Alcoholism is responsible for more than 6% of deaths internationally per annum. The development of acute tolerance to ethanol (EtOH) is a critical component of alcoholism. Previous studies identified large conductance calcium-activated potassium (BK) channels as potential EtOH targets in a variety of species and cells. In order to elucidate mechanisms underlying tolerance development, I used inside-out patch clamp techniques to measure EtOH induced changes in channel activity (measured as open probability) of hSlo, hSlo+β1, and hSlo+β4 channels exogenously expressed in HEK 293 cells. I show that the human BK channels have subunit dependent responses to acute application of EtOH, and the magnitude of potentiation was dependent on the concentration of ethanol used and the type of β-subunit expressed. In addition the subunit dependent effects on the channels were a function of cytosolic calcium concentration. Furthermore, to determine if BK channels in ripped-off patches can become tolerant to EtOH, I monitored changes in channel activity in response to a second application of the drug, 10-minutes after washing-out the first exposure. I found that channels were less responsive to the second exposure, indicative of tolerance. I examined long-term consequences of EtOH exposure by repeating these experiments on cells cultured in 25 mM EtOH in the culture medium for 24-hours. Under these conditions, all three channel types show chronic tolerance has developed as revealed by the response to acute EtOH applications. Subunit-dependent differences to the development of acute tolerance were apparent, however. In response to a second application to EtOH, hSlo+β4 channels were now inhibited. Overall, these results indicate that BK channels respond to and develop tolerance to EtOH in the absence of cellular context, suggesting the possibility that alcohol tolerance within organisms may be in part mediated by changes imparted by EtOH on BK channels directly.

Introdução: segundo a literatura, sais de lítio podem produzir redução da função renal. A magnitude dessa informação é debatível, uma vez que não há estudo clínico randomizado e controlado entre usuários de lítio, em sua maioria pacientes com depressão ou transtorno bipolar. A possibilidade do uso do lítio para o tratamento da demência de Alzheimer prodrômica reforça a necessidade de maior investigação de efeitos adversos atribuídos ao lítio, especialmente com relação à função renal. Objetivos: avaliar a segurança da utilização do lítio em baixa dosagem com relação à função renal de pacientes idosos. Como objetivos secundários serão avaliadas: a segurança clínica através de exame e questionário específico, as funções tireoidiana, imunológica e o metabolismo glicêmico. Métodos: estudo randomizado e placebo controlado de 2 anos, seguido de fase aberta por mais 2 anos. Foram avaliados 59 idosos com comprometimento cognitivo leve com seguimento mínimo de dois anos (fase controlada). A função renal foi estimada através das fórmulas aMDRD e CKD- EPI, a partir de exames laboratoriais e dados clínicos coletados durante o estudo. As funções tireoidiana, imunológica e glicêmica foram avaliadas respectivamente através de TSH, T4 livre, leucócitos total, neutrófilos, linfócitos, glicemia e insulinemia de jejum, e HOMA-IR. A segurança clínica foi avaliada através de entrevista sistemática realizada a cada 3 meses, utilizando exame físico e a escala UKU para efeitos adversos. Resultados: não houve piora da função renal com o uso do lítio (litemia entre 0,25-0,5 mmol/l) tanto pela aMDRD (p=0,453) como pela CKD-EPI (p=0,181). Houve aumento significativo de neutrófilos (p=0,038) e do TSH (p=0,034). O grupo lítio apresentou incidência significativamente maior de diabetes mellitus (p=0,037) e arritmias (p=0,028), maior ganho de peso (p=0,015), mais sintomas na escala UKU (p=0,045), e maior interferência dos efeitos adversos do lítio em atividades diárias (p<0,001). Houve correlação entre a opinião de médico e do paciente nas interferências das atividades diárias atribuídas aos sintomas adversos (p<0,001). Conclusões: o uso de lítio em baixa dose não alterou a função renal, produziu alterações no sistema imunológico e tireoidiano sem impacto clínico, e foi seguro clinicamente. As razões do aumento de incidência de diabetes e arritmias merecem investigação posterior / Introduction: according to the literature, lithium salts may produce a reduction in kidney function. The magnitude of this information is debatable because there is no randomized and controlled clinical trial among lithium users, being mostly patients with depression or bipolar disorder. The possibility of using lithium for the treatment of prodromal Alzheimer\'s disease dementia increases the need for further investigation of adverse effects attributed to lithium, especially regarding to renal function. Objectives: To evaluate the safety of using low-dose lithium with respect to renal function in elderly patients. Secondary objectives were the evaluation of the clinical safety through specific questionnaire and clinical assessment, and to assess thyroid, immunological and glycemic function. Methods: a randomized and placebo controlled study for 2 years, followed by an open label follow-up of 2 years. We evaluated 59 elderly patients with mild cognitive impairment with accomplishment of at least two years of the controlled phase. Renal function was estimated by the aMDRD and CKD-EPI equation, and by laboratory and clinical data collected during the trial. The thyroid, immunological and glycemic functions were respectively evaluated by TSH, free T4, leukocyte count, neutrophil count, lymphocyte count, fasting plasma glucose and insulin, and the HOMA-IR. The clinical safety was evaluated through systematic examination performed every 3 months, with physical examination, clinical interview and UKU scale for adverse effects. Results: There was no decline of renal function with the use of lithium (litemia between 0.25-0.5 mmol/l) both in the aMDRD (p=0.453) and CKD-EPI (p=0.181) equations. A significant increase of neutrophils (p=0.038) and TSH (p=0.034) were observed. The lithium group showed significantly higher incidence of diabetes mellitus (p=0.037), arrhythmias (p=0.028), weight gain (p=0.015), more symptoms of UKU scale (p=0.045), and greater interference from the adverse effects of lithium during daily activities (p<0.001). There was an observed correlation between the opinion of the attending physician and the patient in respect to the interference in daily activities secondary to the adverse symptoms (p<0.001). Conclusions: The use of lithium in low doses did not result in renal function impairment, produced subtle changes in the immunological system and thyroid function, and was clinically safe for adverse effects. The reasons for the increased incidence of arrhythmias and diabetes mellitus deserve further investigation

Introdução: segundo a literatura, sais de lítio podem produzir redução da função renal. A magnitude dessa informação é debatível, uma vez que não há estudo clínico randomizado e controlado entre usuários de lítio, em sua maioria pacientes com depressão ou transtorno bipolar. A possibilidade do uso do lítio para o tratamento da demência de Alzheimer prodrômica reforça a necessidade de maior investigação de efeitos adversos atribuídos ao lítio, especialmente com relação à função renal. Objetivos: avaliar a segurança da utilização do lítio em baixa dosagem com relação à função renal de pacientes idosos. Como objetivos secundários serão avaliadas: a segurança clínica através de exame e questionário específico, as funções tireoidiana, imunológica e o metabolismo glicêmico. Métodos: estudo randomizado e placebo controlado de 2 anos, seguido de fase aberta por mais 2 anos. Foram avaliados 59 idosos com comprometimento cognitivo leve com seguimento mínimo de dois anos (fase controlada). A função renal foi estimada através das fórmulas aMDRD e CKD- EPI, a partir de exames laboratoriais e dados clínicos coletados durante o estudo. As funções tireoidiana, imunológica e glicêmica foram avaliadas respectivamente através de TSH, T4 livre, leucócitos total, neutrófilos, linfócitos, glicemia e insulinemia de jejum, e HOMA-IR. A segurança clínica foi avaliada através de entrevista sistemática realizada a cada 3 meses, utilizando exame físico e a escala UKU para efeitos adversos. Resultados: não houve piora da função renal com o uso do lítio (litemia entre 0,25-0,5 mmol/l) tanto pela aMDRD (p=0,453) como pela CKD-EPI (p=0,181). Houve aumento significativo de neutrófilos (p=0,038) e do TSH (p=0,034). O grupo lítio apresentou incidência significativamente maior de diabetes mellitus (p=0,037) e arritmias (p=0,028), maior ganho de peso (p=0,015), mais sintomas na escala UKU (p=0,045), e maior interferência dos efeitos adversos do lítio em atividades diárias (p<0,001). Houve correlação entre a opinião de médico e do paciente nas interferências das atividades diárias atribuídas aos sintomas adversos (p<0,001). Conclusões: o uso de lítio em baixa dose não alterou a função renal, produziu alterações no sistema imunológico e tireoidiano sem impacto clínico, e foi seguro clinicamente. As razões do aumento de incidência de diabetes e arritmias merecem investigação posterior / Introduction: according to the literature, lithium salts may produce a reduction in kidney function. The magnitude of this information is debatable because there is no randomized and controlled clinical trial among lithium users, being mostly patients with depression or bipolar disorder. The possibility of using lithium for the treatment of prodromal Alzheimer\'s disease dementia increases the need for further investigation of adverse effects attributed to lithium, especially regarding to renal function. Objectives: To evaluate the safety of using low-dose lithium with respect to renal function in elderly patients. Secondary objectives were the evaluation of the clinical safety through specific questionnaire and clinical assessment, and to assess thyroid, immunological and glycemic function. Methods: a randomized and placebo controlled study for 2 years, followed by an open label follow-up of 2 years. We evaluated 59 elderly patients with mild cognitive impairment with accomplishment of at least two years of the controlled phase. Renal function was estimated by the aMDRD and CKD-EPI equation, and by laboratory and clinical data collected during the trial. The thyroid, immunological and glycemic functions were respectively evaluated by TSH, free T4, leukocyte count, neutrophil count, lymphocyte count, fasting plasma glucose and insulin, and the HOMA-IR. The clinical safety was evaluated through systematic examination performed every 3 months, with physical examination, clinical interview and UKU scale for adverse effects. Results: There was no decline of renal function with the use of lithium (litemia between 0.25-0.5 mmol/l) both in the aMDRD (p=0.453) and CKD-EPI (p=0.181) equations. A significant increase of neutrophils (p=0.038) and TSH (p=0.034) were observed. The lithium group showed significantly higher incidence of diabetes mellitus (p=0.037), arrhythmias (p=0.028), weight gain (p=0.015), more symptoms of UKU scale (p=0.045), and greater interference from the adverse effects of lithium during daily activities (p<0.001). There was an observed correlation between the opinion of the attending physician and the patient in respect to the interference in daily activities secondary to the adverse symptoms (p<0.001). Conclusions: The use of lithium in low doses did not result in renal function impairment, produced subtle changes in the immunological system and thyroid function, and was clinically safe for adverse effects. The reasons for the increased incidence of arrhythmias and diabetes mellitus deserve further investigation

Indiana University-Purdue University Indianapolis (IUPUI) / Methamphetamine (MA) is a widely abused psychostimulant that has been shown to evoke an array of neurobiological abnormalities and cognitive deficits in humans and in rodent models (Marshall & O'Dell, 2012). Alterations in cognitive function after repeated drug use may lead to impaired decision-making, a lack of behavioral control, and ultimately the inability to abstain from drug use. Human studies have shown that alterations in neurobiology resulting from prolonged MA use may lead to a number of cognitive deficits, including impairments in executive function, learning, memory, and impulsivity. These impairments, specifically those that engage the prefrontal cortex (PFC) or hippocampus (HC), may persist or recover based on the duration of abstinence. In rodents, repeated intermittent injections of MA yield protracted changes in neurobiology and behavior, which have been shown to effectively model a number of the biological and cognitive abnormalities observed in addiction. In order to assess the temporal evolution of impaired cognitive function throughout abstinence, sensitization was first induced in rats (7 x 5.0 mg/kg MA over 14 days). MA-treated rats initially exhibited a robust increase in locomotion that transitioned to stereotypy as the induction phase progressed. Then, the effects of MA sensitization on social interaction (SI), temporal order recognition (TOR) and novel object recognition (NOR) was assessed at one-day and 30-days post induction. No differences were observed in SI in either group or after a single injection of MA. However, an acute injection of 5.0 mg/kg of MA 30-minutes prior to testing dramatically reduced SI time. Impairments in TOR and NOR were observed in MA-treated rats after one day of abstinence, and impairments in TOR, but not NOR, were observed on day 30 of abstinence. No differences in TOR and NOR after a single injection of MA or saline were observed. These data establish that after 30 days of abstinence from a sensitizing regimen of MA, the ability to recall the temporal sequence that two stimuli were encountered was impaired and that was not attributable to impaired novelty detection. These data also suggest that at least some of the neurocognitive abnormalities caused by chronic MA administration may normalize after prolonged abstinence, since the ability to detect novelty recovered after 30 days of abstinence. These data provide compelling support that, since MA-sensitization caused temporal deficits in memory, PFC and HC function may be differentially impaired throughout the time course of abstinence.