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The maternal consumption of alcohol during pregnancy produces a wide range of abnormalities in the offspring. The major objectives of this thesis were to investigate (1) the correspondence between prenatal ethanol-induced alterations in behavior and in hypothalamicpituitary- adrenal (HPA) activity, (2) the ability of early postnatal handling as an environmental manipulation to attenuate at least some of the adverse behavioral and physiological consequences of prenatal ethanol exposure, and (3) possible mechanisms mediating the HP A hyperresponsiveness to stressors observed in animals prenatally exposed to ethanol and the possible influence of postnatal handling on those mechanisms. Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum fed control (C) treatment groups were tested as young adults (-35-120 d of age) or mid-aged adults (13-14 months of age). The first study investigated the effects of prenatal ethanol exposure (E) and postnatal handling (H) on behavior and HPA activity during a conditioned taste aversion (CTA) task. We tested the hypothesis that E animals which underwent postnatal handling would show improved conditioned aversion learning and reduced HPA activity compared to E animals that did not experience handling (nonhandled, NH). We found that prenatal ethanol exposure and postnatal handling independently resulted in an increased rate of consumption of a saccharin solution over five preexposure days. In addition, we found that handling differentially affected posttoxicosis consumption of the conditioned solution as well as corticosterone (CORT) levels in E, PF and C animals. H-E animals showed increased posttoxicosis intake compared to H-PF and H-C animals during reexposure under non-deprived conditions; CORT levels were lower in PF and C than E males compared to their N H counterparts during reexposure under food- and waterdeprived conditions. Thus, E animals were less able to utilize environmental cues in the present study, displaying a more rapid reduction in neophobia compared to PF and C animals and, following postnatal handling, showing a decreased acquisition of conditioned aversion and an increased CORT response during reexposure to the conditioned solution. The second study examined spatial learning and memory in young adult (2 months) and mid-aged (13-14 months of age) H and N H E and control animals utilizing a Morris water maze. We investigated the hypothesis that postnatal handling would improve spatial navigation in E animals compared to E animals that did not experience handling and/or attenuate differences among E and control animals, and that this effect might be age-dependent. We also examined whether performance deficits in mid-aged animals would correspond to increases in CORT levels on the last day of testing. Young E males showed impairments in spatial navigation compared to young PF and C animals, taking longer to find the hidden platform over the course of testing and displaying an alteration in search pattern when the platform was removed. Interestingly, differences in young E, PF and C animals in escape latency and in distance traveled prior to finding the platform were apparent in H but not in N H animals. There were no differences in performance on the Morris water maze in mid-aged E, PF and C animals, but CORT levels were elevated in mid-aged E compared to C animals, supporting previous data indicating that E animals demonstrate HPA hyperresponsiveness to stressors. Lastly, although mid-aged animals had longer escape latencies and an altered search pattern compared to young animals, handling did not appear to attenuate impairments associated with aging. The third study investigated the hypothesis that postnatal handling might attenuate stress-induced ACTH and/or CORT differences among E, PF and C animals. Furthermore, the ability pf postnatal handling to modulate HPA feedback deficits in E animals was examined during exposure to a restraint stressor following dexamethasone (DEX) administration. Both E females and males showed increased ACTH and CORT compared to PF and/or C animals following saline administration. Administration of DEX to block HPA activity significantly suppressed both plasma ACTH and CORT in all animals. However, E females exhibited increased and/or prolonged elevations in ACTH and CORT compared to PF and C animals following DEX blockade. These data suggest that the insult of prenatal ethanol exposure affects both male and female offspring, but that there may be a sex-specific difference in sensitivity of the mechanism(s) underlying HPA hyperresponsiveness. Postnatal handling reduced ACTH levels in both females and males following saline administration. Following DEX administration, H males had lower CORT than NH males. Postnatal handling resulted in a more rapid decrease in stress-associated CORT elevations in C females, and attenuated differences in CORT between PF and C females. However, postnatal handling did not attenuate deficits in negative feedback inhibition in E females; E females in both the H and N H treatments showed elevated CORT compared to their C counterparts, and H-E females also showed elevated CORT compared to H-PF females. Thus, postnatal handling did not attenuate the typical HPA hyperresponsiveness to stressors observed in E animals (saline condition), nor did it eliminate deficits in HPA feedback inhibition in E females (DEX condition). The fourth study examined whether the mechanisms resulting in HPA hyperresponsiveness in E animals are similar to those underlying the effects of postnatal handling. Differences in HPA responsiveness between H and NH animals appear to be dependent upon basal CORT activity and not stress-induced elevations in CORT. Therefore, we tested the hypothesis that differences in HPA activity among E and control animals would not occur following adrenalectomy (ADX) but could be reestablished following replacement with basal levels of exogenous CORT. In the absence of a CORT feedback signal or in the presence of a constant, basal CORT feedback signal, E, PF and C animals did not significantly differ in their abilities to regulate ACTH secretion, indicating that during the trough of the circadian rhythm, E, PF and C animals are equally capable of regulating HPA activity utilizing either CORT-independent feedback or feedback mediated through basal CORT activity. Thus, the effects of prenatal ethanol exposure on HPA function do not appear to be dependent upon the feedback signal provided by basal CORT levels. In conclusion, handling did not attenuate the effects of prenatal ethanol exposure examined in the present experiments. This may be because the effects of postnatal handling and prenatal ethanol exposure on HPA function are mediated through different mechanisms as well as the finding that handling is, at least partly, mediated through mother-pup interactions. Therefore, postnatal handling might exert differential effects on litters in which pup behavior has already been altered by prenatal treatments, underscoring the enduring effects of prenatal ethanol exposure.

In order to assess cognitive function in multiple sclerosis (MS) and the effect of cholinergic modulation, experiments were conducted using functional magnetic resonance imaging (fMRI) to assess the brain activation during cognitive tasks. A study comparing the processing of verbal working memory with an N-back task found that patients showed smaller increase in activation than healthy controls with greater task difficulty, suggesting a reduced functional reserve. Controls and patients showed differences of correlations between brain regions activated. Interactions between prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. The effect of Rivastigmine on the cognitive processing in MS patients was tested in a longitudinal study, involving serial fMRI scans. Changes in the brain activation patterns were demonstrated with drug administration, without any changes in behavioural measures. Rivastigmine may act to increase the functioning of the normal neural network reducing the need for previously recruited compensatory mechanisms in MS patients. A study on healthy subjects examined the effect of cholinergic inhibition on cognitive processing and brain activation. Changes in functional activation due to Hyoscine during verbal working memory were found analogous to that in MS patients without any changes in behavioural measures. Processes that potentially impair brain cognitive function may recruit similar compensatory functional adaptive mechanisms. Studies on rats and MS patients explored the effect of Rivastigmine on the relationship of the BOLD fMRI signal with the underlying neural activity. Rivastigmine may be influencing the cortical excitability after direct cortical stimulation but showed only a small effect on the BOLD signal under more physiological neural activity. The neural activity in response to visual stimulation is slightly increased with Rivastigmine in MS patients, a change not detected with functional imaging. These studies suggest that changes in BOLD signal do represent sufficiently large changes of underlying neural activity in the presence of Rivastigmine. The relationship of damage in MS to measures of connectivity was studied using diffusion tensor imaging (DTI). Correlation was found between measures of connectivity and callosal size, a measure of fibre loss. The distribution of lesions was spatially correlated with changes in connectivity due to MS. Thus DTI could be utilized to explore the connectivity changes associated with MS, and the relationship with changes in functional activation.

The maternal consumption of alcohol during pregnancy produces a wide range of abnormalities in the offspring. The major objectives of this thesis were to investigate (1) the correspondence between prenatal ethanol-induced alterations in behavior and in hypothalamicpituitary- adrenal (HPA) activity, (2) the ability of early postnatal handling as an environmental manipulation to attenuate at least some of the adverse behavioral and physiological consequences of prenatal ethanol exposure, and (3) possible mechanisms mediating the HP A hyperresponsiveness to stressors observed in animals prenatally exposed to ethanol and the possible influence of postnatal handling on those mechanisms. Sprague-Dawley rats from prenatal ethanol (E), pair-fed (PF) and ad libitum fed control (C) treatment groups were tested as young adults (-35-120 d of age) or mid-aged adults (13-14 months of age). The first study investigated the effects of prenatal ethanol exposure (E) and postnatal handling (H) on behavior and HPA activity during a conditioned taste aversion (CTA) task. We tested the hypothesis that E animals which underwent postnatal handling would show improved conditioned aversion learning and reduced HPA activity compared to E animals that did not experience handling (nonhandled, NH). We found that prenatal ethanol exposure and postnatal handling independently resulted in an increased rate of consumption of a saccharin solution over five preexposure days. In addition, we found that handling differentially affected posttoxicosis consumption of the conditioned solution as well as corticosterone (CORT) levels in E, PF and C animals. H-E animals showed increased posttoxicosis intake compared to H-PF and H-C animals during reexposure under non-deprived conditions; CORT levels were lower in PF and C than E males compared to their N H counterparts during reexposure under food- and waterdeprived conditions. Thus, E animals were less able to utilize environmental cues in the present study, displaying a more rapid reduction in neophobia compared to PF and C animals and, following postnatal handling, showing a decreased acquisition of conditioned aversion and an increased CORT response during reexposure to the conditioned solution. The second study examined spatial learning and memory in young adult (2 months) and mid-aged (13-14 months of age) H and N H E and control animals utilizing a Morris water maze. We investigated the hypothesis that postnatal handling would improve spatial navigation in E animals compared to E animals that did not experience handling and/or attenuate differences among E and control animals, and that this effect might be age-dependent. We also examined whether performance deficits in mid-aged animals would correspond to increases in CORT levels on the last day of testing. Young E males showed impairments in spatial navigation compared to young PF and C animals, taking longer to find the hidden platform over the course of testing and displaying an alteration in search pattern when the platform was removed. Interestingly, differences in young E, PF and C animals in escape latency and in distance traveled prior to finding the platform were apparent in H but not in N H animals. There were no differences in performance on the Morris water maze in mid-aged E, PF and C animals, but CORT levels were elevated in mid-aged E compared to C animals, supporting previous data indicating that E animals demonstrate HPA hyperresponsiveness to stressors. Lastly, although mid-aged animals had longer escape latencies and an altered search pattern compared to young animals, handling did not appear to attenuate impairments associated with aging. The third study investigated the hypothesis that postnatal handling might attenuate stress-induced ACTH and/or CORT differences among E, PF and C animals. Furthermore, the ability pf postnatal handling to modulate HPA feedback deficits in E animals was examined during exposure to a restraint stressor following dexamethasone (DEX) administration. Both E females and males showed increased ACTH and CORT compared to PF and/or C animals following saline administration. Administration of DEX to block HPA activity significantly suppressed both plasma ACTH and CORT in all animals. However, E females exhibited increased and/or prolonged elevations in ACTH and CORT compared to PF and C animals following DEX blockade. These data suggest that the insult of prenatal ethanol exposure affects both male and female offspring, but that there may be a sex-specific difference in sensitivity of the mechanism(s) underlying HPA hyperresponsiveness. Postnatal handling reduced ACTH levels in both females and males following saline administration. Following DEX administration, H males had lower CORT than NH males. Postnatal handling resulted in a more rapid decrease in stress-associated CORT elevations in C females, and attenuated differences in CORT between PF and C females. However, postnatal handling did not attenuate deficits in negative feedback inhibition in E females; E females in both the H and N H treatments showed elevated CORT compared to their C counterparts, and H-E females also showed elevated CORT compared to H-PF females. Thus, postnatal handling did not attenuate the typical HPA hyperresponsiveness to stressors observed in E animals (saline condition), nor did it eliminate deficits in HPA feedback inhibition in E females (DEX condition). The fourth study examined whether the mechanisms resulting in HPA hyperresponsiveness in E animals are similar to those underlying the effects of postnatal handling. Differences in HPA responsiveness between H and NH animals appear to be dependent upon basal CORT activity and not stress-induced elevations in CORT. Therefore, we tested the hypothesis that differences in HPA activity among E and control animals would not occur following adrenalectomy (ADX) but could be reestablished following replacement with basal levels of exogenous CORT. In the absence of a CORT feedback signal or in the presence of a constant, basal CORT feedback signal, E, PF and C animals did not significantly differ in their abilities to regulate ACTH secretion, indicating that during the trough of the circadian rhythm, E, PF and C animals are equally capable of regulating HPA activity utilizing either CORT-independent feedback or feedback mediated through basal CORT activity. Thus, the effects of prenatal ethanol exposure on HPA function do not appear to be dependent upon the feedback signal provided by basal CORT levels. In conclusion, handling did not attenuate the effects of prenatal ethanol exposure examined in the present experiments. This may be because the effects of postnatal handling and prenatal ethanol exposure on HPA function are mediated through different mechanisms as well as the finding that handling is, at least partly, mediated through mother-pup interactions. Therefore, postnatal handling might exert differential effects on litters in which pup behavior has already been altered by prenatal treatments, underscoring the enduring effects of prenatal ethanol exposure. / Arts, Faculty of / Psychology, Department of / Graduate

3,4-methlenedioxymethamphetamine (MDMA), the main constituent of Ecstasy, is a ring-substituted amphetamine commonly abused in recreational users. High doses of MDMA determined by allometric scaling produce serotonin (5-HT) axon deneveration. Studies suggest that this interspecies scaling does not reflect human use. An 'effects' scale comparing similar behavioral and physiological effects between species has been postulated as more accurate for translational studies. Experiment 1 examined the effects of MDMA on serotonergic forebrain innervation using immunohistochemical labeling targeting the serotonin transporter protein (SERT). Experiments 2 and 3 examined low and high doses of MDMA on spatial memory, prefrontal functioning, and serotonergic neurotoxicity using 'effects' scaling. Long Evans rats were given MDMA regimens of: chronic low dose (daily injections of 1.5 mg/kg for 10 days); binge low dose (2 days of 4 x 1.5 mg/kg spaced 2 hours apart), binge high dose (2 x 7.5 mg/kg sp aced 2 hours apart). Acquisition, retention, and spatial reversal (SR) were measured in a water maze task. A 2.0 mg/kg MDMA drug challenge was then given prior to a serial spatial reversal (SSR) task to assess performance while under the effect of the drug. Attentional set shifting and behavioral flexibility were assessed in an intradimensional extradimensionl (IED) task using odor/texture discriminations. MDMA chronic and binge low doses did not impair water maze or IED performance and produced no reductions in SERT expression. MDMA binge high dose resulted in significant reductions of SERT density in the prefrontal cortex, striatum, cortical mantle, hippocampus, amygdala, and many thalamic nuclei. Despite prominent 5-HT denervation, water maze performance was unaffected. Selective impairment in behavioral flexibility on the IED test was found. / This suggests that low doses of MDMA do not produce long-term deleterious effects. But, high doses of MDMA taken in 'binges' produces widespread loss of forebrain SERT fiber innervation and significant impairments in reversal learning, while leaving attentional set shifting and spatial navigation unscathed. / by Stephanie Brooke Linley. / Thesis (Ph.D.)--Florida Atlantic University, 2011. / Includes bibliography. / Electronic reproduction. Boca Raton, Fla., 2011. Mode of access: World Wide Web.

Bibliography: p. 207-236. / 236 p. : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis examines the systemic and cerebral pharmacokinetics and pharmacodynamics of propofol following rapid administration, using regional pharmacokinetic techniques in a sheep preparation. New methods for measurement of cerebral blood flow, cerebral metabolic rate and depth of anaesthesia are developed and validated. The final studies show that distribution of propofol to the brain is dependent on cardiac output. / Thesis (Ph.D.)--University of Adelaide, Dept. of Anaesthesia and Intensive Care, 1997?

DHA depletion in brain was associated with impairment on spatial learning and memory in rat. The Morris water maze test found that the n-3 deficient rats spent more time and swam a longer distance to find the hidden platform compared with the n-3 adequate group, indicating that n-3 Def rats had a poorer spatial learning ability and memory. The results suggest that learning and memory are partially related to the brain DHA status in rat. / Docosahexaenoic acid (DHA, 22-6n-3) and arachidonic acid (AA, 22:4n-6) are long-chain polyunsaturated fatty acids (LCPUFA), which are important for the structural development of mammalian central nervous system and are accumulated in large amounts in the developing brain, retina and sperm. Deficiency in DHA and AA syndromes can occur if these fatty acids and their precursors (linoleic and linolenic acid) are insufficient in diet. It had been reported that DHA deficiency in animal brain led to a poor performance in learning ability and other abnormal behavior in rodents. In addition, DHA and AA are the unique fatty acids in human milk. Many studies reported that children who were breast-fed got higher intelligent scores than those who were formula-fed. Thus, a large number of studies suggested that DHA and AA should be added into infant formula to mimic the composition of human milk. / In summary, DHA distribution, depletion and recovery were region-specific in rat brain. DHA deficiency could lead to impairment on spatial learning in rat. The underlying mechanism of learning deficit might not be attributed to changes in antioxidant enzymes in rat brain. Although impairment on spatial learning was observed in DHA-deficient rat, a meta-analysis of published data demonstrated that DHA and AA supplement in infant formula had no effect on cognitive development in children. / No significant relationship between DHA level and brain antioxidant enzyme activities was observed, including catalase (CAT), Cu-Zn superocide dismutase (Cu-Zn SOD), Mn superocide dismutase (Mn SOD) and glutathione peroxidase (GPx). These enzyme activities varied with regions of brain. A lower activity of CAT, Mn SOD and GPx in hippocampus and cortex would make them particularly susceptible to oxidation damage compared with other regions. The present results did not support the view that the spatial learning and memory impairment in DHA depletion was associated with antioxidant status in brain. / The meta-analysis indicated that breast-feeding was positively associated with a higher cognitive development than formula-feeding. However, no benefit was found for infants who received formula supplemented with DHA alone or DHA plus AA compared with those fed traditional formula based on available data. The results suggest that the beneficial effect of breast-feeding over formula-feeding can not be solely attributed to DHA and AA present in breast milk. / The objectives of present study were to (1) examine the distribution, depletion and recovery of DHA in rat brain; (2) investigate the effect DHA deficiency in rat brain on spatial learning behavior; (3) study the effect of DHA deficiency on antioxidant enzymes in rat brain; and (4) analyze whether DHA and AA supplementation has any beneficial effect on cognitive development and quantify their effect size in children by conducting a meta-analysis of the published data, and adult rats, the region with the highest DHA percentage was cortex, whereas in aged rats, both cortex and cerebellum were the regions with the highest DHA percentage. DHA concentration in rat brain increased with age. DHA was not proportionally depleted and recovered in different regions of rat brain when the rats were maintained on an n-3 fatty acid deficient diet for two generations. The present results demonstrated that the distribution of DHA and AA was region-specific. / Xiao Ying. / "August 2006." / Adviser: Zhen Yu Chen. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1566. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 140-156). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

This dissertation aims at determining the possible effects of alcoholic hangover on human behaviour by examining the effects of acute alcohol consumption (> 1g/kg) 14-16 hours following alcohol ingestion on simple and choice reaction times, divided attention tasks and driving skills. The hypotheses are that cognitive and behavioural functioning is impaired even after the blood alcohol concentration level has returned to zero The California Computerised Assessment Package (CALCAP) together with selected driving skills tasks, repeated breath analysis measures, a biographical questionnaire, a subjective hangover rating scale, and blood glucose tests were administered to a group of 63 mixed gender student volunteers. The experimental group and was tested prior to, and during hangover. The control group was pre- and post-tested in order to determif.le the impact of practice effects. Results indicate that hangover individuals performed less well than control subjects on measures of reaction time and driving precision. Further more, the findings show that subjective experience of hangover is not a good predictor of reaction time or driving performance, and that the absence of hangover symptoms does not guarantee full mental recovery. Statistical analysis of the data showed that post-test findings could not be attributed to a gender effect. / Thesis (M.A.)-University of Natal, Pietermaritzburg, 2000.

This thesis examined how pharmacological treatment and cortical injury during development affects brain plasticity. Rats were given either a low dose of perinatal fluoxetine or a mild postnatal day 7 Hypoxic‐Ischemic (HI) injury, both, or neither. The functional outcome was assessed using a series of behavioral tasks and anatomical measures. To assess how HI affects the development of motor maps, forelimb motor maps were evoked at P19. The findings indicate that fluoxetine treatment or HI injury mostly negatively affected functional outcome. The combined treatment with fluoxetine and HI injury only interacted on a limited number of measures. There was no delay in the emergence of evoked motor movements, or change in map location in the HI animals. These results suggest that the pharmacological treatment and cortical injury described in this thesis may have different mechanisms whereby plastic changes are induced and the interaction between these two mechanisms is limited. / xii, 169 leaves : ill. ; 29 cm.

Background. Various studies show that cannabis use alters attention and cognitive functioning in healthy humans and may contribute to development of schizophrenia or worsening of pre-existing psychosis. However, the impact of cannabis use on brain function in humans is not well understood. Schizophrenia is associated with a deficit in prepulse inhibition (PPI), the normal inhibition of the startle reflex by a non-startling stimulus (prepulse), presented before the startle stimulus at short time intervals (lead-time intervals). Such PPI deficit is thought to reflect a sensorimotor gating dysfunction in schizophrenia. PPI is also modulated by attention and PPI reduction in schizophrenia is observed when patients are asked to attend to, not ignore, the stimuli producing PPI. The aim of the current study was to investigate the association between self-reported chronic cannabis use and attentional modulation of PPI in healthy controls and in patients with schizophrenia. Furthermore, the association between cannabis use and other startle reflex modulators, including prepulse facilitation (PPF) of the startle reflex magnitude at long lead-time intervals, prepulse facilitation of the startle reflex onset latency and habituation of the startle reflex magnitude, were examined. Method. Auditory-evoked electromyographic signals were recorded from orbicularis oculi muscles in chronic cannabis users (29 healthy controls and 5 schizophrenia patients) and non-users (22 controls and 14 patients). The data for 36 participants (12 non-user controls, 16 healthy cannabis users, and eight non-user patients) were used in the final analyses and the patient data were used as a pilot study, because relatively few participants met the rigorous exclusionary criteria. Participants were instructed to attend to or to ignore either the startle stimuli alone (70 100 dB) or prepulse (70 dB) and startle stimuli (100 dB) separated by short lead-time intervals (20 200 ms) and long lead-time intervals (1600 ms). In order to ignore the auditory stimuli the participants played a visually guided hand-held computer game. A pilot study showed that the response component of playing the game had no effects on attentional modulation of the startle reflex magnitude and onset latency. Results. Relative to controls, cannabis use in healthy humans was associated with a reduction in PPI similar to that observed in schizophrenia while attending to stimuli, and with an attention-dependent dysfunction in the startle reflex magnitude habituation. While ignoring the stimuli there were no statistical differences in PPI between cannabis users and controls, although PPI in cannabis users tended to differ from that of the patients. The reduction in PPI in cannabis users was correlated with the increased duration of cannabis use, in years, but not with the concentration of cannabinoid metabolites in urine or with the recency of cannabis use in the preceding 24 hours. Furthermore, cannabis use was not associated with any differences in PPF, onset latency facilitation, and startle reflex magnitude in the absence of prepulses. The accuracy of self-reports of substance use was also investigated in this study and was found to be excellent. In addition, the study examined the validity of the substance use module of the diagnostic interview, CIDI-Auto 2.1, which was found to be acceptable for cannabis misuse diagnoses (abuse and/or dependence). Finally, cannabis dependence was found to be associated with more diagnoses of mental illness other than schizophrenia (mainly depression). Conclusions. The results of the current study suggest that chronic cannabis use is associated with schizophrenia-like deficit in PPI in otherwise healthy humans. This PPI reduction is associated with attentional impairment rather than a global sensorimotor gating deficit in healthy cannabis users.