O pinguim-de-Magalhães é a espécie de pinguim mais presente em águas jurisdicionais brasileiras e frequente na clínica de animais marinhos, vítimas de desorientação, da poluição, da pesca e outras ações antrópicas. Com o estudo objetivou-se estabelecer as concentrações anestésicas mínimas (CAM) do isofluorano e sevofluorano em pinguins-de-Magalhães e posteriormente avaliá-las sob a influência de diferentes frações inspiradas de O2 (FiO2). Foram utilizados 20 animais adultos, saudáveis e sem distinção quanto ao sexo. Durante a primeira etapa, focou-se no estabelecimento da CAM para ambos os anestésicos. Os animais foram inicialmente submetidos à contenção física e sequencialmente induzidos a anestesia com auxílio de máscara facial, seguindo-se a intubação traqueal, após adequada indução e posterior manutenção sob ventilação controlada, para ambos os halogenados. A determinação da CAM foi realizada de acordo com o delineamento \"up-and-down\". Desta forma, cada animal foi exposto uma única vez a uma concentração anestésica pré-determinada, por um período de 15 minutos, seguido da aplicação de um estímulo elétrico. De acordo com a resposta obtida, o próximo animal foi submetido a uma fração aumentada em 0,1 (resposta positiva) ou reduzida em 0,1 (resposta negativa). Para realização da segunda etapa, 12 animais foram distribuídos entre os grupos isofluorano e sevofluorano, com seis indivíduos em cada um. Todos os animais foram anestesiados e mantidos com 1 CAM de cada halogenado, obtido na primeira etapa, sendo ambos os agentes anestésicos diluídos em frações de 1,0, 0,6, 0,4 e 0,2 de O2. As aves foram mantidas sob anestesia por 80 minutos, sendo que a cada 20 minutos era alterada a fração de O2, por sorteio, seguindo-se um modelo de quadrado latino. Foram monitorados durante a anestesia FC, FR, PAS, PAM, PAD, temperatura, pH, HCO3-, PaO2 e PaCO2 e eletrólitos (Na+ e K+). Os valores de CAM para isofluorano e sevofluorano foram de 1,91 V% e 3,53 V% respectivamente. Diante dos resultados obtidos conclui-se que as FiO2 de 1,0, 0,6 e 0,4 mostram-se seguras para pinguins-de-Magalhães anestesiados com 1 CAM de isofluorano ou sevofluorano mantidos sob ventilação controlada. / The Magellanic penguin is the most present penguin species in Brazilian coast. It is frequent in the marine animal clinic, victims of disorientation, pollution, fishing and other anthropic actions. The objective of this study was to establish the minimum anesthetic concentrations (MAC) of isofluorane and sevoflurane in Magellanic penguins and later evaluate them under the influence of different inspired fractions of O2 (FiO2). Twenty adult animals, healthy and without distinction as to sex, were used. During the first stage, we focused on the establishment of MAC for both anesthetics. The animals were initially submitted to physical restraint and sequentially induced anesthesia with the aid of facial mask, followed by tracheal intubation, after adequate induction and subsequent maintenance under controlled ventilation, for both halogenates. MAC determination was performed according to the up-and-down design. In this way, each animal was exposed once to a predetermined anesthetic concentration, for a period of 15 minutes, followed by the application of an electric stimulus. According to the answer obtained, the next animal was submitted increased by 0.1 fraction (positive response) or reduced by 0.1 (negative response). To perform the second step, 12 animals were divided between the isofluorane and sevofluoran groups, with 6 individuals in each. All animals were anesthetized and maintained with 1 MAC of each halogenated, obtained in the first step, both anesthetic agents being diluted in fractions of 1.0, 0.6, 0.4 and 0.2 of O2. The penguins were kept under anesthesia for 80 minutes, and every 20 minutes the O2 fraction was changed, by lot, followed by a Latin square model. They were monitored during anesthesia FC, FR, PAS, MAP, PAD, temperature, pH, HCO3-, PaO2 and PaCO2 and electrolytes (Na+ and K+). The MAC values for isofluorane and sevoflurane were 1.91 V% and 3.53 V% respectively. In view of these results, FiO2 of 1.0, 0.6 and 0.4 were shown to be safe for Magellanic penguins anesthetized with 1 MAC of isofluorane or sevofluorane maintained under controlled ventilation.

The objective of this study was to investigate a population of identified inhalant users at Intermountain Intertribal School, comparing and contrasting two user groups to a control group of nonusers on a number of selected research variables. The subjects included 42 identified inhalant users. Subjects were further classified into two user groups: one-time users and repeat users, and 20 nonusers. The nonuser group comprised the control group. Each subject was individually interviewed and administered the research and data collection instruments. In addition, other essential information was taken from permanent school records. A one-way analysis of variance was computed to ascertain the relationship between group membership and 11 selected research variables. A discriminant function analysis was computed to determine differences in the 11 research variables as well as to classify and predict group membership. A descriptive analysis of a questionnaire was also reported. Statistically significant differences were found among the three research groups on six of the 11 variables. The discriminant function correctly classified 72% of the subjects, and analysis of the group centroids indicated that the greatest distinctions among the groups were between the nonuser group and the repeat user group. The data present a pattern of inhalant use similar to other populations. The importance of early identification and treatment as well as preventative programs is discussed. Implications of the study and recommendations for further research were made.

Submitted by ROZANA WENDLER DA ROCHA null (rozana_wendler@hotmail.com) on 2016-04-04T14:38:19Z No. of bitstreams: 1 Dissertação_Rozana_Wendler_da_Rocha.pdf: 1573323 bytes, checksum: 6a37403f1c98b1ddce3c6930587f5742 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-04-05T19:46:16Z (GMT) No. of bitstreams: 1 rocha_rw_me_jabo.pdf: 1573323 bytes, checksum: 6a37403f1c98b1ddce3c6930587f5742 (MD5) / Made available in DSpace on 2016-04-05T19:46:16Z (GMT). No. of bitstreams: 1 rocha_rw_me_jabo.pdf: 1573323 bytes, checksum: 6a37403f1c98b1ddce3c6930587f5742 (MD5) Previous issue date: 2016-02-22 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Objetivou-se determinar o efeito do fentanil sobre a concentração anestésica mínima (CAM) do isofluorano em função do tempo em galinhas e avaliar os efeitos cardiorrespiratórios causados por essa associação. A CAM individual de dezessete galinhas foi previamente determinada pelo método bracketing. Os animais foram anestesiados com isofluorano e mantidos sob ventilação controlada para a avaliação do efeito da administração intravenosa única de 10 ou 30 μg/kg de fentanil sobre a CAM do isofluorano. Na etapa seguinte, foram avaliados os efeitos cardiorrespiratórios decorrentes da associação de 30 μg/kg de fentanil em sete galinhas anestesiadas com isofluorano sob ventilação espontânea, por meio do método up-and-down. A redução da CAM do isofluorano em cada intervalo de tempo foi estimada por meio de regressão logística e o intervalo de confiança de Wald de 95 % foi calculado. Os dados das variáveis fisiológicas foram analisados pelo teste Shapiro-Wilk e ANOVA de uma única via com repetições múltiplas, seguido pelo teste de Tukey. Os resultados foram considerados significativos quando p < 0,05. Aos cinco e 15 minutos após a administração de 10 μg/kg de fentanil a redução da CAM foi de 18 % (6,1 a 29,1) e 6 % (-0,6 a 12,9), respectivamente. A aplicação de 30 μg/kg de fentanil reduziu a CAM em 43 % (13,3 a 71,9) e 13 % (-0,9 a 27,3) aos cinco e 15 minutos, respectivamente. As variáveis cardiorrespiratórias das aves anestesiadas com isofluorano isoladamente ou associado à administração de 30 μg/kg de fentanil não diferiram significativamente. O fentanil reduziu de forma dose-dependente a CAM do isofluorano após 5 minutos da administração e não promoveu depressão cardiorrespiratória significativa em galinhas anestesiadas sob ventilação espontânea. Sua aplicabilidade na rotina clínica torna-se limitada, já que a duração do efeito foi curta. / The aim of this study was to evaluate the effect of fentanyl on the isoflurane MAC over time and to evaluate the cardiorespiratory effects caused by this association in chickens. The individual isoflurane MAC of seventeen chickens was previously determined using the bracketing method. Hens were anesthetized with isoflurane under controlled ventilation to evaluate the effects of intravenous administration of 10 or 30 μg kg-1 of fentanyl over isoflurane MAC. In the next stage, cardiorespiratory effects of intravenous administration of 30 μg kg-1 of fentanyl were evaluated in seven chickens anesthetized with isoflurane under spontaneous ventilation through up-and-down method. Reduction of MAC was determined using logistic regression in each time interval and the 95 % Wald confidence interval was calculated. Data from physiological variables was analyzed using the Shapiro-Wilk test and RM one way ANOVA followed by the Tukey’s test. Results were considered significant when p < 0.05. At five and 15 minutes after administration of 10 μg kg-1 IV of fentanyl, isoflurane MAC was reduced by 18 % (6.1 to 29.1) e 6 % (-0.6 to 12.9), respectively. Administration of 30 μg kg-1 IV of fentanyl reduced isoflurane MAC by 43 % (13.3 to 71.9) e 13 % (-0.9 to 27.3) at five and 15 minutes, respectively. Cardiorespiratory data of birds anesthetized with isoflurane alone or associated with fentanyl did not differ. Fentanyl reduced dose-dependent the isoflurane MAC after 5 minutes of administration and did not cause significant cardiorespiratory depression in chickens anesthetized under spontaneous ventilation. Its applicability in clinical practice becomes limited since the duration of effect was short. / CNPq: 475127/2012-9

O pinguim-de-Magalhães é a espécie de pinguim mais presente em águas jurisdicionais brasileiras e frequente na clínica de animais marinhos, vítimas de desorientação, da poluição, da pesca e outras ações antrópicas. Com o estudo objetivou-se estabelecer as concentrações anestésicas mínimas (CAM) do isofluorano e sevofluorano em pinguins-de-Magalhães e posteriormente avaliá-las sob a influência de diferentes frações inspiradas de O2 (FiO2). Foram utilizados 20 animais adultos, saudáveis e sem distinção quanto ao sexo. Durante a primeira etapa, focou-se no estabelecimento da CAM para ambos os anestésicos. Os animais foram inicialmente submetidos à contenção física e sequencialmente induzidos a anestesia com auxílio de máscara facial, seguindo-se a intubação traqueal, após adequada indução e posterior manutenção sob ventilação controlada, para ambos os halogenados. A determinação da CAM foi realizada de acordo com o delineamento \"up-and-down\". Desta forma, cada animal foi exposto uma única vez a uma concentração anestésica pré-determinada, por um período de 15 minutos, seguido da aplicação de um estímulo elétrico. De acordo com a resposta obtida, o próximo animal foi submetido a uma fração aumentada em 0,1 (resposta positiva) ou reduzida em 0,1 (resposta negativa). Para realização da segunda etapa, 12 animais foram distribuídos entre os grupos isofluorano e sevofluorano, com seis indivíduos em cada um. Todos os animais foram anestesiados e mantidos com 1 CAM de cada halogenado, obtido na primeira etapa, sendo ambos os agentes anestésicos diluídos em frações de 1,0, 0,6, 0,4 e 0,2 de O2. As aves foram mantidas sob anestesia por 80 minutos, sendo que a cada 20 minutos era alterada a fração de O2, por sorteio, seguindo-se um modelo de quadrado latino. Foram monitorados durante a anestesia FC, FR, PAS, PAM, PAD, temperatura, pH, HCO3-, PaO2 e PaCO2 e eletrólitos (Na+ e K+). Os valores de CAM para isofluorano e sevofluorano foram de 1,91 V% e 3,53 V% respectivamente. Diante dos resultados obtidos conclui-se que as FiO2 de 1,0, 0,6 e 0,4 mostram-se seguras para pinguins-de-Magalhães anestesiados com 1 CAM de isofluorano ou sevofluorano mantidos sob ventilação controlada. / The Magellanic penguin is the most present penguin species in Brazilian coast. It is frequent in the marine animal clinic, victims of disorientation, pollution, fishing and other anthropic actions. The objective of this study was to establish the minimum anesthetic concentrations (MAC) of isofluorane and sevoflurane in Magellanic penguins and later evaluate them under the influence of different inspired fractions of O2 (FiO2). Twenty adult animals, healthy and without distinction as to sex, were used. During the first stage, we focused on the establishment of MAC for both anesthetics. The animals were initially submitted to physical restraint and sequentially induced anesthesia with the aid of facial mask, followed by tracheal intubation, after adequate induction and subsequent maintenance under controlled ventilation, for both halogenates. MAC determination was performed according to the up-and-down design. In this way, each animal was exposed once to a predetermined anesthetic concentration, for a period of 15 minutes, followed by the application of an electric stimulus. According to the answer obtained, the next animal was submitted increased by 0.1 fraction (positive response) or reduced by 0.1 (negative response). To perform the second step, 12 animals were divided between the isofluorane and sevofluoran groups, with 6 individuals in each. All animals were anesthetized and maintained with 1 MAC of each halogenated, obtained in the first step, both anesthetic agents being diluted in fractions of 1.0, 0.6, 0.4 and 0.2 of O2. The penguins were kept under anesthesia for 80 minutes, and every 20 minutes the O2 fraction was changed, by lot, followed by a Latin square model. They were monitored during anesthesia FC, FR, PAS, MAP, PAD, temperature, pH, HCO3-, PaO2 and PaCO2 and electrolytes (Na+ and K+). The MAC values for isofluorane and sevoflurane were 1.91 V% and 3.53 V% respectively. In view of these results, FiO2 of 1.0, 0.6 and 0.4 were shown to be safe for Magellanic penguins anesthetized with 1 MAC of isofluorane or sevofluorane maintained under controlled ventilation.

ABSTRACT Background: Few studies have focused on early alcohol, tobacco and drug use prior to 18 years of age and their relationship with anxiety; while no study has checked the gender differences of these factors with anxiety. Methods: This study included 6,057 adults with anxiety in the past year and 71,868 controls from the combined data of 2013 and 2014 National Survey on Drug Use and Health (NSDUH). The weighted multiple logistic regression analyses were used to estimate the associations of early alcohol, tobacco and drug use prior to 18 years of age with anxiety. The odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Results: The overall prevalence of anxiety was 6.8% (4.4% and 9.1% for males and females, respectively). Weighted multiple logistic regression showed that cigarettes use, inhalant use, marijuana use and other illicit drugs use revealed significant associations with anxiety (OR = 1.18, 95% CI = 1.04-1.33, OR = 1.31, 95% CI = 1.10-1.56, OR = 1.16, 95% CI = 1.01-1.32, and OR = 1.31, 95% CI = 1.17-1.48, respectively). Stratified by gender, cigarettes use, inhalant use, marijuana use and other illicit drugs use were associated with anxiety in females only. Conclusion: Early tobacco and drug use prior to 18 years of age were found to be associated with increased odds of adult anxiety and that such associations differed by gender.

Introdução: Os anestésicos inalatórios empregados atualmente na prática clinica (isoflurano, sevoflurano e desflurano) possuem propriedades farmacocinéticas que favorecem rápida recuperação da anestesia, porém seu uso pode causar instabilidade hemodinâmica dose-dependente, relacionado à depressão direta da contratilidade miocárdica ou à hipovolemia relativa, derivado de um sequestro de sangue devido à vasodilatação do leito vascular periférico. Este estudo visa avaliar o comportamento da VPP durante a anestesia inalatória. Para tanto se utilizou três diferentes agentes inalatórios (isoflurano, sevoflurano e desflurano) em diferentes concentrações inaladas. Métodos: Foram utilizados 25 suínos divididos aleatoriamente em três grupos. Os animais foram submetidos à anestesia com o anestésico do respectivo grupo. Imediatamente após a determinação da CAM individual do agente inalatório em cada animal, ocorreu a primeira coleta de dados. O animal foi, então, exposto a diferentes níveis de CAM (1,0 CAM; 1,25 CAM) seguido por uma exposição decrescente de CAM (1,0 CAM); provocou-se então uma hemorragia correspondente a 30% da volemia e exposição a dois níveis de CAM (1,0 e 1,25), com 20 minutos em cada exposição. Ao final de cada período os valores ecocardiográficos e do VPP foram mensurados. A análise estatística foi realizada através de provas paramétricas empregando-se o método de comparações múltiplas para análise de variância com medidas repetidas (ANOVA). O grau de significância foi de 5% (p < 0,05). Resultados: Há aumento na variação de pressão de pulso com incremento de 25% na CAM dos anestésicos inalatórios (de 8±1 para 11±3% no grupo DESF, de 7±2 para 9±2 no grupo SEVO e de 9±4 para 10±3% no grupo ISO) sem diferença estatística entre os anestésicos. Apesar deste aumento na CAM e significativa hipotensão e queda no débito cardíaco, o aumento na VPP não torna o paciente responsivo a infusão de fluidos (o VPP permaneceu abaixo de 13%). Há pequena queda na PAM quando se eleva a CAM dos anestésicos em 25%, porém só há queda estatisticamente significativa no grupo DESF (de 84±7 para 68±12 mmHg). Não foram observadas alterações importantes em relação à contratilidade miocárdica. Conclusão: Observou-se que a VPP não é influenciada como o uso dos diferentes anestésicos inalatórios e apesar dos efeitos cardiovasculares esperados destes agentes, mantem-se a capacidade de demonstrar alterações de pré-carga mesmo em concentrações correspondentes a 1,25 CAM / Background: Inhalant anesthetics, such as isoflurane, sevoflurane and desflurane are widely used in daily clinical practice due to its pharmacological properties allowing a rapid recovery from anesthesia. Nevertheless, its use can lead to dose-dependent hemodynamic instability related to direct depression in myocardial contractility or to a relative hypovolemia caused by vasodilation of peripheral capillary bed. This study aims to evaluate the behavior of PPV during inhalant anesthesia. For this, three different anesthetics were used (isoflurane, sevoflurane and desflurane) with different inhaled concentrations. Methods: 25 young pigs were randomly assigned into three groups. Animals were anesthetized with its correspondent agent according to its group. After individual determination of minimal alveolar concentration (MAC), first data collection occurred. Pigs were then exposed to different MAC (1MAC and 1,25 MAC) followed by a decrease in MAC (1 MAC). At this point a 30% of estimated volemia hemorrhage was caused and pigs were exposed to a period of 1 MAC and after that 1,25 MAC. Each period lasted 20 minutes. At the end of each period, hemodynamic parameters and echocardiography were collected. Data were submitted to analysis of variance for repeated measures (ANOVA). P<0,05 was considered statistically significant. Results: There was an increase in PPV when with 1,25 MAC of all anesthetics. (from 8±1 to 11±3% in group DESF, from 7±2 to 9±2 in group SEVO and from 9±4 to 10±3% in group ISO), but without statistical difference among groups. Although there was an increase in PPV, followed by hypotension and drop in cardiac index, patients werent fluid responsive with a 25% increase in MAC, since PPV was lower than 13%. The decrease in blood pressure followed by 1,25MAC was only significant in DESF group (from 84±7 to 68±12 mmHg). No important alterations related to myocardial contractility were observed. Conclusion: PPV is not influenced by the use of different inhalant anesthetics and although there are cardiovascular effects of these agents which are expected, and were able to demonstrate alterations in preload even in concentration of 1,25 MAC

Introdução: Os anestésicos inalatórios empregados atualmente na prática clinica (isoflurano, sevoflurano e desflurano) possuem propriedades farmacocinéticas que favorecem rápida recuperação da anestesia, porém seu uso pode causar instabilidade hemodinâmica dose-dependente, relacionado à depressão direta da contratilidade miocárdica ou à hipovolemia relativa, derivado de um sequestro de sangue devido à vasodilatação do leito vascular periférico. Este estudo visa avaliar o comportamento da VPP durante a anestesia inalatória. Para tanto se utilizou três diferentes agentes inalatórios (isoflurano, sevoflurano e desflurano) em diferentes concentrações inaladas. Métodos: Foram utilizados 25 suínos divididos aleatoriamente em três grupos. Os animais foram submetidos à anestesia com o anestésico do respectivo grupo. Imediatamente após a determinação da CAM individual do agente inalatório em cada animal, ocorreu a primeira coleta de dados. O animal foi, então, exposto a diferentes níveis de CAM (1,0 CAM; 1,25 CAM) seguido por uma exposição decrescente de CAM (1,0 CAM); provocou-se então uma hemorragia correspondente a 30% da volemia e exposição a dois níveis de CAM (1,0 e 1,25), com 20 minutos em cada exposição. Ao final de cada período os valores ecocardiográficos e do VPP foram mensurados. A análise estatística foi realizada através de provas paramétricas empregando-se o método de comparações múltiplas para análise de variância com medidas repetidas (ANOVA). O grau de significância foi de 5% (p < 0,05). Resultados: Há aumento na variação de pressão de pulso com incremento de 25% na CAM dos anestésicos inalatórios (de 8±1 para 11±3% no grupo DESF, de 7±2 para 9±2 no grupo SEVO e de 9±4 para 10±3% no grupo ISO) sem diferença estatística entre os anestésicos. Apesar deste aumento na CAM e significativa hipotensão e queda no débito cardíaco, o aumento na VPP não torna o paciente responsivo a infusão de fluidos (o VPP permaneceu abaixo de 13%). Há pequena queda na PAM quando se eleva a CAM dos anestésicos em 25%, porém só há queda estatisticamente significativa no grupo DESF (de 84±7 para 68±12 mmHg). Não foram observadas alterações importantes em relação à contratilidade miocárdica. Conclusão: Observou-se que a VPP não é influenciada como o uso dos diferentes anestésicos inalatórios e apesar dos efeitos cardiovasculares esperados destes agentes, mantem-se a capacidade de demonstrar alterações de pré-carga mesmo em concentrações correspondentes a 1,25 CAM / Background: Inhalant anesthetics, such as isoflurane, sevoflurane and desflurane are widely used in daily clinical practice due to its pharmacological properties allowing a rapid recovery from anesthesia. Nevertheless, its use can lead to dose-dependent hemodynamic instability related to direct depression in myocardial contractility or to a relative hypovolemia caused by vasodilation of peripheral capillary bed. This study aims to evaluate the behavior of PPV during inhalant anesthesia. For this, three different anesthetics were used (isoflurane, sevoflurane and desflurane) with different inhaled concentrations. Methods: 25 young pigs were randomly assigned into three groups. Animals were anesthetized with its correspondent agent according to its group. After individual determination of minimal alveolar concentration (MAC), first data collection occurred. Pigs were then exposed to different MAC (1MAC and 1,25 MAC) followed by a decrease in MAC (1 MAC). At this point a 30% of estimated volemia hemorrhage was caused and pigs were exposed to a period of 1 MAC and after that 1,25 MAC. Each period lasted 20 minutes. At the end of each period, hemodynamic parameters and echocardiography were collected. Data were submitted to analysis of variance for repeated measures (ANOVA). P<0,05 was considered statistically significant. Results: There was an increase in PPV when with 1,25 MAC of all anesthetics. (from 8±1 to 11±3% in group DESF, from 7±2 to 9±2 in group SEVO and from 9±4 to 10±3% in group ISO), but without statistical difference among groups. Although there was an increase in PPV, followed by hypotension and drop in cardiac index, patients werent fluid responsive with a 25% increase in MAC, since PPV was lower than 13%. The decrease in blood pressure followed by 1,25MAC was only significant in DESF group (from 84±7 to 68±12 mmHg). No important alterations related to myocardial contractility were observed. Conclusion: PPV is not influenced by the use of different inhalant anesthetics and although there are cardiovascular effects of these agents which are expected, and were able to demonstrate alterations in preload even in concentration of 1,25 MAC

The glycine receptor (GlyR) is a ligand-gated ion channel member of the cys-loop receptor superfamily, responsible for inhibitory neurotransmission in the brain and spinal cord. Both glycine and the partial agonist taurine act as endogenous ligands of the GlyR. Taurine-activated GlyR may have a role in the rewarding effects of drugs of abuse, such as ethanol. As a partial agonist, taurine has a decreased efficacy relative to glycine, resulting in a decreased maximum response. We investigated the effects of ethanol, anesthetics, inhalants, and zinc to determine if these allosteric modulators could increase the efficacy of the taurine-activated GlyR. Whole cell recordings of wild type GlyR revealed that each of the allosteric modulators potentiated currents generated by saturating concentrations of taurine but not glycine, implying an increase in efficacy. Zinc is found at GlyR-potentiating concentrations throughout the nervous system, so we examined the combinatorial effects of these allosteric modulators with zinc to mimic in vivo conditions. Whole cell recordings revealed that zinc potentiation of saturating taurine-generated currents decreased further potentiation by another allosteric modulator, indicating no synergistic effects on efficacy. We next investigated the actions of ethanol and isoflurane on the taurine-activated GlyR at the single channel level, finding that both allosteric modulators stabilized the channel open state, increasing the efficacy of the taurine-activated GlyR. We previously identified a mutation in the ligand-binding domain of the GlyR (D97R) that produces spontaneously activating channels, on which taurine has increased efficacy. We identified a residue, R131, as a possible binding partner of D97 in forming an electrostatic interaction that holds the channel in the closed state. We found that disruption of this interaction results in greatly increased taurine efficacy, indicating that efficacy for partial agonists may be determined by agonist ability to break this bond early in the activation process following binding. Thus we find differential mechanisms of allosteric modulation and efficacy determinations for the GlyR when activated by taurine vs. glycine. / text

The glycine receptor (GlyR) is a ligand-gated ion channel member of the cys-loop receptor superfamily, responsible for inhibitory neurotransmission in the brain and spinal cord. Both glycine and the partial agonist taurine act as endogenous ligands of the GlyR. Taurine-activated GlyR may have a role in the rewarding effects of drugs of abuse, such as ethanol. As a partial agonist, taurine has a decreased efficacy relative to glycine, resulting in a decreased maximum response. We investigated the effects of ethanol, anesthetics, inhalants, and zinc to determine if these allosteric modulators could increase the efficacy of the taurine-activated GlyR. Whole cell recordings of wild type GlyR revealed that each of the allosteric modulators potentiated currents generated by saturating concentrations of taurine but not glycine, implying an increase in efficacy. Zinc is found at GlyR-potentiating concentrations throughout the nervous system, so we examined the combinatorial effects of these allosteric modulators with zinc to mimic in vivo conditions. Whole cell recordings revealed that zinc potentiation of saturating taurine-generated currents decreased further potentiation by another allosteric modulator, indicating no synergistic effects on efficacy. We next investigated the actions of ethanol and isoflurane on the taurine-activated GlyR at the single channel level, finding that both allosteric modulators stabilized the channel open state, increasing the efficacy of the taurine-activated GlyR. We previously identified a mutation in the ligand-binding domain of the GlyR (D97R) that produces spontaneously activating channels, on which taurine has increased efficacy. We identified a residue, R131, as a possible binding partner of D97 in forming an electrostatic interaction that holds the channel in the closed state. We found that disruption of this interaction results in greatly increased taurine efficacy, indicating that efficacy for partial agonists may be determined by agonist ability to break this bond early in the activation process following binding. Thus we find differential mechanisms of allosteric modulation and efficacy determinations for the GlyR when activated by taurine vs. glycine. / text

Abstract The aim of this study was to investigate the association between adolescent substance use and psychosis in later life, after taking into account a wide range of known confounders, using data from the Northern Finland Birth Cohort 1986 (N = 9432). Adolescence is a vulnerable neurodevelopmental period, during which many brain maturation processes take place. Substance use during this critical period may disrupt these processes, ultimately leading to mental health problems. Several meta-analyses have demonstrated associations between cannabis use and tobacco smoking and increased risk of psychotic disorders. However, lack of data on the temporal order of the association and uncertainty in relation to the role of confounding factors warranted further studies. Furthermore, there are no longitudinal studies on the association between adolescent inhalant use and psychotic disorders. The study sample consisted of the Northern Finland Birth Cohort 1986. There were 7344 adolescents who participated in the follow-up study in 2001-2002, when they were aged 15-16 years. Adolescents who answered the questions on substance use and psychotic experiences (PROD-screen) were included in the present study. The final sample included 6542 subjects. In this study, an increased risk of psychosis was found in those subjects who had used cannabis five times or more, smoked 10 or more cigarettes daily or had used inhalants 2-4 times or more. Each of these substances were associated with psychosis in a dose-response manner, even after adjustments for confounders. In addition, initiation of daily smoking at 13 years of age or earlier was associated with increased risk of psychosis compared to later initiation. In this comprehensive longitudinal population-based study, frequent cannabis use, daily tobacco smoking and frequent inhalant use in adolescence were independently associated with increased risk of incident psychosis, even after adjusting for confounders such as baseline psychotic experiences, other substance use and history of parental psychosis and substance abuse disorder. The results supply yet another reason to implement effective prevention strategies. / Tiivistelmä Väitöstutkimuksen tarkoituksena oli selvittää, onko teini-iän päihteidenkäytöllä yhteyttä psykoosiin sairastumiseen senkin jälkeen, kun sekoittavat tekijät on huomioitu. Aineistona käytettiin vuoden 1986 Pohjois- Suomen syntymäkohorttia (N = 9 432). Teini-iässä aivot muovautuvat ja kypsyvät nopeasti, minkä vuoksi se on erityisen herkkää aikaa päihteiden haitallisille vaikutuksille. Nuorena aloitettu päihteidenkäyttö saattaa häiritä aivojen kypsymistä, ja kehityksen häiriintyminen voi myöhemmin altistaa mielenterveysongelmille. Aiempien tutkimusten pohjalta tiedetään, että kannabiksen käyttö ja tupakointi ovat yhteydessä korkeampaan riskiin sairastua psykoosiin. Päihteidenkäytön ja psykoosiin sairastumisen välistä ajallista yhteyttä ei olla kuitenkaan aiemmin kyetty tutkimaan vakuuttavasti, eikä huomioon ole otettu nuoruuden aikaisia psykoottisia kokemuksia. Inhalanttien käytön eli imppaamisen yhteydestä psykoosiriskiin ei ole julkaistu yhtään pitkittäistutkimusta. Tutkimusaineisto koostui Pohjois-Suomen syntymäkohortista vuodelta 1986. Vuosina 2001–2002 järjestettyyn seurantatutkimukseen osallistui 7344 15–16- vuotiasta nuorta. Lopullisessa otoksessa (n=6542) huomioitiin henkilöt, jotka vastasivat kysymyksiin psykoottisista kokemuksista ja päihteidenkäytöstä. Kannabiksen käyttö 5 kertaa tai enemmän, päivittäinen tupakointi 10 savuketta tai enemmän ja inhalanttien käyttö 2-4 kertaa tai enemmän olivat yhteydessä korkeampaan riskiin sairastua psykoosiin seurannan aikana sekoittavien tekijöiden huomioimisenkin jälkeen. Tutkittujen päihteiden käyttö kasvatti psykoosiin sairastumisen riskiä päihteen käyttömäärän mukaan. Lisäksi päivittäisen tupakoinnin aloittaminen 13-vuotiaana tai aiemmin oli yhteydessä korkeampaan psykoosiriskiin tupakoinnin myöhemmin aloittaneisiin verrattuna. Tässä suuressa pitkittäisessä, yleisväestöön perustuvassa tutkimuksessa havaittiin, että toistuva kannabiksen käyttö, päivittäinen ja runsas tupakointi sekä toistuva inhalanttien käyttö teini-iässä olivat itsenäisesti yhteydessä kohonneeseen psykoosiriskiin, vaikka aiemmat psykoottiset kokemukset, muu päihdekäyttö, vanhempien psykoosisairaudet ja päihdeongelmat otettiin huomioon. Tulosten perusteella nuorten runsaan päihteidenkäytön ennaltaehkäisy on tärkeää ja sillä on todennäköisesti positiivisia vaikutuksia nuorten mielenterveyteen.