Abstract ESTABLISHING THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE Antipsychotic medications are used to treat schizophrenia. The present study used the drug discrimination paradigm to measure the subjective effects of the atypical antipsychotic amisulpride and to examine the underlying neuropharmacological mechanisms responsible for the discriminative stimulus property of the drug. Male C57BL/6 mice were trained to discriminate 10 mg/kg (-)S amisulpride from vehicle in a two-lever drug discrimination task. A dose effect curve for (-)S amisulpride yielded an ED50 = 1.77 mg/kg 95% CI [1.28, 2.45 mg/kg]. Substitution testing was conducted for the isomer (+)R amisulpride, racemic (±)SR amisulpride, the atypical antipsychotics clozapine, aripiprazole and the typical antipsychotic haloperidol. There was partial substitution for (+)R amisulpride, and full substitution for (±)SR amisulpride with a significant rightward shift in the dose effect curves. Clozapine, aripiprazole, and haloperidol failed to fully substitute with significant rate suppression at the higher doses. These results demonstrated that (-)S amisulpride has a unique discriminative stimulus that differs from other antipsychotic drugs.

No description available.

It is now clear that estrogen not only modulates the differentiation and function of reproductive systems, but it also profoundly regulates the immune system of normal and autoimmune individuals. An important mechanism by which estrogen regulates the immune system is by altering the secretion and/or response to cytokines. We hypothesized that estrogen may alter the levels and/or response to IFN-g, a prototype Th1 cytokine, that plays a pivotal role in immunity against intracellular infections and in many autoimmune and inflammatory disorders. We found that estrogen treatment tended to upregulate the secretion of IFN-g protein and mRNA expression from Concanavalin-A (Con-A)-activated splenic lymphocytes. Impressively, we found that splenocytes from estrogen-treated mice when activated with Con-A also resulted in increased release of nitric oxide compared to placebo-treated mice. Furthermore, Con-A-activated splenocytes from estrogen-treated mice also had upregulated iNOS mRNA, iNOS protein, and nitric oxide-regulated COX-2 protein when compared to control mice. Blocking co-stimulatory signals mediated through interactions of CD28 and B7 molecules by using CTLA-4Ig markedly decreased not only IFN-g, but also nitric oxide, thereby implying an important role for CD28/B7 interactions in IFN-g/nitric oxide. Estrogen-induced upregulation of iNOS/nitric oxide is mediated through IFN-g since: (i) Estrogen alone did not upregulate iNOS/nitric oxide in IFN-g knockout mice; (ii) addition of rIFN-g to activated splenocytes from estrogen-treated mice further upregulated nitric oxide levels. We next investigated whether estrogen also upregulated IFN-g-inducing cytokines and select IFN-g-inducing transcription factors. Estrogen treatment resulted in increased mRNA and/or protein expression of IFN-g inducing cytokines and their receptors, including: IL-18, IL-15, IL-27, IL-12Rb2, and IL-18Rb. We also found that T-bet, a critical Th1 transcription factor, and STAT-4 phosphorylation, a key molecule in IL-12 signaling were both increased, while IRF-4, an important player in Th2 differentiation, was diminished in Con-A-activated splenocytes from mice treated with estrogen. Altogether, these studies are the first to demonstrate that estrogen regulates IFN-g-dependent iNOS and describes the potential mechanisms of how estrogen alters IFN-g-inducible genes, IFN-g inducing cytokines, and transcription factors in normal C57BL/6 mice. These studies may have profound implications to many autoimmune and inflammatory disorders, where estrogen is known to regulate the course of these diseases. Since estrogen may promote inflammatory disorders by upregulating pro-inflammatory biomolecules including IFN-g, nitric oxide, and COX-2, these studies may help in the design of therapeutic agents that regulate or block secretion and/or response to these inflammatory molecules. / Ph. D.

Due to its unique receptor binding profile and its relationship to clozapine, N-desmethylclozapine (NDMC) has been examined as a possible antipsychotic drug (APD). Clozapine has been trained as discriminative stimulus in our lab, but NDMC has not yet been established as a discriminative stimulus. In experiment 1, 12 C57BL/6 mice were trained to discriminate 10.0 mg/kg NDMC from VEH using a standard-two lever operant procedure to assess antipsychotic substitution. The typical APD clozapine fully substituted for NDMC at 2 doses tested (2.5 and 5.0 mg/kg), while typical APD haloperidol failed to substitute for NDMC. In Experiment 2, 11 mice were given repeated administration of NDMC to assess cross-tolerance development to the discriminative stimulus of clozapine. NDMC was successfully trained as a discriminative stimulus and was also shown to induce cross-tolerance to clozapine’s discriminative stimulus, indicating similar underlying pharmacological mechanisms of action between NDMC and clozapine.

O gênero Capsicum compreende mais de 200 espécies de pimentas e pimentões e diversas atividades farmacológicas são descritas na literatura. Estudos prévios do nosso grupo de pesquisa têm explorado diferentes atividades biológicas de Capsicum baccatum var. Pendulum (Solanaceae), como antioxidante, antiinflamatória, hipoglicemiante e antidislipidêmica. A prevalência da síndrome metabólica, caracterizada por fatores como obesidade, resistência à insulina, dislipidemia e hipertensão, tem atingido proporções epidêmicas e acomete cerca de 20% da população mundial. Muitas vezes, apenas a mudança no estilo de vida não é eficaz para impedir a progressão da doença, sendo necessário aderir ao tratamento farmacológico. No entanto, não existem fármacos específicos para o tratamento da síndrome, levando à utilização de polifarmácia, que gera dificuldades de adesão ao tratamento e risco de interações medicamentosas. O principal objetivo desse estudo foi avaliar o efeito do extrato butanólico (BUT) e da fração ativa (AF) dos frutos de C. baccatum em um modelo de síndrome metabólica induzido por dieta em camundongos C57BL/6. Inicialmente apresentamos uma revisão de estudos publicados, que utilizam diferentes tipos de dietas hipercalóricas para induzir a síndrome metabólica em roedores. Ao compararmos esses estudos, observamos a forte tendência à utilização de camundongos da linhagem C57BL/6 machos e jovens, respondendo de forma satisfatória à indução da síndrome metabólica. Após, apresentamos o efeito do BUT e AF, nas doses de 200 e 50 mg/kg, respectivamente, sobre os parâmetros glicídicos e lipídicos em modelo de síndrome metabólica em camundongos C57BL/6 submetidos a uma dieta hiperpalatável (HPD) durante 120 dias. Nesse estudo foi visto que o tratamento com C. baccatum via oral, preveniu o ganho de peso, o desenvolvimento de um perfil de intolerância à glicose, o acúmulo de gordura na região abdominal e a elevação nos níveis de insulina e leptina plasmáticas quando comparados ao grupo HPD. Além disso, também preveniu o acúmulo de colesterol e triglicerídeos no fígado e preservou a morfologia do tecido hepático. Assim, C. baccatum se mostrou promissor, prevenindo alterações dos diversos componentes importantes da síndrome metabólica. / The genus Capsicum comprises more than 200 species of peppers and a range of pharmacological activities are described in the literature. Previous studies of our research group have explored several activities for Capsicum baccatum var. pendulum (Solanaceae) species, as antioxidant, anti-inflammatory, hypoglycemic and antidyslipidemic, since the studies with this species are scarce. The prevalence of metabolic syndrome, characterized by the association of factors such as obesity, insulin resistance, dyslipidemia and hypertension, is reaching epidemic proportions worldwide, affecting approximately 20% of world's population. Often, only lifestyle change is not effective in preventing the progression of the disease, being necessary adherence to pharmacological treatment. However, there are no specific drugs for the treatment of the syndrome, leading to the use of polypharmacy, which generates an increase in public spending, difficulties of adherence to treatment, and enhanced risk to drug interactions. The main objective of this study was to evaluate the effect of butanolic extract (BUT) and the active fraction (AF) of C. baccatum on a model of diet-induced metabolic syndrome in C57BL/6 mice. We first present a review of published studies, which use different types of hypercaloric diets to induce metabolic syndrome in rodents. When comparing these studies, we observed a strong trend towards the use of male and young C57BL/6 mice, responding satisfactorily to the metabolic syndrome induction through hypercaloric diets. After, we present the effect of BUT and AF, on glucose and lipid parameters in a model of metabolic syndrome in C57BL/6 mice submitted to a hyperpalatable diet (HPD) for 120 days. In this study, it was seen that oral C. baccatum treatment prevented weight gain, development of a glucose intolerance profile, accumulation of fat in the abdominal area and the increase in plasma insulin and leptin levels when compared to group HPD. Also, it prevented the accumulation of cholesterol and triglycerides in the liver, and preserved the liver tissue morphology. Thus, these results showed the effects of C. baccatum, especially AF, preventing changes in several important components of the metabolic syndrome.

Voluntary wheel running is rewarding and believed to activate the same brain reward system as in alcohol and drug addiction. Brain-derived neurotrophic factor (BDNF), a well-known growth factor widely expressed in the brain, is modulated by both voluntary exercise and alcohol consumption. The aim of this study was to evaluate how voluntary exercise affects the expression levels of BDNF and its receptor TrkB in brain regions involved in positive and negative reinforcement. Additionally we wanted to evaluate the effect it may have on alcohol drinking behaviors in C57BL/6 mice, a mouse model which are naturally prone for engaging in voluntary exercise and voluntary alcohol consumption. We found a small upregulation in DG and CA1 after three weeks of exercise, confirming findings by others, and a significant 3-fold downregulation of BDNF in NAc after both three weeks of exercise and exercise followed by a five week period of either ethanol intake or not. Interestingly, we here show a significant 100-fold increase in BDNF after exercise and a 120-fold increase after both exercise and alcohol consumption in amygdala, a region involved in regulation of anxiety-related behavior and negative reinforcement. Additionally a slightly lower 10-fold increase in BDNF was seen after exercise and a 15-fold increase after exercise followed by ethanol in prefrontal cortex, a structure contributing to reward-related behavior. Behaviorally, we could not either directly following exercise or at five weeks post-exercise detect any significant effect of wheel-running on depression-related behavior. However, we did find that exercise significantly increased the alcohol intake.

O gênero Capsicum compreende mais de 200 espécies de pimentas e pimentões e diversas atividades farmacológicas são descritas na literatura. Estudos prévios do nosso grupo de pesquisa têm explorado diferentes atividades biológicas de Capsicum baccatum var. Pendulum (Solanaceae), como antioxidante, antiinflamatória, hipoglicemiante e antidislipidêmica. A prevalência da síndrome metabólica, caracterizada por fatores como obesidade, resistência à insulina, dislipidemia e hipertensão, tem atingido proporções epidêmicas e acomete cerca de 20% da população mundial. Muitas vezes, apenas a mudança no estilo de vida não é eficaz para impedir a progressão da doença, sendo necessário aderir ao tratamento farmacológico. No entanto, não existem fármacos específicos para o tratamento da síndrome, levando à utilização de polifarmácia, que gera dificuldades de adesão ao tratamento e risco de interações medicamentosas. O principal objetivo desse estudo foi avaliar o efeito do extrato butanólico (BUT) e da fração ativa (AF) dos frutos de C. baccatum em um modelo de síndrome metabólica induzido por dieta em camundongos C57BL/6. Inicialmente apresentamos uma revisão de estudos publicados, que utilizam diferentes tipos de dietas hipercalóricas para induzir a síndrome metabólica em roedores. Ao compararmos esses estudos, observamos a forte tendência à utilização de camundongos da linhagem C57BL/6 machos e jovens, respondendo de forma satisfatória à indução da síndrome metabólica. Após, apresentamos o efeito do BUT e AF, nas doses de 200 e 50 mg/kg, respectivamente, sobre os parâmetros glicídicos e lipídicos em modelo de síndrome metabólica em camundongos C57BL/6 submetidos a uma dieta hiperpalatável (HPD) durante 120 dias. Nesse estudo foi visto que o tratamento com C. baccatum via oral, preveniu o ganho de peso, o desenvolvimento de um perfil de intolerância à glicose, o acúmulo de gordura na região abdominal e a elevação nos níveis de insulina e leptina plasmáticas quando comparados ao grupo HPD. Além disso, também preveniu o acúmulo de colesterol e triglicerídeos no fígado e preservou a morfologia do tecido hepático. Assim, C. baccatum se mostrou promissor, prevenindo alterações dos diversos componentes importantes da síndrome metabólica. / The genus Capsicum comprises more than 200 species of peppers and a range of pharmacological activities are described in the literature. Previous studies of our research group have explored several activities for Capsicum baccatum var. pendulum (Solanaceae) species, as antioxidant, anti-inflammatory, hypoglycemic and antidyslipidemic, since the studies with this species are scarce. The prevalence of metabolic syndrome, characterized by the association of factors such as obesity, insulin resistance, dyslipidemia and hypertension, is reaching epidemic proportions worldwide, affecting approximately 20% of world's population. Often, only lifestyle change is not effective in preventing the progression of the disease, being necessary adherence to pharmacological treatment. However, there are no specific drugs for the treatment of the syndrome, leading to the use of polypharmacy, which generates an increase in public spending, difficulties of adherence to treatment, and enhanced risk to drug interactions. The main objective of this study was to evaluate the effect of butanolic extract (BUT) and the active fraction (AF) of C. baccatum on a model of diet-induced metabolic syndrome in C57BL/6 mice. We first present a review of published studies, which use different types of hypercaloric diets to induce metabolic syndrome in rodents. When comparing these studies, we observed a strong trend towards the use of male and young C57BL/6 mice, responding satisfactorily to the metabolic syndrome induction through hypercaloric diets. After, we present the effect of BUT and AF, on glucose and lipid parameters in a model of metabolic syndrome in C57BL/6 mice submitted to a hyperpalatable diet (HPD) for 120 days. In this study, it was seen that oral C. baccatum treatment prevented weight gain, development of a glucose intolerance profile, accumulation of fat in the abdominal area and the increase in plasma insulin and leptin levels when compared to group HPD. Also, it prevented the accumulation of cholesterol and triglycerides in the liver, and preserved the liver tissue morphology. Thus, these results showed the effects of C. baccatum, especially AF, preventing changes in several important components of the metabolic syndrome.

O gênero Capsicum compreende mais de 200 espécies de pimentas e pimentões e diversas atividades farmacológicas são descritas na literatura. Estudos prévios do nosso grupo de pesquisa têm explorado diferentes atividades biológicas de Capsicum baccatum var. Pendulum (Solanaceae), como antioxidante, antiinflamatória, hipoglicemiante e antidislipidêmica. A prevalência da síndrome metabólica, caracterizada por fatores como obesidade, resistência à insulina, dislipidemia e hipertensão, tem atingido proporções epidêmicas e acomete cerca de 20% da população mundial. Muitas vezes, apenas a mudança no estilo de vida não é eficaz para impedir a progressão da doença, sendo necessário aderir ao tratamento farmacológico. No entanto, não existem fármacos específicos para o tratamento da síndrome, levando à utilização de polifarmácia, que gera dificuldades de adesão ao tratamento e risco de interações medicamentosas. O principal objetivo desse estudo foi avaliar o efeito do extrato butanólico (BUT) e da fração ativa (AF) dos frutos de C. baccatum em um modelo de síndrome metabólica induzido por dieta em camundongos C57BL/6. Inicialmente apresentamos uma revisão de estudos publicados, que utilizam diferentes tipos de dietas hipercalóricas para induzir a síndrome metabólica em roedores. Ao compararmos esses estudos, observamos a forte tendência à utilização de camundongos da linhagem C57BL/6 machos e jovens, respondendo de forma satisfatória à indução da síndrome metabólica. Após, apresentamos o efeito do BUT e AF, nas doses de 200 e 50 mg/kg, respectivamente, sobre os parâmetros glicídicos e lipídicos em modelo de síndrome metabólica em camundongos C57BL/6 submetidos a uma dieta hiperpalatável (HPD) durante 120 dias. Nesse estudo foi visto que o tratamento com C. baccatum via oral, preveniu o ganho de peso, o desenvolvimento de um perfil de intolerância à glicose, o acúmulo de gordura na região abdominal e a elevação nos níveis de insulina e leptina plasmáticas quando comparados ao grupo HPD. Além disso, também preveniu o acúmulo de colesterol e triglicerídeos no fígado e preservou a morfologia do tecido hepático. Assim, C. baccatum se mostrou promissor, prevenindo alterações dos diversos componentes importantes da síndrome metabólica. / The genus Capsicum comprises more than 200 species of peppers and a range of pharmacological activities are described in the literature. Previous studies of our research group have explored several activities for Capsicum baccatum var. pendulum (Solanaceae) species, as antioxidant, anti-inflammatory, hypoglycemic and antidyslipidemic, since the studies with this species are scarce. The prevalence of metabolic syndrome, characterized by the association of factors such as obesity, insulin resistance, dyslipidemia and hypertension, is reaching epidemic proportions worldwide, affecting approximately 20% of world's population. Often, only lifestyle change is not effective in preventing the progression of the disease, being necessary adherence to pharmacological treatment. However, there are no specific drugs for the treatment of the syndrome, leading to the use of polypharmacy, which generates an increase in public spending, difficulties of adherence to treatment, and enhanced risk to drug interactions. The main objective of this study was to evaluate the effect of butanolic extract (BUT) and the active fraction (AF) of C. baccatum on a model of diet-induced metabolic syndrome in C57BL/6 mice. We first present a review of published studies, which use different types of hypercaloric diets to induce metabolic syndrome in rodents. When comparing these studies, we observed a strong trend towards the use of male and young C57BL/6 mice, responding satisfactorily to the metabolic syndrome induction through hypercaloric diets. After, we present the effect of BUT and AF, on glucose and lipid parameters in a model of metabolic syndrome in C57BL/6 mice submitted to a hyperpalatable diet (HPD) for 120 days. In this study, it was seen that oral C. baccatum treatment prevented weight gain, development of a glucose intolerance profile, accumulation of fat in the abdominal area and the increase in plasma insulin and leptin levels when compared to group HPD. Also, it prevented the accumulation of cholesterol and triglycerides in the liver, and preserved the liver tissue morphology. Thus, these results showed the effects of C. baccatum, especially AF, preventing changes in several important components of the metabolic syndrome.

No description available.

All five classes of vertebrates use the geomagnetic field for spatial orientation. The geomagnetic field can be used to derive both 'map' and 'compass' information. There is evidence for two different mechanisms used to sense the magnetic field, the radical pair mechanism (RPM) and the magnetite based mechanism (MBM). C57BL/6 laboratory mice can rely on directional information from the magnetic field to position their nests and to solve a water maze task. The primary objective of this research was to characterize the magnetic compass of C57BL/6 laboratory mice in the plus water maze task. These experiments explored sources of variation in magnetic responses and investigated the underlying magnetic compass orientation mechanism in C57BL/6 mice. The results provide evidence that the mouse magnetic compass is sensitive to low-level radiofrequency fields, consistent with the use of the RPM for magnetic orientation. Surprisingly, the results also suggest that C57BL/6 mice have a polarity sensitive compass, consistent with the use of a MBM for magnetic orientation. These experiments confirm that mice have a specialized magnetic compass sense. Furthermore, despite the controlled environment in which these laboratory experiments were conducted, a variety of factors can increase the variability in the response. Future experiments are needed to further characterize the mouse magnetic compass, as there is a possibility of a hybrid magnetic response where both magnetoreception mechanisms could be used for spatial orientation. / Master of Science