Browsing by Subject "Withdrawal"
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Item Central amygdala CART modulates ethanol withdrawal-induced anxiety(2013-08) Salinas, Armando; Morrisett, Richard A.Cocaine- and amphetamine-regulated transcript (CART), as its name implies, was initially identified as an upregulated transcript in response to psychostimulant administration. Consequently, it has been posited to play a role in psychostimulant abuse and dependence. Spurred on by the finding that a polymorphism in the CART gene was associated with alcoholism, we initiated studies designed to elucidate the role of CART peptide in alcohol dependence. We first investigated the functional significance of CART peptide in alcohol dependence in vivo using a CART KO mouse. We found that CART KO mice had a significant decrease in ethanol consumption that could not be attributed to differences in total intake, taste perception, metabolism, or sensitivity to ethanol. In vitro we found that CART peptide facilitated NMDA receptor-mediated currents in central amygdala neurons. Given the emerging role of CART peptide in anxiety and stress, we decided to examine basal and stress-induced anxiety behaviors in CART KO mice. Under basal and acute stress conditions, CART KO mice did not differ in anxiety-like behaviors from WT mice; however, in response to a stressor, CART KO mice exhibited a potentiated corticosterone response. Using chronic intermittent ethanol exposure (CIE), we tested CART KO and WT mice for common signs of ethanol dependence including an escalation of volitional consumption and the presence of withdrawal-induced anxiety. We further investigated glutamatergic neuroadaptations within the central amygdala of CART KO and WT mice following CIE exposure and early withdrawal. CIE increased ethanol consumption and anxiety-like behaviors in mice of both genotypes but to a lower extent in CART KO mice. Electrophysiologically, CIE enhanced spontaneous excitatory postsynaptic currents in both genotypes and decreased the probability of presynaptic release in WT mice only. We believe that these electrophysiological neuroadaptations contribute to the development of ethanol dependence and may mediate withdrawal-induced anxiety behaviors. Overall, these studies indicate a role for CART peptide in alcohol dependence and specifically in modulating ethanol withdrawal-induced anxiety.Item Cigarette smoking: attentional mediation of anxiety as a predictor of nicotine withdrawal severity(Texas Tech University, 2007-08) Morrell, Holly E.; Cohen, Lee M.; Borrego, Joaquin P.; Harter, Stephanie; Richards, StevenAlthough a majority of cigarette smokers report that they smoke to relieve anxiety (Schneider & Houston, 1970), studies examining the anxiolytic properties of smoking have yielded equivocal results. Kassel and colleagues proposed that the anxiolytic effects of nicotine might be mediated by the presence or absence of distracting stimuli (Kassel & Shiffman, 1997; Kassel & Unrod, 2000). More specifically, Kassel and Shiffman (1997) postulated that smoking “constrains smokers’ attention to the most immediate and salient stimuli in their environment—when such stimuli are available” (p. 360). As a result, smokers are more likely to focus on immediate and distracting stimuli than more distal anxiogenic stimuli, thus reducing anxious mood. Further, smokers who rely more heavily on attentional mediation to relieve anxiety may experience more severe nicotine withdrawal, which may ultimately make it more difficult for them to quit smoking. The current study was designed to assess the degree to which attentional mediation influences the experience of self-reported nicotine withdrawal severity in a sample of 21 adult heavy smokers. Participants completed the attentional mediation paradigm, as developed by Kassel and Shiffman (1997), and then abstained from smoking for 24 hours. As expected, results indicated that anxiety and withdrawal symptoms increased during abstinence from smoking. However, the primary hypothesis was not supported: smokers who displayed greater reductions in anxiety in the presence of a distracting stimulus did not experience more severe nicotine withdrawal. These findings leave the relationship between anxiety and nicotine withdrawal open to speculation. Implications and directions for future research are discussed.Item Comparison of ethanol-related behaviors and FosB mapping in hybrid mice with distinct drinking patterns(2009-05) Ozburn, Angela Renee; Harris, R. Adron; Blednov, Yuri A.Distinct alcohol self-administration behaviors are observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (B6xNZB) show reduced alcohol preference (RAP) after experience with high concentrations of alcohol and abstinence periods and C57BL/6J x FVB/NJ (B6xFVB) show sustained alcohol preference (SAP), providing models of stable, high alcohol consumption and moderate drinking. The purpose of this dissertation is to characterize ethanol-related behaviors and define neurocircuits engaged by SAP and RAP. We performed a battery of behavioral tests to define behaviors that predict SAP and RAP. B6xFVB exhibited less severe ethanol-induced conditioned taste aversion and were less sensitive to ethanol-induced loss of righting reflex (LORR) than B6xNZB. Both hybrids demonstrated ethanol-induced place preference and low ethanol withdrawal severity. Hybrids differ in sensitivity to the aversive and sedative, but not rewarding, effects of ethanol. Results of elevated plus maze, mirror chamber, and locomotor tests reveal B6xFVB mice are less anxious and more active than B6xNZB mice. The validity of the SAP behavioral phenotype in B6xFVB mice was determined by testing whether chronic self-administration of ethanol produced tolerance or dependence. We measured responses from ethanol-naïve and ethanol-experienced mice in tests of ethanol-induced hypothermia, withdrawal severity, and LORR. Chronic ethanol self-administration resulted in tolerance to sedative and hypothermic effects of ethanol; however, physical dependence was not evident as measured by ethanol withdrawal severity. We tested the hypothesis that SAP and RAP behavioral differences are represented by differential production of the inducible transcription factor, FosB. FosB immunoreactivity was quantified in 16 brain structures after chronic ethanol consumption or only water. Neuronal activity (as measured by FosB levels) depended on ethanol experience, brain region, and genotype, further supporting the notion that neuronal circuitry underlies motivational aspects of ethanol consumption. For B6xNZB mice, ethanol consumption resulted in increased neuronal activity in the EW, VTA, and amygdala, known ethanol- reward-, and stress-related brain regions. In B6xFVB, ethanol consumption resulted in a larger network of correlated regional activity, whereas in B6xNZB ethanol consumption resulted in a smaller network. These studies characterized genetic models of stable, high consumption (SAP) and moderate drinking (RAP) in two hybrid mouse strains.Item Effect of lawsuits on stock price compared to product withdrawal: a focus on the consequences of Vioxx's adverse effects(Texas Tech University, 2006-08) Watson, Kimberly S.; Xu, Ke Tom; Steinmeier, Thomas L.Pharmaceutical companies are plagued with lawsuits in today’s society. Some companies will hastily remove a product from the market before the negative side effects of the drug can be fully established for fear of severe losses due to lawsuits. Lawsuits will occur whether the drug is left on the market or not, as seen with the multiple cases both decided and pending against Merck for their drug, Vioxx. Using stock analysis as a measurement, it is evident in the case of Vioxx that removing a product from market will have a more detrimental effect on the manufacturer than the lawsuits will. In the cases where a drug could ethically be left on the market with additional warnings for those that may experience negative side effects, it is better for the company to continue to market the product and endure the lawsuits than remove the product and face the lawsuits alone.