothesis of this study was that HFD would lead to hepatic steatosis as well as lipid accumulation in pectoralis and cardiac muscles, tissues responsible for the majority of postprandial glucose disposal. Prior studies also indicated that HFD leads to increased inflammation and oxidative stress within the vasculature resulting in impaired endothelium-dependent vasodilation, however biomarkers of immune system reactivity were not assessed. Therefore, the second aim of this study was to explore additional pathways of immune system reactivity and stress (natural antibodies; heat shock protein 60 (HSP60)) in rats fed either a control (chow) or high fat (HFD) diet. HSP60 has also recently been recognized as an early marker of vascular dysfunction in humans. The hypothesis was that immune system reactivity and early vascular dysfunction would be heightened in rats fed a HFD compared to chow-fed controls. Young male Sprague-Dawley rats (140-160g) were maintained on a chow diet (5% fat, 57.33% carbohydrate, 3.4kcal/g) or HFD (60% fat, 20% carbohydrate, 5.24 kcal/g) for 6 weeks. HFD rats developed hepatic steatosis with significantly elevated liver triglyceride concentrations compared to chow-fed controls (20.73±2.09 vs.9.75±0.52 mg triglycerides/g tissue, respectively; p=0.001). While lipid accumulation appeared to be evident in the pectoralis muscle from HFD rats, triglyceride concentrations were not significantly different from controls. Likewise, there was no evidence of lipid infiltration in cardiac muscles of HFD rats. Lipid accumulation in the liver of overweight HFD rats may contribute to the observed insulin resistance in these animals. Contrary to the second hypothesis, there were no significant differences in plasma HSP60 expression between HFD and chow rats (p>0.05). Likewise, hemagglutination and hemolysis responses were similar between HFD and chow-fed rats (p>0.05). These findings suggest that immune system responses may not be affected by 6 weeks of high fat intake and that HSP60 is not an early marker of vascular dysfunction in this rodent model.
ContributorsLiss, Tyler Jessee (Author) / Sweazea, Karen (Thesis director) / Shaibi, Gabriel (Committee member) / Johnston, Carol (Committee member) / Barrett, The Honors College (Contributor) / School of Nutrition and Health Promotion (Contributor) / School of Historical, Philosophical and Religious Studies (Contributor)
Created2013-05
Description
Previous findings from our lab have demonstrated that nicotine and social reward have synergistic effects when experienced together versus when experienced separately. The purpose of this experiment is to understand the neural mechanisms underlying this synergistic effect by quantifying Fos protein, a marker for neural activation, in various brain regions. We utilized the conditioning place preference (CPP) model to assess reward. Four groups of adolescent male rats (n=120) were given either nicotine (Nic) (0.1 mg/kg/mL) or saline (Sal) and were placed in the CPP apparatus either with a social partner (Soc) or alone (Iso). Thus, groups were: 1.)Sal+Iso, 2).Sal+Soc, 3).Nic+Iso, 4).Nic+Soc. Brains of some the rats (n=40) were collected for Fos staining 90 minutes after the last conditioning session to obtain Fos data in response to direct exposure to the stimuli. The following regions were analyzed for Fos expression: central amygdala (CeA), medial amygdala (MeA), basolateral amygdala (BLA), nucleus accumbens core (NAcCore), and nucleus accumbens shell (NAcShell). Place preference changes occurred in socially-conditioned groups reflecting social reward and in nicotine-conditioned groups reflecting nicotine reward. As expected, the Sal+Iso control group failed to display a preference change. Fos data revealed a significant increase in Fos expression in the CeA, MeA, NAcCore and NAcShell for socially-conditioned animals and a significant decrease in the NAcCore for nicotine-conditioned groups. Experiencing both social and nicotine rewards together appeared to produce greater activation in the BLA. However, there was an increase in Fos expression in the negative control group relative to Nic+Iso group. The results of CPP suggest that social, nicotine and their combination are rewarding. The combination of the nicotine and social reward could have been more rewarding than social and nicotine separately, but the test was not sensitive to reward magnitude. The increase in Fos expression in the negative control group in the BLA could be due to isolation stress. Overall, these results suggest that these brain regions had greater activation to social reward.
ContributorsGoenaga, Julianna Gloria (Author) / Neisewander, Janet (Thesis director) / Orchinik, Miles (Committee member) / Olive, Michael (Committee member) / Barrett, The Honors College (Contributor) / School of Historical, Philosophical and Religious Studies (Contributor) / School of Life Sciences (Contributor)
Created2013-05