Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 109-154) Also available in print.

Thesis (Ph. D.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains vi, 95 p. Includes abstract. Includes bibliographical references (p. 56-64).

Thesis (Ph.D.)--OGI School of Science & Engineering at OHSU, July 2006. / Includes bibliographical references (leaves 97-114).

Made available in DSpace on 2014-06-11T19:32:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-12-13Bitstream added on 2014-06-13T18:44:37Z : No. of bitstreams: 1 munhoz_e_dr_arafo.pdf: 3085541 bytes, checksum: f014aca5c4e34e1bd024219270c2acaf (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O estresse, atualmente, é considerado um fator importante na fisiopatologia de muitos distúrbios psiquiátricos. Embora os efeitos do estresse agudo possam ser contrabalanceados por respostas adaptativas, o estresse intenso, repetido ou prolongado pode eliciar alterações neuronais duradouras que constituirão as bases de doenças psiquiátricas, como a depressão. Levantamentos epidemiológicos também mostram elevada prevalência de tabagistas entre pacientes com depressão maior. Estas altas taxas de comorbidade sugerem uma provável relação causal: pacientes com depressão proeminente procurariam a nicotina para alívio dos sintomas. Assim, este trabalho investigou as alterações neuroquímicas e neuroendócrinas mediadas pela nicotina na resposta de adaptação ao estresse, utilizando-se, para tanto, o teste modificado da natação forçada (TNF). Para tanto, ratos Wistar machos foram submetidos ao TNF (30 cm de água, 24 ± 1ºC) por 15 min e tratados (1, 19 e 23h) com nicotina (NIC: 0,5 mg/kg, sc), imipramina (IMI: 15 mg/kg, ip) ou salina (SAL). Uma hora após a última injeção, os animais foram reexpostos (5 min) à mesma cuba. Imediatamente após o teste, os animais foram sacrificados; o hipocampo dorsal (HD) e ventral (HV), hipotálamo (HT) e os núcleos dorsal (DR) e mediano (MR) da rafe foram coletados por punch para quantificação de 5-HT, 5-HIAA e NA por HPLC e o sangue, para quantificação da corticosterona plasmática por radioimunoensaio. O hipocampo total também foi utilizado para avaliar a expressão do receptor serotoninérgico 5-HT1A e do glicorreceptor (GR) por western blot. Ainda, avaliou-se o efeito da prazosina nas alterações neuroquímicas induzidas pelo TNF. O tratamento subcrônico com NIC e IMI reduziu em 39% e 50%, respectivamente, o parâmetro de imobilidade e aumentou em 52% e 66%, respectivamente, as contagens de escalada, em relação ao grupo... / Stress is considered a key component in the pathophysiology of several psychiatric diseases. Although the effects of acute stress can be counterbalanced by adaptative responses, intense, repeated or prolonged stress can elicit long lasting neuronal alterations that are related to the occurrence of psychiatric disorders, such as depression. Epidemiological studies have also identified a high prevalence of smokers among depressive patients. These observations suggest a causal relationship: smoking is a self-medication effort to alleviate some symptoms of depression by nicotine. Then, this study investigated nicotine mediatedneurochemical and neuroendocrine alterations in the adaptation response to stress. The modified forced swmming test (FST), a protocol originally employed for screnning new antidepressant drugs, was employed. Male Wistar rats were placed individually into a container (30-cm of water, 24±1ºC, 15 min - pretest). Then animals received nicotine (0.5 mg/kg, s.c.), imipramine (15 mg/kg, i.p.) or saline injections at 1, 19 and 23h after the pretest. One hour after the injections, animals were placed in the same container for 5 min. Immediately after, the animals were sacrificed; dorsal (DH) and ventral (VH) hippocampus, hypothalamus (HT) and dorsal (DR) and median (MR) raphe nuclei were collected by punch for measurement of 5-HT, 5-HIAA and NA by HPLC (expressed in ng/mg tissue). Blood samples were collected for determination of plasma corticosterone levels by radioimmunoassay. The whole hippocampus was also used to evaluate the expression of the 5-HT1A serotoninergic receptor and glucocorticoid receptor by western blot. The effects of prazosin in TNF induced-neurochemical alterations was also evaluated. Nicotine and imipramine decreased in 39% and 50%, respectively, the immobility behavior and increased in 52% and 66%, respectively, the climbing scores, in relation to saline... (Complete abstract click electronic access below)

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Nicotine (NIC) abuse involves activation of midbrain dopamine (DA) neurons and NIC addiction involves neuroadaptive changes in the mesolimbic DA reward system. GABA neurons in the midbrain ventral tegmental area (VTA) express α4β2-containing nicotinic acetylcholine receptors (nAChRs), whose activation increases GABAergic input to DA neurons. However, this initial effect is decreased after chronic NIC treatment (as in the case of smokers) by inducing nAChR desensitization. Thus, GABA neuron inhibition results in increased DA release in limbic structures such as the nucleus accumbens. To support this hypothesis, we evaluated the effects of acute and chronic NIC on GAD-67 positive neurons in the VTA of GAD GFP mice using in vivo and in vitro electrophysiological methods. In in vivo studies in naïve mice, stimulation of the peduncopontine tegmental nucleus (PPT) activated VTA GABA neurons orthodromically and antidromically. Orthodromic activation of VTA GABA neuron spikes by PPT stimulation was blocked by the nAChR mecamylamine (1 mg/kg). Acute systemic NIC (0.15-0.5 mg/kg IV) had mixed overall effects on VTA GABA neuron firing rate, but in situ microelectrophoretic application of NIC produced a brisk and consistent enhancement (200-500 %) of VTA GABA neuron firing rate that showed no acute tolerance or sensitization with repeated, periodic current application. Local NIC activation was blocked by systemic administration of mecamylamine. Compared to 12 day chronic saline injections, chronic NIC injections (2 mg/kg IP/day) significantly increased VTA GABA neuron firing rate. In in vitro studies, compared to 12 day chronic saline injections, chronic NIC injections decreased DA neuron firing rate. In addition, chronic NIC increased DA neuron, but decreased GABA neuron GABA-mediated sIPSCs. These findings demonstrate that there is reciprocal innervation between the PPT and VTA and that cholinergic input from the PPT is excitatory on VTA GABA neurons. Moreover, VTA GABA neurons are excited by acute NIC and sensitize to chronic NIC, suggesting that α4β2 nAChR subunits on these neurons may play an important role in the adaptations to chronic NIC. Thus, quantitative molecular studies are ongoing to determine specific alterations in nAChRs on VTA GABA neurons to chronic NIC.

One of the main reasons smokers struggle to quit is the cognitive deficits caused by abstinence. Bupropion (BUP) and nicotine replacement therapy (NRT) are two of the three FDA-approved efficacious pharmacotherapies to assist in nicotine abstinence. Very little is known about the differences between the neurocognitive effects of NRT and BUP. This dissertation analyzed a dataset of electroencephalogram (EEG) collected while participants performed a visuospatial dot-localization task (DOTLOC). In the study, 119 smokers were randomly divided into 4 groups (BUP, NRT, placebo, and delayed-quit controls) for 6 sessions – one baseline experimental session, four treatment sessions and one post-treatment session after 67 days of abstinence. During the task, source-localized theta, alpha, and beta activity were obtained for the four groups (NRT and BUP, placebo, and delay-quit smokers) at three network-related regions of interest (ROIs). After 3 and 24 days of abstinence, NRT contrasted with placebo showed increases in high frequency current source density (CSD) and decrease in low-frequency CSD. After 3 days of abstinence, BUP contrasted with placebo showed increase in theta and beta CSD at parietal sites and decrease in spectral CSD at frontal and temporal sites. When contrasted with NRT, BUP showed an increase in low-frequency CSD at parietal regions, and decrease in low and high-frequency at temporal and frontal regions. A significant difference was also found in abstinent smokers at 66 days compared to pre-quit session and smoking controls, with a significant increase in parietal alpha activity and a significant decrease in beta CSD. This was the first research to look at the neurocognitive effects of bupropion compared to NRT, as well as the first to identify the long-term changes caused by tobacco abstinence on task-related cortical activity.