Dissertations / Theses on the topic 'Alcohol Rats'

Rationale. Alcohol use disorders (AUDs) and tobacco dependence are frequently identified as co-morbid. Although less than 20% of the general population smokes, over 80% of people with AUDs are considered daily smokers. In fact, people with AUDs are more likely to die from smoking-related health issues, than from alcohol related health issues. Surprisingly, there is very little evidence that alcohol and nicotine are concurrently self-administered in pre-clinical models. We hypothesized that low doses of nicotine that enhancing responding for other rewards would be self-administered and enhance self-administration of alcohol. Objective. The goal of this study was to determine if low-doses of nicotine, typically not self-administered alone, would promote alcohol self-administration in a concurrent access paradigm. Method. Alcohol preferring rats (females) were requested from the University of Indiana Medical School breeding facility. They were randomly assigned to one of three groups – NIC-Alone, ALC-Alone, or ALC+NIC. All rats were fluid restricted and shaped to lick for water at two sipper tubes that could record lick responses and deliver aliquiots of fluid into the sipper tube via a solenoid valve. After shaping, rats were instrumented for IV self-administration. During self-administration tests, rats in the ALC-Alone received access to oral ethanol (15% v/v) for meeting the schedule of reinforcement at one sipper tube (e.g., right) and saline infusions for meeting the schedule of reinforcement at the other sipper tube (e.g., left). The NIC-Alone group received IV nicotine infusions (15 ug/kg/inf) and oral licorice (1%) for meeting the schedule of reinforcement at one sipper tube (e.g., left) and oral water for meeting the schedule of reinforcement at the other sipper tube (e.g., right). The ALC+NIC group received IV nicotine and oral licorice for meeting the schedule of reinforcement on the left sipper, and oral ethanol for meeting the schedule of reinforcement on the right sipper. Price manipulations for nicotine were performed by adjusting the schedule of reinforcement on the sipper associated with nicotine infusions. Results. During acquisition, nicotine did not enhance alcohol self-administration – alcohol intake was comparable between ALC-Alone and ALC+NIC rats. In addition, alcohol did not enhance nicotine self-administration as responding for NIC was comparable between ALC+NIC and NIC-Alone rats. However, when the price of nicotine was manipulated, alcohol created a greater demand for nicotine, as indicated by higher rates of nicotine consumption with increases in price. Manipulating the price of nicotine did not alter demand for alcohol. Conclusion. The interaction between alcohol and nicotine reinforcers may depend on changes in demand for nicotine. Future studies should investigate whether demand for alcohol is altered by concurrently available nicotine infusions. *the first and second authors contributed equally to this project

The co-dependence of nicotine and alcohol addiction occurs at high rates, complicates treatment, and is often associated with significant morbidity and mortality. Treatment options of alcohol and tobacco co-dependence are limited. Currently, there are drugs available for nicotine dependence or alcohol dependence. However, there are no therapeutic drugs available on the market for the co-dependence of nicotine and alcohol. Therefore, and important opportunity of new therapeutic options and drug development has presented itself. NT69L, a non-selective neurotensin (NT) agonist, provides a potential novel therapy for nicotine addiction in alcoholics by interacting with the common neurotransmitter circuits supporting the rewarding process for both nicotine and alcohol. Considering the behavioral effects of NT69L in attenuating nicotine self-administration in rats and alcohol consumption in mice, the present study was designed to assess the effects of NT69L as a new drug. NT69L was used in the treatment of nicotine addiction in an animal model of alcoholics and in attempts to attenuate withdrawal signs associated with nicotine and alcohol dependence. Wistar rats pre-exposed to alcohol vapor or air were allowed to self-infuse nicotine (0.03mg/kg/infusion) or saline. When the rats reached a stable level of responding, the effect of pretreatment with NT69L (1mg/kg i.p.) on the reinforcing effect of nicotine was determined. Animals self-infused nicotine at a significantly (p < .05) higher rate compared to saline in both air and alcohol vapor exposed groups. Acute pretreatment with a single injection of NT69L significantly (p < .05) reduced nicotine self-infusion in both the alcohol vapor and the air exposed groups for 5 days post-injection. Additionally, NT69L attenuated the alcohol- and nicotine-induced withdrawal signs associated with the discontinuation of alcohol and nicotine administration. Neurotensin agonist, NT69L, may represent a potential novel therapy to treat the co-addiction of alcohol and nicotine.

Orientadores: Francisco Eduardo Martinez, Marcelo Martinez
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Considerando-se o uso do álcool entre mulheres questão atual e preocupante, o presente trabalho objetivou avaliar as conseqüências do abuso do álcool sobre o epitélio uterino de ratas. Foram formados os grupos UChA e UCh8, bebedores voluntários de etanol a 10% e Wistar, consumidores de água. Após 120 dias, dez animais de cada grupo foram sacrificados, amostras de sangue coletadas, o peso corporal e dos órgãos genitais mensurado e os cornos uterinos coletados e processados para análise morfométrica e microscópica. A análise do peso corporal e dos órgãos genitais não revelou diferença significativa entre os grupos, embora o peso corporal do grupo UCh8 tenha sido significativamente maior quando comparado ao UChA. A análise morfométrica revelou que a altura do epitélio uterino do grupo UChA foi significativamente menor, quando comparada aos grupos controle e UCh8, embora não tenha sido observada diferença significativa na concentração plasmática dos hormônios FSH, LH, progesterona e estradiol. A microscopia de luz não mostrou diferença nas características histológicas do epitélio uterino entre os grupos, enquanto a microscopia eletrônica de transmissão mostrou gotas lipídicas, vacúolos digestivos, cisternas do retículo endoplasmático granular dilatadas e núcleos com deformidades nos grupos UChA e UCh8. Mitocôndrias volumosas foram observadas no grupo UChA. A microscopia eletrônica de varredura dos grupos UChA e UCh8 evidenciou espaços intercelulares aumentados e gotas lípidicas no citoplasma e luz. Conclui-se, portanto, que a ingestão crônica de etanol esta relacionada a várias alterações na ultraestrutura do epitélio uterino da linhagem UChA e UChB
Abstract: Considering the use of alcohol among women, a current and concerning issue, this paper aims at assessing the consequences of the abuse of alcohol on the uterine epithelium of rats. The UChA and UChB study groups. were formed for voluntary 10% ethanol consumption and the Wistar group for voluntary intake of water. After 120 days; ten animais from each group were sacrificed, blood samples were taken, the body weight and genital organs were measured, and the uterine horns were collected and processed for morphometric and microscopic analysis. The analysis of body weight and genital organs did not reveal a significant difference among the study groups, although the body weight of animais in group UChB was significantly greater in comparison with the UChA. The morphometric analysis revealed that the height of the uterine epithelium of animais in group UChA was significantly smaller in comparison with the control and UChB groups, although no significant difference was observed in the plasma concentration of hormones FSH, LH, progesterone, and estradiol. The light microscopy did not show differences in the histological characteristics of the uterine epithelium among the groups, while the transmission electronic microscopy showed the presence of fat drops, digestive vacuoles, dilated cisterns of the rough endoplasmic reticulum and nuclei with deformities In groups UChA and UChB. Voluminous mitochondria were observed in group UChA. The scanning electronic microscopy in groups UChA and UChB showed increased intercellular spaces and fat drops in the cytoplasm and lighí. It can therefore be concluded that the chronic intake of ethanol is related to various alterations in the ultrastructure of the uterine epithelium of UChA and UChB rat strains
Mestrado
Anatomia
Mestre em Biologia Celular e Estrutural

The co-abuse of alcohol and marijuana is widespread, although the mechanisms underlying this behavior are unclear. There is some evidence of a relationship between the neural processes that mediate the effects of ethanol and marijuana. For example, research has shown that exposure to marijuana increases responding for, and intake of, ethanol. The alcohol deprivation effect is an anima l model of alcoholism that suggests that the reinforcing efficacy of ethanol, as measured by intake, increases following a period of deprivation. Recent research indicates that rats chronically exposed to marijuana during periods of alcohol deprivation consume ethanol above and beyond deprivation alone. It is unclear, however, whether the marijuana exposure or the repeated deprivations increased motivation to consume ethanol. In the present experiment, rats were trained to self-administer ethanol on a progressive ratio schedule and subjected to two separate periods of deprivation during which either drug or saline was chronically administered for 7 days. Breakpoint (i.e., last ratio completed) was recorded as a measure of the reinforcing efficacy of ethanol. Following deprivations, breakpoint was initially lower than baseline, regardless of whether the drug or saline was administered. Breakpoint recovered to, but did not exceed, baseline levels following both deprivations, indicating a lack of increased reinforcing efficacy of ethanol after repeated deprivation or chronic exposure to marijuana. The lack of an expression of an alcohol deprivation effect following deprivation may have been due to the length and number of deprivations employed. Furthermore, lowered breakpoint recorded following chronic drug administration during deprivation may have been due to the dose administered or stress generated by chronic injections . Further investigation is necessary to separate and clarify the variables responsible for the present results.

The objective of the present study was to examine the effects of prenatal exposure to alcohol on sensorimotor coordination, emotionality, learning and memory in young adult Wistar rats. Most of the recent reports concerning behavioral effects of fetal alcohol exposure refer to the juvenile period of life and very few studies investigated different aspects of behavior simultaneously in the same subjects. In the current study, alcohol was delivered to the pregnant dams by intragastric infusions, throughout gestation days (GD) 7-20, at the dose of 6g /kg maternal body weight /day. This dose resulted in relatively high peak blood alcohol concentration (340 mg/dl) as assessed on GD 20. A pair-fed isocaloric and untreated control groups were included. Prenatal alcohol administration retarded dams&rsquo
weight gain significantly, and had an adverse effect on pups&rsquo
weight at birth but not in adulthood. No between-group differences were observed in the litter size and in the pups&rsquo
mortality. The adult brain weight was neither affected. Pups were subjected to a series of behavioural tests as young adults (at 2.5 months of age). In adulthood, rats prenatally treated with alcohol were not impaired in sensorimotor coordination and/or did not show muscle weakness as assessed by rotarod/accelerod tests. Their behavior in the open field and plus maze suggested alcohol-induced increase in iv anxiety level and some decrease in behavioral flexibility, but hyperactivity was not observed. In cognitive tasks, alcohol treated rats showed slightly slower rate of initial place learning in the water maze. However, memory retention tested after 1 and 10-day delay, reversal learning, rate of extinction of place preference, as well as working memory capacity appeared to be the same in alcohol exposed and control rats. The possible reasons of this negative result are discussed.

Sucrose fading and intermittent access are two common procedures that induce alcohol consumption in rodents. Sucrose fading procedures involve exposing ethanol naïve rats to a mixture of ethanol and sucrose and gradually reducing the concentration of sugar. Intermittent access procedures involve providing rats with access to ethanol on alternating days. Given that rats will consume ethanol without sucrose, the role of sugar in the sucrose fading procedure is unclear. Rats must be ethanol naïve when they are exposed to treatment with sucrose fading, so there is no point of comparison to show that exposure to sugar in sucrose fading produces higher levels of drinking. There has yet to be any work that isolates the effects of sugar on the consumption of alcohol. The purpose of the present experiment was to examine the effects of sucrose on ethanol consumption in rats with different alcohol histories. Two groups of six rats were exposed to two successive sucrose fading procedures, 30 days apart and their drinking was measured 30 days after each one. One group was exposed to an intermittent access procedure to establish drinking prior to treatment with sucrose fading, the other was ethanol naïve. Following sucrose fading, all rats drank pharmacologically active doses of ethanol. For both groups consumption correlated with the concentration of sucrose and decreased in a step-wise manner as it was faded. For the ethanol experienced rats, consumption dropped below baseline levels as sucrose was faded and decreased further with the second exposure. In contrast, the ethanol-naïve rats did not decrease consumption from the first sucrose fading procedure to the second. Slight differences in peak force of responses were also observed.

Behavioral deficits caused by fetal-alcohol are well expressed in juvenile subjects but usually ameliorate with maturation. It suggests some kind of postnatal regeneration. The aim of the present study was to examine the potential correlation between behavioral recovery and the postnatal hippocampal development in the fetal-alcohol rats. This study included behavioral tests applied to juvenile and adult subjects, unbiased stereology to investigate changes in neuron numbers and hippocampal volumes, the postnatal tracing and analysis of the hippocampal principal neuron&rsquo
s morphology, investigation of age-dependent changes in the distribution of doublecortin-expressing neurons, and evaluation of synaptic development by assessing age-dependent changes in the regional immunoreactivity/expression of synaptophysin and PSD95. Rats have been exposed to ethanol throughout 7-21 gestation days with daily ethanol dose of 6g/kg delivered by intragastric intubation to the pregnant dams. The morphological characteristics were examined on postnatal days P1, P10, P30, P60, in hippocampal CA1, CA3, and DG subregions, in fetal-alcohol and control rats. Both, stereological and doublecortin-immunoreactivity data pointed towards a possibility of limited neurogenesis taking place during a protracted postnatal period not only in the germinal zones (SGZ and SVZ) but also in the hippocampal CA regions. Ethanol effect on postnatal hippocampal development was limited to marginally lower number of granular cells in DG on P30. It correlated with poorer cognitive performance in the fetal-alcohol group. The treatment effect on the morphology of hippocampal neurons was observed mainly in CA region at P1 and seemed to be attributed more to the intubation stress than the ethanol itself.

The effect of alcohol and/or zinc deficiency was evaluated in seven groups of pregnant rats and their pups. Females which had been acclimated to alcohol before breeding were fed liquid alcohol diets with either 14 or 0.1 ppm Zn. Comparisons were made with animals pair fed isocaloric liquid carbohydrate diets with the same Zn levels. Other comparisons were made by pair feeding a high zinc diet to a low zinc diet, and by feeding a high zinc diet ad lib. A reduced food intake and Zn deficiency affected maternal status by decreasing weight gain, liver Zn and plasma Zn concentration. Litter size, litter weight, and fetal liver and brain weight were decreased only in the alcohol zinc deficient group compared to adequately fed controls. The concentration and total quantity of fetal liver Zn were decreased due to a Zn deficiency. The combination of Zn deficiency and alcohol decreased only total Zn in fetal brain. The concentrations of protein, DNA, and RNA in fetal liver and brain were similar regardless of dietary treatment. The quantities of protein, DNA, and RNA were decreased in fetal liver due to Zn deficiency. ln fetal brain, only the combination of alcohol and Zn deficiency decreased total protein and RNA, while DNA was not affected. Although alcohol by itself had no effect on the above variables, its combination with a Zn deficiency did. In addition, there were 58 resorptions and 15 malformations seen in Zn deficient alcoholic dams compared with no more than 15 and 2, respectively, in any of the other groups. Teratogenesis caused by a Zn deficiency was increased with alcohol consumption.
Ph. D.
incomplete_metadata

Using a rat model, the effects of a single dose or six to twelve months of daily oral administration of ethanol on the immune system were determined. The rats were challenged with sheep red blood cells after the various dosing periods to elicit an immune response. Immune system responsiveness was determined by means of white blood cell counts and differentials, antibody titers, and T-cell numbers. No deleterious effects of the ethanol on the immune response were seen, while the female alcohol-fed rats showed a significant increase in T-Cell numbers, white blood cell counts, and lymphocytes over the sham group.

Thesis (Ph.D.)--University of Tennessee Health Science Center, 2007.
Title from title page screen (viewed on February 29, 2008). Research advisor: Robert S. Waters, Ph.D. Document formatted into pages (xix, 179 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 152-178).

The purpose was to examine the effect of chronic alcohol abuse on the androgen receptor content (AR) in skeletal muscle, and to determine if this effect was influenced by resistance training. Thirty-four male rats (456 ± 1 g; mean ± SE) were divided into 4 groups: Sham exercise-Ethanol, Sham exercise-Normal diet, Exercise-Ethanol, and Exercise-Normal diet. Both Exercise groups underwent a 6-week "squat" resistance training protocol and both Ethanol groups received an alcohol-rich diet throughout the 6-week period. Western blot analysis showed no effect of alcohol or resistance training on the AR of the extensor digitorum longus. For the rectus femoris, alcohol caused a decline in the AR (p=0.01). This reduction was not attenuated by resistance training. The AR of the soleus was not affected by chronic alcohol abuse alone; however, the resistance training induced increase in the AR was prevented by chronic alcohol abuse (p=0.03).

The effects of single injections and daily oral administration of ethanol on plasma levels of ACTH, beta endorphin, and corticosterone in response to cold stress were examined. The long-term experimental animals were given 0.25 ml of 28% ethanol or water orally once a day, five days a week, for fourteen months. Plasma levels of ACTH, beta endorphin, and corticosterone were lower in alcohol-treated rats as compared with water-treated rats when exposed to cold stress. The effects of a single injection of ethanol significantly elevated plasma levels of all three hormones. Mortality in sham-treated males was higher than ethanol-treated.

The effects of moderate, long-term intake of ethanol on the hypothalamic response to cold stress were examined. The long-term experimental animals were given .25 ml of 28% ethanol or .25 ml of water orally once a day, five days a week for fourteen months. A stainless steel electrode was then surgically implanted into the paraventricular nucleus, after which the animal was subjected to cold stress (-150 C, 10 min.). Recordings were taken in the forms of frequency and activity. The data clearly indicate that: (1) alcohol fed rats exhibited a suppressed response to cold stress compared to sham-fed rats; (2) this suppression of activity occurred at the level of the hypothalamus, and (3) mortality was significantly lower in alcohol-fed males than it was in sham fed males. This study clearly points out the need for further work in the area of the beneficial effects of moderate doses of alcohol.

Thesis (Ph.D.)--Indiana University, 2009.
Title from screen (viewed on September 30, 2009). Department of Medical Neuroscience, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): William J. McBride, R. Andrew Chambers, James M. Murphy, Zachary A. Rodd. Includes vita. Includes bibliographical references (leaves 131-143).

Orientador: Francisco Eduardo Martinez
Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: O alcoolismo crônico está inserido no grupo das principais doenças classificadas como oriundas de distúrbios mentais, sendo as mulheres mais atingidas em relação aos homens. Embora, o álcool conduza inicialmente a estímulos emocionais benéficos para o organismo, proporcionando aumento da euforia, do prazer, entre outros, seu uso excessivo e prolongado pode promover efeitos colaterais indesejáveis, inclusive sobre a reprodução. Na literatura existem poucos estudos envolvendo as conseqüências do alcoolismo crônico em fêmeas. O presente trabalho tem como objetivo elucidar as alterações manifestadas no ovário de ratas adultas UChA e UChB (consumidoras voluntárias de etanol a 10%). Após o período de tratamento, 42 ratas subdivididas em três grupos experimentais (UChA, UChB e Wistar) foram eutanasiadas por decapitação, e os ovários coletados e processados para análise em microscopia de luz e eletrônica de transmissão. O material foi corado com Hematoxilina e Eosina, Tricrômico de Masson, Azul de Toluidina, ácido periódico de Schiff, Giemsa, Feulgen e, empregou-se o método enzimológico para atividade da fosfatase ácida e alcalina. Os parâmetros: peso corpóreo e dos genitais, índice de ganho de peso, duração dos ciclos estrais e dosagens hormonais (FSH, LH, _-estradiol e progesterona) foram avaliados. A análise estatística foi realizada com 5% de significância. Não houve diferença significativa entre o peso dos animais no início e final do experimento, embora, ao final do experimento, os animais do grupo UChB apresentaram maior índice de ganho de massa. O peso relativo dos ovários dos animais UChB mostrou-se significativamente menor comparado ao grupo Wistar. As dosagens hormonais não apresentaram diferenças estatísticas entre os grupos. Os animais UChA e UChB revelaram as maiores médias de duração dos ciclos estrais e permanência na fase de estro. Nota-se estágios diferenciados de proliferação celular e atresia folicular avançada nos ovários, variando entre os grupos UChA e UChB. Nas variedades bebedoras, a túnica albugínea apresentou-se fibrosa e o estroma medular predominantemente celular. Estroma fibrocelular e túnica albugínea fibrosa estão presente no grupo controle. O grupo UChA apresentou reações metacromáticas entre as células da granulosa dos folículos em crescimento, enquanto regiões delimitadas na parede dos folículos primários, em desenvolvimento e antrais apresentaram intensa metacromasia nos animais UChB. Os grupos UChA e UChB apresentaram reações PAS-positivo no tecido glandular intersticial, enquanto nos animais controles essas reações ficaram restritas na zona pelúcida de ovócitos e entre as células da granulosa de folículos secundários. Os folículos antrais do grupo UChB apresentaram forte reação à fosfatase ácida (FA), comparados aos grupos UChA e controle. Nos animais UChA, os corpos lúteos hemorrágicos e em regressão, destacaram reação à FA com presença de grumos associados. A fosfatase alcalina (FAL) demarcou ampla vascularização nos corpos lúteos dos animais UCh, enquanto que a teca interna dos folículos secundários do grupo UChB reagiram intensamente com a FAL. A análise ultra-estrutural revelou corpos lúteos com vacúolos autofágicos no citoplasma e início de picnose nuclear nas linhagens UCh. As células da granulosa apresentaram núcleos com marginalização da cromatina e mitocôndrias edemaciadas. Conclui-se que há irregularidades do ciclo estral e, consequentemente, alterações estruturais nos ovários das linhagens UChA e UChB
Abstract: Chronic alcoholism belongs to the group of diseases classified as originated from mental disturbs, being the women more affected than men. Although ethanol intake causes benefic stimulus to the organism, like increase in euphoria and pleasure, excessive and prolonged use can cause side effects, even to the reproduction. On the literature, there were few researches involving chronic alcoholism and female. In regard to the current incidence of early and late alcoholism in women, and its consequences to the reproduction, the aim of this study was to evaluate the UChA and UChB (10% ethanol voluntary intake) adult rat ovary structure. After the experimental period, 42 rats divided into three groups (UChA, UChB and Wistar control) were killed, by decapitation method, and their ovaries collected to the light and electronic microscopy analysis. Ovary slides were stained with HE, Masson¿s tricromic, toluidine blue, Periodic Acid Schiff and tissue was cryofrozen to further acid/alkaline phosphatase histochemical techniques. Final body weight, reproductive organs weight, body weight gain index, estrous cycle duration and hormone dosages (FSH, LH, _-oestradiol and progesterone) were analyzed. The statistical analysis was made using 5% of significance. There was no significative difference between the groups as to initial and final body weights, although the UChB rats showed an increased body mass gain at the final treatment period. The UChB ovaries relative weight was significantly lower comparing to the control. The hormonal levels did not differ among the groups. The UChA and UChB groups presented prolonged estrous cycles and persistent oestrous phases. Different stages of atresia and proliferation on follicle cells were found varying in UChA and UChB ovaries. The tunica albuginea showed fibrous tissue and cellular stromal components in ethanol drinking animals. Fibrocellular stroma and fibrous tunica albuginea were present in the control group. The UChA group showed metachromatic reaction between the growing follicles granulosa cells, whereas, in the UChB rats, intense metachromasia appeared on small, growing and antral follicles. The UCh groups presented PAS-positive reaction in the interstitial glandular tissue, while in control animals these reactions were restricted to the zona pelucida of oocytes and among granulosa cells of secondary follicles. The antral follicles of the UChB rats showed a high intensity reaction to acid phosphatase (AP), when compared to UChA and control groups. In UChA animals, the hemorrhagic and regression corpora lutea had AP reaction with the presence of associated clumps. Alkaline phosphatase (ALP) marked a hypervascularization in corpora lutea of UCh rats. In UChB strain, internal theca layers of growing follicles, reacted strongerly with ALP in contrast to UChA and control groups. The ultrastructural analysis revelated in UCh strain, corpus luteum with autofagic vacuoles and pyknotic nuclei at the initial stage. The UCh granulosa cells resented irregular nucleus with chromatin marginalization and edematous itochondria. In conclusion, there were estral cyclicity irregularities, caused by chronic ethanol intake in the UCh groups, which were consequently reflected as morphologic alterations in the ovaries structure
Mestrado
Biologia Celular
Mestre em Biologia Celular e Estrutural

[EN] Alcohol abuse is one of the most alarming issues for the health authorities. It is estimated that at least 23 million of European citizens are affected by alcoholism causing a cost around 270 million euros. Excessive alcohol consumption is related with physical harm and, although it damages the most of body organs, liver, pancreas, and brain are more severally affected. Not only physical harm is associated to alcohol-related disorders, but also other psychiatric disorders such as depression are often comorbiding. As well, alcohol is present in many of violent behaviors and traffic injures. Altogether reflects the high complexity of alcohol-related disorders suggesting the involvement of multiple brain systems. With the emergence of non-invasive diagnosis techniques such as neuroimaging or EEG, many neurobiological factors have been evidenced to be fundamental in the acquisition and maintenance of addictive behaviors, relapsing risk, and validity of available treatment alternatives. Alterations in brain structure and function reflected in non-invasive imaging studies have been repeatedly investigated. However, the extent to which imaging measures may precisely characterize and differentiate pathological stages of the disease often accompanied by other pathologies is not clear. The use of animal models has elucidated the role of neurobiological mechanisms paralleling alcohol misuses. Thus, combining animal research with non-invasive neuroimaging studies is a key tool in the advance of the disorder understanding. As the volume of data from very diverse nature available in clinical and research settings increases, an integration of data sets and methodologies is required to explore multidimensional aspects of psychiatric disorders. Complementing conventional mass-variate statistics, interests in predictive power of statistical machine learning to neuroimaging data is currently growing among scientific community. This doctoral thesis has covered most of the aspects mentioned above. Starting from a well-established animal model in alcohol research, Marchigian Sardinian rats, we have performed multimodal neuroimaging studies at several stages of alcohol-experimental design including the etiological mechanisms modulating high alcohol consumption (in comparison to Wistar control rats), alcohol consumption, and treatment with the opioid antagonist Naltrexone, a well-established drug in clinics but with heterogeneous response. Multimodal magnetic resonance imaging acquisition included Diffusion Tensor Imaging, structural imaging, and the calculation of magnetic-derived relaxometry maps. We have designed an analytical framework based on widely used algorithms in neuroimaging field, Random Forest and Support Vector Machine, combined in a wrapping fashion. Designed approach was applied on the same dataset with two different aims: exploring the validity of the approach to discriminate experimental stages running at subject-level and establishing predictive models at voxel-level to identify key anatomical regions modified during the experiment course. As expected, combination of multiple magnetic resonance imaging modalities resulted in an enhanced predictive power (between 3 and 16%) with heterogeneous modality contribution. Surprisingly, we have identified some inborn alterations correlating high alcohol preference and thalamic neuroadaptations related to Naltrexone efficacy. As well, reproducible contribution of DTI and relaxometry -related biomarkers has been repeatedly identified guiding further studies in alcohol research. In summary, along this research we demonstrate the feasibility of incorporating multimodal neuroimaging, machine learning algorithms, and animal research in the advance of the understanding alcohol-related disorders.
[ES] El abuso de alcohol es una de las mayores preocupaciones de las autoridades sanitarias en la Unión Europea. El consumo de alcohol en exceso afecta en mayor o menor medida la totalidad del organismo siendo el páncreas e hígado los más severamente afectados. Además de estos, el sistema nervioso central sufre deterioros relacionados con el alcohol y con frecuencia se presenta en paralelo con otras patologías psiquiátricas como la depresión u otras adicciones como la ludopatía. La presencia de estas comorbidades demuestra la complejidad de la patología en la que multitud de sistemas neuronales interaccionan entre sí. El uso imágenes de resonancia magnética (RM) han ayudado en el estudio de enfermedades psiquiátricas facilitando el descubrimiento de mecanismos neurológicos fundamentales en el desarrollo y mantenimiento de la adicción al alcohol, recaídas y el efecto de los tratamientos disponibles. A pesar de los avances, todavía se necesita investigar más para identificar las bases biológicas que contribuyen a la enfermedad. En este sentido, los modelos animales sirven, por lo tanto, a discriminar aquellos factores únicamente relacionados con el alcohol controlando otros factores que facilitan el desarrollo del alcoholismo. Estudios de resonancia magnética en animales de laboratorio y su posterior evaluación en humanos juegan un papel fundamental en el entendimiento de las patologías psiquatricas como la addicción al alcohol. La imagen por resonancia magnética se ha integrado en entornos clínicos como prueba diagnósticas no invasivas. A medida que el volumen de datos se va incrementando, se necesitan herramientas y metodologías capaces de fusionar información de muy distinta naturaleza y así establecer criterios diagnósticos cada vez más exactos. El poder predictivo de herramientas derivadas de la inteligencia artificial como el aprendizaje automático sirven de complemento a tradicionales métodos estadísticos. En este trabajo se han abordado la mayoría de estos aspectos. Se han obtenido datos multimodales de resonancia magnética de un modelo validado en la investigación de patologías derivadas del consumo del alcohol, las ratas Marchigian-Sardinian desarrolladas en la Universidad de Camerino (Italia) y con consumos de alcohol comparables a los humanos. Para cada animal se han adquirido datos antes y después del consumo de alcohol y bajo dos condiciones de abstinencia (con y sin tratamiento de Naltrexona, una medicaciones anti-recaídas usada como farmacoterapia en el alcoholismo). Los datos de resonancia magnética multimodal consistentes en imágenes de difusión, de relaxometría y estructurales se han fusionado en un esquema analítico multivariable incorporando dos herramientas generalmente usadas en datos derivados de neuroimagen, Random Forest y Support Vector Machine. Nuestro esquema fue aplicado con dos objetivos diferenciados. Por un lado, determinar en qué fase experimental se encuentra el sujeto a partir de biomarcadores y por el otro, identificar sistemas cerebrales susceptibles de alterarse debido a una importante ingesta de alcohol y su evolución durante la abstinencia. Nuestros resultados demostraron que cuando biomarcadores derivados de múltiples modalidades de neuroimagen se fusionan en un único análisis producen diagnósticos más exactos que los derivados de una única modalidad (hasta un 16% de mejora). Biomarcadores derivados de imágenes de difusión y relaxometría discriminan estados experimentales. También se han identificado algunos aspectos innatos que están relacionados con posteriores comportamientos con el consumo de alcohol o la relación entre la respuesta al tratamiento y los datos de resonancia magnética. Resumiendo, a lo largo de esta tesis, se demuestra que el uso de datos de resonancia magnética multimodales en modelos animales combinados en esquemas analíticos multivariados es una herramienta válida en el entendimiento de patologías
[CAT] L'abús de alcohol es una de les majors preocupacions per part de les autoritats sanitàries de la Unió Europea. Malgrat la dificultat de establir xifres exactes, se estima que uns 23 milions de europeus actualment sofreixen de malalties derivades del alcoholisme amb un cost que supera els 150.000 milions de euros per a la societat. Un consum de alcohol en excés afecta en major o menor mesura el cos humà sent el pàncreas i el fetge el més afectats. A més, el cervell sofreix de deterioraments produïts per l'alcohol i amb freqüència coexisteixen amb altres patologies com depressió o altres addiccions com la ludopatia. Tot aquest demostra la complexitat de la malaltia en la que múltiple sistemes neuronals interactuen entre si. Tècniques no invasives com el encefalograma (EEG) o imatges de ressonància magnètica (RM) han ajudat en l'estudi de malalties psiquiàtriques facilitant el descobriment de mecanismes neurològics fonamentals en el desenvolupament i manteniment de la addició, recaiguda i la efectivitat dels tractaments disponibles. Tot i els avanços, encara es necessiten més investigacions per identificar les bases biològiques que contribueixen a la malaltia. En aquesta direcció, el models animals serveixen per a identificar únicament dependents del abús del alcohol. Estudis de ressonància magnètica en animals de laboratori i posterior avaluació en humans jugarien un paper fonamental en l' enteniment de l'ús del alcohol. L'ús de probes diagnostiques no invasives en entorns clínics has sigut integrades. A mesura que el volum de dades es incrementa, eines i metodologies per a la fusió d' informació de molt distinta natura i per tant, establir criteris diagnòstics cada vegada més exactes. La predictibilitat de eines desenvolupades en el camp de la intel·ligència artificial com la aprenentatge automàtic serveixen de complement a mètodes estadístics tradicionals. En aquesta investigació se han abordat tots aquestes aspectes. Dades multimodals de ressonància magnètica se han obtingut de un model animal validat en l'estudi de patologies relacionades amb el consum d'alcohol, les rates Marchigian-Sardinian desenvolupades en la Universitat de Camerino (Italià) i amb consums d'alcohol comparables als humans. Per a cada animal es van adquirir dades previs i després al consum de alcohol i dos condicions diferents de abstinència (amb i sense tractament anti-recaiguda). Dades de ressonància magnètica multimodal constituides per imatges de difusió, de relaxometria magnètica i estructurals van ser fusionades en esquemes analítics multivariats incorporant dues metodologies validades en el camp de neuroimatge, Random Forest i Support Vector Machine. Nostre esquema ha sigut aplicat amb dos objectius diferenciats. El primer objectiu es determinar en quina fase experimental es troba el subjecte a partir de biomarcadors obtinguts per neuroimatge. Per l'altra banda, el segon objectiu es identificar el sistemes cerebrals susceptibles de ser alterats durant una important ingesta de alcohol i la seua evolució durant la fase del tractament. El nostres resultats demostraren que l'ús de biomarcadors derivats de varies modalitats de neuroimatge fusionades en un anàlisis multivariat produeixen diagnòstics més exactes que els derivats de una única modalitat (fins un 16% de millora). Biomarcadors derivats de imatges de difusió i relaxometria van contribuir de distints estats experimentals. També s'han identificat aspectes innats que estan relacionades amb posterior preferències d'alcohol o la relació entre la resposta al tractament anti-recaiguda i les dades de ressonància magnètica. En resum, al llarg de aquest treball, es demostra que l'ús de dades de ressonància magnètica multimodal en models animals combinats en esquemes analítics multivariats són una eina molt valida en l'enteniment i avanç de patologies psiquiàtriques com l'alcoholisme.
Cosa Liñán, A. (2017). Analytical fusion of multimodal magnetic resonance imaging to identify pathological states in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/90523
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