Browsing by Subject "Biological Factors"
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Item Asthma Mortality and Toxic Release in Texas - An Ecological Study 1980-2001(2004-05-01) Maddipatla, Sreeram; Bayona, ManuelMaddipatla, S., Asthma Mortality and Toxic Release in Texas - An Ecological Study 1980-2001. Master of Public Health (Environmental Health) April 2004, 97 pp., 4 tables, bibliography, 94 titles. There is a lack of literature examining how the spatiotemporal trend of asthma may have impacted different ethnic/racial compositions of Texans. The present study sought to evaluate the geographic-temporal variations in asthma mortality in Texans over a 22-year period, retrospectively, and examine whether the trend of environmental Toxic Release Inventory (TRI) concentrations and their spatiotemporal persistence might place an uneven burden on particular racial groups. The study concentrates on the time period between 1980-2001 and first evaluates geographic excess of asthma mortality in different racial groups at the county level and characterizes the excess burden by spatiotemporal variations. After this assessment, the impact of TRI on asthma mortality over this period of time is analyzed. Based on these two analyses, this would identify which racial/ethnic groups in which Texas regions might have been affected the most by regarding mortality over time, and suggested priority geographic areas for policy intervention. At the end of this study, it could be said that there might be an association between the TRI release and increased asthma mortality in the Black male population.Item Estrogen Signaling Protects Mitochondrial Membrane Potential Integrity from Oxidative Stress in Lens Epithelial Cells(2008-05-01) Flynn, James Martin; Cammarata, Patrick R.; Wordinger, Robert J.; Dimitrijevich, S. DanFlynn, James Martin, Estrogen Signaling Protects Mitochondrial Membrane Potential Integrity from Oxidative Stress in Lens Epithelial Cells. Doctor of Philosophy, (Cell Biology and Genetics) May, 2008, 265 pages, 36 figures, bibliography, 190 titles. Loss of mitochondrial membrane potential has been determined to be one of the initiating factors in activation of apoptosis after cellular damage. Estrogen and estrogen analogues have been shown to enhance cell survival in numerous tissues through rapid pro-survival cell signaling. This study was focused on elucidating mechanisms through which estrogen protects the cells by preventing the activation of mitochondrial permeability transition pores and the subsequent loss of mitochondrial membrane potential. It is hypothesized that the anti-apoptotic mitochondrial protein BAD, once phosphorylated by estrogen activated upstream kinases, can prevent the formation of the permeability transition pre via direct interaction. To address this, lens epithelial cells were used as a model system for the examination of mitochondrial depolarization during periods of either oxidative or hyperglycemic stress. Estrogen attenuated the loss of impermeability of the mitochondrial membrane, thus maintaining the cells during acute periods of stress. It was discovered that a number of the estrogen receptor isoforms are expressed in lens epithelium, and that the wild-type estrogen receptor-β1 isoform is localized to the mitochondria in lens epithelial cultures derived from both human males and females. siRNA treatment against estrogen receptor-β determined that is a required component to elicit estrogen’s protective abilities against oxidative stress induced mitochondrial depolarization. Furthermore, administration of exogenous estrogen rapidly activated signaling pathways, particularly ERK, which were shown to have influence over the loss of mitochondrial membrane potential. Studies using both pharmacological inhibitors of MAPK signaling, as well as siRNA of ERK2 kinase demonstrate a correlation between the activation of ERK and the severity of response to oxidative stress. Investigation of downstream substrates of ERK revealed that the mitochondrial protein BAD is phosphorylated after the administration of estrogen, yet it is not required for the prevention of mitochondrial depolarization as originally hypothesized. In conclusion, these studies have confirmed a mitochondrial targeted mechanism activated by estrogen which is rapid, gender independent, estrogen receptor-β mediated signal transduction pathway. The targeting of mitochondrial function to reduce oxidative or hyperglycemic stress, thereby preventing activation of the permeability transition pore, defines a novel concept which will contribute to innovative regimens for prevention or treatment of mitochondrial pathology.Item Exploratory Analysis on the Prevalence of Rapid Growth and Overweight in Normal Weight Infants(2004-06-01) Bell, Karen; Urrutia-Rojas, Ximena; Cipher, Daisha; Menchaca, JohnBell, Karen. Exploratory Analysis on the Prevalence of Rapid Growth and Overweight in Normal Birth Weight Infants. Master of Public Health. June 2004. 33 pp, 5 tables, bibliography, 24 titles. Rapid growth can be defined as a period of growth acceleration that occurs in infants who are born of normal birth weight. Research has shown that children who experience this phenomenon exhibit future health conditions such as cardiovascular disease and obesity. Furthermore, these conditions can manifest in childhood and persist to adulthood. The exploratory study reported here examined rapid growth and overweight in this group. This study also included a review of literature that examined health complications and predictors associated with rapid growth and overweight in this group. This study also included a review of literature that examined health complications and predictors associated with rapid growth. In addition, the author investigated the history of the Centers for Disease Control and Prevention (CDC) growth charts. The exploratory analysis studied data on ninety-one infants from a Cook Children’s Network pediatric office. The infants’ weight and height information were obtained every two months after birth for a six-month time period. This information was used to plot each infant’s growth on 2000 CDC growth charts which would indicate if a child was either growing rapidly, or overweight. Nineteen infants exhibited rapid growth within the first six to nine months of life. Eight were found to be either obese, overweight or at risk of being overweight. The health complications associated with rapid growth in these infants needs to be assessed. Therefore, it is important that more research is performed that examines this phenomenon.Item Interleukin-6 and its Relationship to Coronary Artery Calcium Burden-North Texas Healthy Heart Study(2008-05-01) AbdulRahim, Nashila; Roberto Cardarelli; Sejong Bae; Richard VirgilioAbdulRahim, Nashila, Interleukin-6 and its Relationship to Coronary Artery Calcium Burden- North Texas Healthy Heart Study. Master of Science (Primary Care Clinical Research), May, 2008, pp., 7 tables, 5 figures, bibliography, 73 titles. Atherosclerosis is highly associated with increased serum inflammatory markers. Coronary artery calcium (CAC) burden has allowed researchers to have a non-invasive proxy measure of atherosclerosis. We hypothesized that interleukin-6 (IL-6), after controlling for CV risk factors, would be associated with CAC scores, and this association will be modified by race/ethnicity. 344 subjects were recruited. IL-6 concentrations were measured, and computed tomography was used to calculate CAC scores. After accounting for age, gender, race, smoking, hypertension, diabetes, and cholesterol, a one-unit increase in IL-6 concentration is associated with 1.03 greater odds of an abnormal calcium score (OR: 1.03, 95% CI: 0.98, 1.07). Race/ethnicity did not modify this association. IL-6 did not prove to be a simple clinical marker of CAC.Item Leucine-Enkephalin and Sympathetic Control of Heart Rate(2001-12-01) Stanfill, Amber; Caffrey, James L.; Downey, H. Fred; Shi, XiangrongStanfill, Amber A., Leucine-enkephalin and Sympathetic Control of Heart Rate. Master of Science (Biomedical Sciences), December, 2001, 51 pp., 1 table, 4 figures, references, 48 titles. The following study examined the role of leucine-enkephalin in the sympathetic regulation of the cardiac pacemaker. Leucine-enkephalin (0.3 mM) was administered, by microdialysis into the interstitium of the sinoatrial node in 10 mongrel dogs in conjunction with either sympathetic nerve stimulation or infused norepinephrine. In study one, the right cardiac sympathetic nerves were isolated as they exit the stellate ganglion and stimulated to produce graded (low, 20-30; high 40-50 bpm) increases in heart rate. Once stimulation frequencies were determined, leucine-enkephalin (0.3mM) was added to the dialysis inflow and perfused at 5: 1/min thereafter. The sympathetic stimulations were repeated after 5 and 20 min exposure to leucine-enkephalin. The resulting increases in heart rate during sympathetic stimulation were attenuated at both low (18.2 ±1.3 to 11.4 ±1.4 bpm) and high (45 ±1.5 to 22.8 ±1.5 bpm) frequency stimulation. The degree of inhibition was nearly identical after 20 minutes exposure providing no evidence for a progressively evolving response and for desensitization. Vagal function was also evaluated at 5 and 20 min by stimulating the right cervical vagus at 1 and 3 Hz. Leucine-enkephalin reduced the vagal bradycardia approximately 50% at both time intervals. The administration of the delta-selective opioid antagonist, naltrindole, restored only one third of the sympathetically medicated tachycardia. The same dose of naltrindole completely reversed the coincident vagolytic of leucine-enkephalin. These observations suggested that the sympatholytic effect was either non-opioid or mediated by a different opioid receptor subtype. Study two was conducted to determine if the sympatholytic effect was prejunctional and post-junctional in character. Norepinephrine was added to the dialysis inflow into the SA node in a concentration (6-9 μM) sufficient to produce an intermediate increase in heart rate. The average increase in heart rate was 35.2 ±1.8 bpm. Leucine-enkephalin was then combined with norepinephrine and sympathetic and parasympathetic responses were recorded at 5-min intervals for 20 minutes. The tachycardia mediated by added norepinephrine was unaltered by leucine-enkephalin or the subsequent addition of naltrindole. At the same time intervals, vagal control of heart rate was reduced by more than 50% and then completely restored by naltrindole. When combined with observations in study one, the data support the conclusion that the local nodal sympatholytic effect of leucine-enkephalin was the result of a reduction in the effective interstitial concentration of norepinephrine and not the result of a post-junctional interaction between leucine-enkephalin and norepinephrine.Item Neural Control of the Carotid Baroreflex During Exercise(2000-05-01) Gallagher, Kevin Matthew; Peter B. Raven; Stephen R. Grant; H. Fred DowneyGallagher, Kevin Matthew, Neural Control of the Carotid Baroreflex During Exercise. Doctor of Osteopathic Medicine/Doctor of Philosophy (Biomedical Sciences), May 2000; 151 pages; 13 tables; 19 figures; bibliography; 161 titles. Carotid baroreflex (CBR) function is reset upward and rightward to the prevailing blood pressure during dynamic and static exercise. Feedforward central neural inputs (central command) and negative feedback from skeletal muscle (exercise pressor reflex) both contribute to the resetting. The purpose of this investigation was to identify the individual roles of central command and the exercise pressor reflex in the resetting of the CBR during dynamic and static exercise. First, it was necessary to determine which receptor group that comprises the exercise pressor reflex, chemically-sensitive (chemoreceptors) or mechanically-sensitive (mechanoreceptors) receptors, was primarily involved in the regulation of the cardiovascular system. We observed the cardiovascular responses during exercise to individual action of the chemoreceptors and the mechanoreceptors. We demonstrated an increased mean arterial pressure (MAP) response to mechanoreceptor activation that was not identified during chemoreceptor stimulation. This finding suggested that the mechanoreflex was the primary exercise pressor mediated of arterial blood pressure during exercise. To identify the role of central command on CBR resetting, a second investigation increased central command by partial neuromuscular blockade during dynamic and static exercise. Resetting of CBR control of heart rate (carotid-cardiac; CSP-HR) and MAP (carodtid-vasomotor; CSP-MAP) during control exercise was further reset upward and rightward by increased central command without alterations in sensitivity. In conclusion, central command, a feedforward mechanism, was actively involved in the resetting of the CBR during exercise. To investigate the role of the exercise pressor reflex on CBR function, a third investigation activated by the exercise pressor reflex with the application of medical anti-shock trousers (MAS) during dynamic and static exercise. From control exercise, carotid-vasomotor function was further reset upward and rightward by the application of MAS trousers while CSP-HR function was only reset rightward. Sensitivity of the CSP-MAP and CSP-HR function curves were unaltered. The negative feedback mechanism of exercise pressor reflex, primarily mediated by mechanoreceptors, appeared to act as a modulator of CBR resetting during exercise.Item Obesity Genetics: The Prevalence of DRD2, DAT1 and DBH Genes in the Obese Individual(1998-08-01) Davis, Karla R.; Eisenberg, Arthur; Agarwal, Neeraj; Sherman, MarkDavis, Karla R., Obesity Genetics: The prevalence of DRD2, DAT1 and DBH Genes in the obese individual. Master of Science (Biomedical Sciences), August, 1998, 106 pp., 3 tables, 14 illustrations, reference, 44 titles. Obesity has been presented in research literature as a polygenic or multiple gene disorder. Currently, 3 genes have been associated with obesity, dopamine receptor D2 (DRD2), dopamine transporter (DAT1), and dopamine beta hydroxylase (DBH). The primary objective of this study is to analyze the DRD2, DAT1 and DBH genes to determine if a correlation exists between certain allelic variations of these 3 genes and the body mass index of obese individuals. We have developed an assay for the DRD2, DAT1 and DBH genes, utilizing polymerase chain reaction (PCR) technology. Within the DRD2 gene, 2 allelic variants have been identified, the A1 and A2 alleles. The A1 allele consists of a 310 bp fragment in which the Taq 1 restriction site has been deleted. The A2 allele consists of 180 bp fragment and a 130 bp fragment. The presence of the A1 allele after enzyme digestion has shown a strong correlation to obesity in prior studies. With respect to the DAT1 gene, a VNTR of 40 bp’s has been correlated to other disorders within the ‘reward deficiency syndrome’. The fragment length identified most often is 440 or 480 bp, with 480 as the primary fragment in obesity. The DBH gene is similar to the DRD2 in that it also contains a Taq I restriction. Two allelic variants are also identified, B1 and B2. The B1 allele contains no Taq I site and produces a 316 bp fragment while the B2 does cleave, exhibiting an 86 bp and a 230 bp fragment after enzyme digestion. The presence of one or more of the aberrant alleles could be associated with and a predisposing factor to obesity.Item Opioid and Nitric Oxide Interaction in the Control of Heart Rate(2002-12-01) Farias III, Martin; James Caffrey; Fred H. Downey; Patricia GwirtzFarias III, Martin, Opioid and Nitric Oxide Interaction in the Control of Heart Rate. Doctor of Philosophy (Biomedical Sciences), December 2002, 130 pp, 2 tables, 30 figures. Understanding of the role endogenous opioids play as modulators of parasympathetic function has increased. The endogenous opioid, methionine-enkephalin arginine phenylalanine (MEAP) attenuates vagal control of heart rate when delivered by microdialysis directly in the canine sinoatrial node. This effect was mimicked by the δ-2 agonist, deltorphin-II indicating involvement by a δ-opioid receptor. The nodal delivery of the δ-antagonist naltrindole abolished the effect of deltorphin-II, further supporting the delta character of the receptor. Although the findings suggested that the opioid receptor mediating vagolysis was delta in character, the exact subtype of δ-receptor remained in question. Selective agonist and antagonists for δ-1 and δ-2 opioid receptors were employed to determine which subtype of δ-receptor mediated MEAP vagolysis. In these experiments, vagolysis produced by the nodal delivery of MEAP was unaltered by the highly selective δ-1 antagonist BNTX but abolished by the δ-2 antagonist, naltriben. Nodal delivery of deltorphin-II attenuated vagal bradycardia similar to MEAP while δ-1 agonists, DPDPE and TAN-67 failed to interrupt vagal bradycardia. TAN-67 actually improved vagal transmission and this effect was reversed by BNTX. These data indicate that δ-2 opioid receptors in the sinoatrial node and vagolytic and support the presence of vagotonic δ-1-opioid receptors in the same location. Nitric Oxide/Opioid Interaction. The hypothesis that intranodal nitric oxide synthase (NOS) modulates vagal transmission and that MEAP attenuates vagal bradycardia via the interruption of the NOS-cGMP pathway was tested. The general (L-NAME) and neuronal (7-nitroindazole) NOS inhibitors each attenuated vagal bradycardia and both effects were reversed by adding excess of the NOS substrate, L-arginine. These findings suggested that nNOS was a necessary component of vagal bradycardia in the canine sinoatrial node. Various probes of the NOS-cGMP pathway (L-arginine, SNAP, cGMP, and IBMX) were employed to determine if MEAP interrupted this pathway to produce vagolysis. The delivery of MEAP into the sinoatrial node for sixty minutes exerted a consistent vagolytic effect during vagal simulations. When MEAP was combined with a NOS pathway components, the vagolytic effect was reversed after 15-45 minutes of treatment. These findings suggested that MEAP exerted its effect by interacting with the NOW-cGMP system. The site of convergence maybe cAMP since the phosphodiesterase inhibitor, IBMX (by allowing the accumulation of cAMP) reversed the vagolytic effect of MEAP. To rule out a postjunctional effect, MEAP and the NOS inhibitors were combined with the direct acting muscarinic agonist, methacholine. The bradycardia produced by methacholine was unaltered by MEAP or nNOS inhibitors. This suggested that the effect of NOS inhibitors and MEAP were prejunctional. In summary, the cumulative findings suggest that MEAP, by activating δ-2-opioid receptors, attenuated vagal bradycardia prejunctionally, through modulating the cAMP component of the NOS-cGMP pathway in the canine sinoatrial node.Item Regulation of TNF-Mediated Cell Death in Breast Cancer Cells(2006-05-01) Lu, Dongmei; Basu, Alakananda; Simpkins, James W.; Wu, Ming-ChiDongmei Lu, Regulation of TNF-mediated cell death in breast cancer cells. Doctor of Philosophy (Biochemistry & Molecular Biology), May 2006, 173 pp., 32 illustrations, 329 references. Protein kinase C-ε (PKCε), a novel PKC, has been shown to attenuate tumor necrosis factor-α (TNF)-induced apoptosis in breast cancer cells. The purpose of this dissertation is to delineate the mechanism(s) by which PKCε exerts its antiapoptotic effect. Comparison of PKCε level in several breast cancer cells revealed that PKCε level alone could not explain sensitivity of breast cancer cells to TNF. Protein kinase B/Akt (Akt) was constitutively active in breast cancer cells resistant to TNF. Inhibition of phosphatidyl-inositol 3-kinase (P13-K0 by Ly294003 increased TNF-mediated apoptosis in MCF-7 cells that overexpress Akt and sensitized BT-20 and SKBR-3 cells that express constitutively active (CA) Akt to TNF. PKC inhibitor bisindolylmaleimide (BIM) also sensitized BT-20 and MCF-7 cells to TNF. Overexpression of CA-Akt in MCF-7 cells attenuated TNF-induced apoptosis. Therefore, both PKCε and Akt are important for deciding TNF sensitivity. The cross-talk between PKCε and Akt was examined in MCF-7 cells. PKCε overexpression increased basal Akt phosphorylation and enhanced TNF-induced Akt activation. Knockdown of PKCε by siRNA decreased TNF-induced Akt activation. Depletion of Akt abolished the antiapoptotic effect of PKCε. Akt was constitutively associated with PKCε and DNA-dependent protein kinase (DNA-PK), and this association was increased by TNF. Knockdown of DNA-PK diminished the effect of PKCε on Akt phosphorylation and increased TNF-mediated apoptosis. These results suggest that PKCε activates Akt via DNA-PK to mediate its antiapoptotic function. We also investigated whether PKCε regulates mitochondrial cell death pathway by inhibiting the proapoptotic function of Bcl-2 family member Bax. Overexpression of wild-type but not dominant-negative PKCε inhibited TNF-mediated mitochondrial depolarization. Depletion of Bax inhibited TNF-induced apoptosis. PKCε overexpression abolished Bax dimerization and translocation to mitochondria, while PKCε depletion had the opposite effect. Bax was associated with PKCε in PKCε-overexpressing cells. These results indicate that PKCε attenuates mitochondrial cell death pathway by inhibiting Bax translocation. These findings demonstrate the PKCε activates Akt via DNA-PK and inhibits proapoptotic Bax to mediate its antiapoptotic effect in breast cancer cells. An understanding of the mechanism(s) by which PKCε inhibits apoptosis in breast cancer cells is important for developing more effective cancer therapies.Item Sensitization to Cocaine: Behavioral and Genetic Characterization(1998-04-01) Odom, Linda Ann; Michael Forster; Glenn Dillon; Harbans LalOdom, Linda Ann, Sensitization to Cocaine: Behavioral and Genetic Characterization. Doctor of Philosophy (Pharmacology). April 1998, 141 pages, 2 tables, 23 figures, 89 references. Conditioned associations between environmental context and cocaine effects may play a significant role in acquisition and maintenance of cocaine dependence. Conditioning may also contribute significantly to cocaine sensitization, a leftward shift in the cocaine dose-response curve that is attributable to cocaine pre-exposure. Both studies examined the sensitization of cocaine’s behavioral effects after one or four prior exposures to cocaine in two distinct environments, allowing evaluation of the acquisition and magnitude of sensitization to cocaine and the contribution of conditioning to sensitization. An extinction component was added to the second study to allow determination of persistence of context-dependent sensitization in C57BL/6 and DBA/2 mice. The purpose of the first study was to fully characterize the quantity and quality of the sensitized behavioral response to cocaine in Swiss Webster mice and to determine parameters for sensitization in the second study. Results of this study indicated that pairing cocaine to the testing environment resulted in a leftward shift of the dose-response curves for both horizontal and stereotypy measures and a concurrent decrease in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on horizontal distance and an increase in maximal effect of cocaine on stereotypy. The multivariate behavior profile indicated that the sensitized response to cocaine was best observed in response to 1 to 5 mg/kg cocaine, and that the conditioned response elicited by saline following cocaine pre-exposure closely resembled the 10 mg/kg acute cocaine response. The overall purpose of the second study was to determine if genetic differences in various aspects of such conditioned associations could contribute to individual differences in cocaine dependence. It was determined that, although DBA/2 mice had a faster rate of acquisition of context-dependent sensitization to cocaine than C57/BL6 mice, the multivariate behavior profile of the conditioned response of C57BL/6 mice resembled the behavior observed with a higher dose of acute cocaine and had greater magnitude and greater persistence than that of DBA/2 mice, which may explain in part the susceptibility of the C57BL/6 mice to cocaine dependence.Item Synergy 2007: Annual Research Report(2007-01-01)Item The Effect of Fitness on Cardiac Work with and without Metoprolol(2008-07-01) Hawkins, Megan Nicole; Peter Raven; Michael Smith; Robert MalletHawkins, Megan Nicole, The Effect of Fitness on Cardiac Work with and without Metoprolol. Doctor of Philosophy (Biomedical Science), July 2008; 128 pp; 3 tables; 17 figures; bibliography. Chronic endurance exercise adaptations of the cardiovascular and skeletal muscle systems. The mechanisms by which these adaptations occur, and their effect on the physiological response to exercise, have not been fully elucated. In addition, the classic concept of the role of maximal oxygen consumption (Vo2max) as a parametric index of cardiorespiratory capacity has been questioned. Therefore the purpose of the investigations presented within this dissertation was to: i)retrospectively analyze 156 incremental exercise stress tests and supramaximal exercise tests to verify that VO2 does indeed attain a maximal value; ii)evaluate the effects of cardioselective beta-adrenergic blockade on the ability to maintain cardiac work in average trained and endurance exercise trained subjects during moderate (45% VO2max) and heavy (70% Vo2max) intensity cycling exercise; and iii) determine the effect of aerobic fitness on resting and peak leg vascular conductance and the change in central blood volume observed during the onset of cycling exercise. In the first investigation we demonstrated that highly trained runners capable of maintaining supramaximal workloads achieved a VO2 that rarely exceeded the VO2max value obtained during an incremental exercise stress test. In the second investigation we demonstrated that acute β1-adrenergic receptor (βAR) inhibition reduced cardiac output, cardiac work and cardiac efficiency in endurance trained athletes during moderate and heavy intensity exercise. However, in average trained individuals these same variables were not affected during moderate exercise intensity, but were reduced at heavy intensity exercise. We concluded that βAR blockade impaired the more efficient Frank-Starling mechanism in endurance trained athletes but remained functional in average trained subjects during moderate exercise intensities. In the third investigation we demonstrated that endurance athletes responded to the onset of exercise with a larger increase in central blood volume than average trained individuals. In addition, resting and post-ischemic leg blood glow and leg vascular conductance were greater in the exercise training-induced adaptations of the skeletal muscle vasculature resulted in larger conductance capacity of the working muscle in response to increases in oxygen demand and enabled a greater increase in muscle blood flow from rest to exercise.Item The Effect of Late-Life Antioxidant Supplementaion on Brain Function(2007-10-01) Shetty, Ritu A.; Forster, Michael J.; Sumien, Nathalie; Singh, MeharvanShetty, Ritu A., The effect of late-life antioxidant supplementation on brain function. Doctor of Philolosophy (Biomedical Sciences), October, 2007, 229 pp., 5 tables, 18 figures, bibliography, 284 titles. Purpose: Aging is associated with mild to moderate loss in brain function over time. These functional losses are thought to involve reversible changes disrupting important cellular signaling processes. One of the theories that proposes to explain the reversible losses of function is the ‘oxidative stress’ hypothesis of aging. According to the oxidative stress hypothesis, there is an inherent cellular imbalance between production of oxidants and antioxidative defenses that increases with age and that leads to an increase in oxidative damage to macromolecules that are involved in crucial cell functions. Previous studies have established a link between these cellular changes associated with aging and the impairments in cognitive and psychomotor function. Further it has also been suggested that dietary interventions can modulate the level of oxidative stress, reducing oxidative damage and perhaps even ameliorate age-related dysfunction. Most interventions have been implemented relatively early in life and maintained until old age. However, the current studies were based on the rationale that interventions initiated in late-life could potentially lower oxidative damage and thereby alter cellular components responsible for functional impairments. Methods: In study I, separate groups of young (4 months) and old mice male C57BL/6 (18 months) were fed a control diet or a diet supplemented with low (105 mg/kg/day) or high (368 mg/kg/day) concentrations of CoQ10 for a period of 15 weeks. After 6 weeks on the diets, the mice were subjected to a battery of age-sensitive behavioral tests. In study II, separate groups of male C57BL/6 young mice aged 3-4 months and old mice 17-18 months (total of n=124) were fed ad libitum either a control diet (cyclodextrin in base diet), or the same diet supplemented with D- α-tocopheryl acetate (Toc) (200 mg/kg body wt/day), or with CoQ10 (148 mg/kg body wt/day) or a diet containing a combination of CoQ and Toc (200 mg/kg body wt/day + 148 mg/kg body wt/day) for a period of 13-14 weeks. In both studies mice were subjected to a battery of behavioral tests that required utilization of various component of memory and learning and sensorimotor reflexes. Results: In study I, low CoQ10 failed to improve cognitive and psychomotor function in old mice. However, the high CoQ10 marginally helped the old mice to navigate in the swim maze task with greater efficiency than control mice but did not affect their performance in probe trials. Conversely, the high CoQ10 diet selectively impaired the spatial performance in young mice in probe trials. The results from study I indicated that intake of CoQ10 initiated in late-life had minimal beneficial effects on behavior function. In study II, an age-associated decline of behavioral functioning was observed; however CoQ10 treatment failed to improve the performance of mice in any of the age-sensitive tests. Moreover, young mice supplemented with a high CoQ diet performed poorly in the probe trial in a swim maze task, suggesting a possible deleterious effect. The results from study II indicated that there was a significant improvement in performance of old mice in the coordinated running and the learning ability in discriminated avoidance task when supplemented with Toc or with a combination of CoQ10 and Toc. Conclusions: In conclusion, these studies suggest that benefits of single antioxidant supplementation when initiated late in life are limited; however dietary supplementation with a combination of antioxidants has a greater impact in reversing age-related decline in behavioral function.Item The Influence of CNS stimulants, opioid antagonists and an NMDA antagonist on the reinforcing effect of cocaine using a progressive-ratio schedule(1996-07-01) Li, Donghang; Forster, Michael J.; Martin, Michael; Luedtke, Robert R.It has been hypothesized that there is a common dopaminergic pathway mediating the reward properties of abused drugs, and that dopamine is involved in tolerance to the reinforcing effect of cocaine. The progressive-ratio (PR) schedule can be used to test both potentiation and reduction of the reinforcing effects of cocaine by other factors. Under the PR schedule, an increasing number of responses is required to obtain each subsequent cocaine injection, and failure to complete the required number of responses within 1 h of the previous cocaine injection terminates the session. The number of total reinforcers obtained during a session is defined as “the breaking point” and was used as the primary dependent measure. Fisher F344 male rats acquired the self-administration task under the PR schedule within forty sessions and showed a stable daily acquisition baseline. The breaking point and inter-reinforcer time (ISRT) were positively correlated within each ratio. A motor-incapacitating side effect of a pretreatment can be determined by a change in the relationship between the ISRT and the breaking point. d-Amphetamine pretreatment (0.32-3.2 mg/kg, i.p., 30 min) potentiates the reinforcing effect of cocaine as demonstrated by a higher breaking point of self-administration without changing the ISRT. Morphine pretreatment (0.32-3.2 mg/kg, i.p., 30 min failed to change the breaking point of cocaine self-administration but it did increase the ISRT. These results support an additive reinforcing effect for amphetamines and cocaine, but do not support an additive reinforcing effect of morphine and cocaine. The reinforcing effect of cocaine was reduced by pretreatment with ketamine (0.032-0.32 mg/kg, i.p., 20 min) as indicated by a reduction in the breaking point. In a concurrent experiment, animals were trained to self-administer cocaine under a fixed ratio 2 schedule (FR2). Ketamine pretreatment did not modify the ISRT in FR2 trained animals except at the highest dose (0.32 mg/kg, i.p., 20 min), where significant motor incoordination was observed. Both chronic treatment with cocaine (20 mg/kg/ 8hr x 7 days, iv) or amphetamine (3.2 mg/kg /12 hr x 7 days, i.p.) resulted in a reduction in breaking point at any given dose, providing direct evidence of tolerance and cross-tolerance to the reinforcing effects of cocaine. Chronic treatment with ketamine (0.32 mg/kg/8hr x 7 days, i.v.) failed to modify either the breaking point under a PR schedule of reinforcement or the ISRT under a FR2 schedule of reinforcement. Co-administration of ketamine (0.32 mg/kg/8hr x 7 days, i.v.) with chronic cocaine (20 mg/kg/8hr x 7days, i.v.) failed to prevent tolerance to the reinforcing effect of cocaine as indicated by either the breaking point under a PR schedule of reinforcement of the ISRT under an FR2 schedule of reinforcement. These data indicate that the breaking point in the PR schedule is more sensitive to changes in the dopamine reward system, whereas changes in rate of response are not consistently related to the changes in the dopamine reward system. These data support the use of PR schedule as a better method than FR schedule for determining reward properties of drugs of abuse with fewer complications due to the central nervous system inhibitory effects of some drugs of abuse.Item The Role of Dopamine, Nicotine Acetylcholine, Opioid and Sigma Receptors in Ketamine Self-Administration and Reward(2000-05-01) Stoffel, Stephen A.; Michael Forster; Glenn Dillon; Robert LuedtkeStoffel, Stephen A., The Role of Dopamine, Nicotinic Acetylcholine, Opioid and Sigma Receptors in Ketamine Self-Administration and Reward. Doctor of Philosophy in Pharmacology, May 2000, 114 pp 15 figures, bibliography. The rewarding effects of ketamine were postulated to involve dopaminergic neural tracts modulated by nicotinic, sigma, or opioid receptor mechanisms. In support of the hypothesized involvement of dopamine, an increase in extracellular dopamine was detected in the nucleus accumbens using electrochemical chronoamperometry following intravenous ketamine self-administration. When rats were permitted unlimited access to ketamine via self-administration, a greater concentration of dopamine was detected in the nucleus accumbens than was detected in the nucleus accumbens than was detected when self-administration was limited. In a subsequent set of experiments, the effects of agonists or antagonists of dopaminergic, nicotinic, sigma, or opioid receptors were examined for their effect on ketamine self-administration. Decreases in the rate of self-administration following treatment were interpreted to represent an increase in rewarding effect, whereas increases in self-administered were interpreted as a decrease in rewarding effect. The rate of self-administered intraperitoneally prior to ketamine self-administration sessions, but intravenous BMS181-100 would not substitute for ketamine in the self-administration occurred following intraperitoneal (i.p.) administration of: ketamine, SCH23390 (a D1 receptor antagonist), naloxonazine (a mu opioid receptor antagonist), and mecamylamine, a central nicotinic acetylcholine receptor antagonist. An increase in the rate of ketamine self-administration followed nicotine and dihydrexidine (a D1 receptor agonist) intraperitoneal injection. In previous studies, published in the literature, SCH23390 increased the rate of self-administration of amphetamines and cocaine, indicating a competitive effect on drug reward. However, the current studies indicate that the rewarding effects of ketamine were facilitated by SCH23390. The results are consistent with the hypothesis that the rewarding effects of ketamine are mediated through dopaminergic neural pathways. The rewarding effects of ketamine were facilitated by SCH23390. The results are consistent with the hypothesis that the rewarding effects of ketamine are mediated through dopaminergic neural pathways. The rewarding effects of ketamine may be modulated, in an inhibitory fashion, via sigma receptors, presynaptic D1 receptors, nicotinic acetylcholine receptors, and/or μ opioid receptors. Ligands at nicotinic acetylcholine and dopamine receptors yielded effects opposite to that hypothesized based on their ability to modulate the rewarding effects of other abused chemicals.