Circadian rhythms dictate the timing of both once-in-a-lifetime adult emergence (eclosion) and daily locomotor activity rhythms in the flesh fly S. crassipalpis. Light cycles are considered the primary environmental time cue (zeitgeber), but the life history of S. crassipalpis suggests that temperature cycles (thermocycles) may also play a key role. This work evaluates the efficacy of thermocycling as a zeitgeber in S. crassipalpis. We found that shifting both light and temperature cycles of sufficient amplitude affect the phasing of eclosion and locomotor activity, but result in different patterns. Additional experiments suggest greater thermocycle sensitivity during the late metamorphic period and that thermocycling reduces variance in eclosion times. Taken together, these findings suggest that temperature cycles can be used by S. crassipalpis to time eclosion and adult locomotor activity, and that S. crassipalpis may be physiologically primed to use thermocycle information during metamorphosis.

Fluoxetine and escitalopram are the only antidepressants approved by the Food and Drug Administration of the United States of America (FDA) for treatment of major depression in children and adolescents. Both drugs are selective serotonin reuptake inhibitors (SSRIs). In recent years there has been a growing concern over the long-term developmental effects of early-life exposure to SSRIs. The current study employed male Flinders Sensitive Line (FSL) rats, a well described and validated translational model of depression, to investigate the long term effects of pre-pubertal fluoxetine exposure. First we examined the effect of such early-life exposure on the development of depressive-like behaviour, locomotor activity and anxiety-like behaviour as manifested in early adulthood. Next, the current study investigated the effect of pre-pubertal fluoxetine exposure on the acute monoaminergic stress response, as displayed later in life. Animals received either saline (vehicle control), or 10 mg/kg/day fluoxetine from postnatal day (ND+) 21 to ND+34 (pre-puberty). The treatment period was chosen to coincide with a developmental phase where the serotonergic system’s neurodevelopment had been completed, yet the noradrenergic and dopaminergic systems had not, a scenario comparable to neurodevelopment in human adolescents. Both behavioural and in vivo intra-cerebral microdialysis experiments were conducted after ND+60 (early adulthood). On ND+60 rats allocated to behavioural experiments were evaluated for depressive-like behaviour in the forced swim test (FST), locomotor activity in the open field test (OFT), and anxiety-like behaviour in the OFT. Corticosterone concentrations were shown to be significantly higher in male FSL rats exposed to a 10 minute forced swim stress when compared to male FSL rats not exposed to a forced swim stress on ND+60. In the microdialysis experiments the rats were exposed to an acute 10 minute forced swim stress and the concentrations of the monoamines and their metabolites were measured before, during, and after the acute stressor. Relative to saline-treated (control) rats, fluoxetine-treated FSL rats did not show long-term changes in immobility in the FST (i.e. no anti-depressant-like activity) on ND+60. Like-wise anxiety-like behaviour in the OFT did not change. However, a significant decrease in locomotor activity was observed in fluoxetine-treated FSL rats compared to saline-treated (control) rats. These data suggest that a long-lasting anti-depressant-like effect of fluoxetine may be masked by the effect on locomotor activity. With measurements from the microdialysis experiments a significant attenuation of the noradrenergic stress response was observed in fluoxetine-treated rats compared to saline controls. A similar picture was observed for 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin (5-HT), although the latter was not statistically significant. At baseline, before the stressor, significant increase in dopamine (DA) levels were observed in fluoxetine treated rats when compared to saline controls, suggesting that enhanced dopamine neurotransmission may comprise a long-term effect of pre-pubertal fluoxetine treatment. There were no discernible differences in homovanilllic acid (HVA) concentrations between fluoxetine-treated rats and saline controls. In conclusion significant developmental effects of pre-pubertal fluoxetine exposure were observed later in life and these findings warrant further investigation. / MPharm (Pharmacology), North-West University, Potchefstroom Campus, 2015

Fluoxetine and escitalopram are the only antidepressants approved by the Food and Drug Administration of the United States of America (FDA) for treatment of major depression in children and adolescents. Both drugs are selective serotonin reuptake inhibitors (SSRIs). In recent years there has been a growing concern over the long-term developmental effects of early-life exposure to SSRIs. The current study employed male Flinders Sensitive Line (FSL) rats, a well described and validated translational model of depression, to investigate the long term effects of pre-pubertal fluoxetine exposure. First we examined the effect of such early-life exposure on the development of depressive-like behaviour, locomotor activity and anxiety-like behaviour as manifested in early adulthood. Next, the current study investigated the effect of pre-pubertal fluoxetine exposure on the acute monoaminergic stress response, as displayed later in life. Animals received either saline (vehicle control), or 10 mg/kg/day fluoxetine from postnatal day (ND+) 21 to ND+34 (pre-puberty). The treatment period was chosen to coincide with a developmental phase where the serotonergic system’s neurodevelopment had been completed, yet the noradrenergic and dopaminergic systems had not, a scenario comparable to neurodevelopment in human adolescents. Both behavioural and in vivo intra-cerebral microdialysis experiments were conducted after ND+60 (early adulthood). On ND+60 rats allocated to behavioural experiments were evaluated for depressive-like behaviour in the forced swim test (FST), locomotor activity in the open field test (OFT), and anxiety-like behaviour in the OFT. Corticosterone concentrations were shown to be significantly higher in male FSL rats exposed to a 10 minute forced swim stress when compared to male FSL rats not exposed to a forced swim stress on ND+60. In the microdialysis experiments the rats were exposed to an acute 10 minute forced swim stress and the concentrations of the monoamines and their metabolites were measured before, during, and after the acute stressor. Relative to saline-treated (control) rats, fluoxetine-treated FSL rats did not show long-term changes in immobility in the FST (i.e. no anti-depressant-like activity) on ND+60. Like-wise anxiety-like behaviour in the OFT did not change. However, a significant decrease in locomotor activity was observed in fluoxetine-treated FSL rats compared to saline-treated (control) rats. These data suggest that a long-lasting anti-depressant-like effect of fluoxetine may be masked by the effect on locomotor activity. With measurements from the microdialysis experiments a significant attenuation of the noradrenergic stress response was observed in fluoxetine-treated rats compared to saline controls. A similar picture was observed for 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin (5-HT), although the latter was not statistically significant. At baseline, before the stressor, significant increase in dopamine (DA) levels were observed in fluoxetine treated rats when compared to saline controls, suggesting that enhanced dopamine neurotransmission may comprise a long-term effect of pre-pubertal fluoxetine treatment. There were no discernible differences in homovanilllic acid (HVA) concentrations between fluoxetine-treated rats and saline controls. In conclusion significant developmental effects of pre-pubertal fluoxetine exposure were observed later in life and these findings warrant further investigation. / MPharm (Pharmacology), North-West University, Potchefstroom Campus, 2015

O estresse por isolamento social aplicado em ratos a partir do desmame e mantido durante o desenvolvimento encefálico tem sido utilizado como um modelo experimental de desordens psiquiátricas como a esquizofrenia. Tem sido demonstrado que o isolamento induz alterações morfológicas, comportamentais (como hiperatividade em um novo ambiente) e neuroquímicas semelhantes àquelas que ocorrem em humanos esquizofrênicos. Evidências sugerem que as sinapses glutamatérgicas sejam o sitio primário das anormalidades que ocorrem na esquizofrenia, sendo as alterações dopaminérgicas secundárias às glutamatérgicas. Nesse sentido, alterações nos mecanismos de regulação desta neurotransmissão pelos transportadores de glutamato podem contribuir para o desenvolvimento e/ou manutenção da esquizofrenia. Neste estudo analisamos o padrão de atividade locomotora e a expressão de transportadores de glutamato (EAAC1 e GLT1) no córtex pré-frontal e córtex entorrinal de ratos criados em isolamento a partir do desmame. Ratos Wistar machos (PND21) foram aleatoriamente alocados em 2 grupos (n=11-12): controle (agrupados, 3 animais/caixa) ou isolados (1 animal/caixa) por 10 semanas. Os animais foram testados no campo aberto (arena) durante 20 min. e registrados: números de cruzamentos (exploração horizontal), número de levantamentos (exploração vertical) e tempo despendido, tanto no centro como na periferia da arena. Os grupos foram comparados utilizando ANOVA ou teste t de Student (significante quando p 0.05). Os animais foram anestesiados (uretana-Sigma, 25%, 5ml/kg), perfundidos e os encéfalos retirados, congelados e posteriormente utilizados nos experimentos de imunoistoquímica. Secções (40m) do córtex pré-frontal (CPF) e córtex entorrinal (CE) foram utilizadas para o estudo da expressão de EAAC1 e GLT1. A criação em isolamento induziu hiperatividade, com um aumento no número total de cruzamentos em relação aos animais agrupados (F1,22=0,38; p<0,05), sendo mais consistente na periferia da arena e após 5 minutos de teste (73%, (F1,22=14,08; p<0,001). Em contraste, o isolamento induziu redução no número total de levantamentos (F1,22=0,27; p=0,05), principalmente no centro da arena (58%, F1,22=12,48; p<0,01), nos primeiros 15 minutos de teste e significante no 1° e 3° blocos de tempo (BT1 e BT3). Na periferia o isolamento induziu aumento significante no número de levantamentos em BT2 e BT3. O tempo despendido no centro e na periferia da arena pelos animais criados em isolamento foi, respectivamente, reduzido (54%; F1,22=11,11; p<0,001) e aumentado (65%; F1,22=11,20; p<0,01) quando comparados aos animais agrupados. A expressão de EAAC1 foi significantemente aumentada pelo isolamento no CPF (38%, t= 2,730, p=0,017). Em contraste, nenhuma diferença foi encontrada no CE (t= 1,892; p= 0,081). O isolamento não induziu alteração no número de células imunopositivas para GLT1 no CPF (t=-1,28; p=0,21). Entretanto, marcação fluorescente de GLT1 foi observada associada a células gliais e neuroniais do CPF e CE. Os resultados comportamentais sugerem: i) ratos Wistar criados em isolamento social apresentam hiperatividade em novo ambiente; ii) a hiperatividade locomotora somente é detectável após períodos maiores que cinco minutos de exposição a um novo ambiente; iii) o padrão de exploração apresentado pelos animais demonstra clara preferência pela periferia da arena. Os resultados moleculares fornecem evidências para a participação dos transportadores de glutamato na redução da neurotransmissão glutamatérgica no CPF de ratos criados em isolamento a partir do desmame. / Isolation rearing of rats from weaning has been used as an experimental model of psychiatric disorders like schizophrenia. It has been demonstrated that isolation induces morphological, behavioral (like hyperactivity in a novel environment) and neurochemical changes similar to those reported for humans with schizophrenia. Evidence suggest that glutamatergic synapses might be the site of primary abnormalities in this disorder with the dopaminergic changes being secundary to the glutamatergic ones. In this context, changes on the mechanisms of regulation of the glutamatergic neurotransmission through glutamate transporters may contribute to the development and/or maintenance of schizophrenia. In this study we analyzed the pattern of locomotor activity and the expression of glutamate transporters (EAAC1 and GLT1) in prefrontal cortex and entorhinal cortex of rats reared in social isolation from weaning. Male Wistar rats (PND 21) were randomly allocated in 2 groups (n=11-12): control (grouped, 3 animals/cage) or isolated (1 animal/cage) for 10 weeks. The animals were tested in the open field (arena) for 20min. and recorded: number of crossings (horizontal exploration), number of rearings (vertical exploration) and time spent either at the center or at the periphery of the arena. The groups were compared using ANOVA or Sudents \"t\" test (significance level was set at p 0.05). The animals were anesthetized (urethane-Sigma, 25%, 5ml/kg), perfused and the brains removed, frozen and further used on the experiments of immunohistochemistry. Sections (40m) of the prefrontal córtex (PFC) and entorhinal córtex (EC) were used for studying the expression of EAAC1 and GLT1. Isolation rearing induced hyperactivity, with an increase in the number of crossings related to grouped animals (F1,22=0,38; p<0,05), being more consistent at the periphery of the arena and after 5 minutes of test (F1,22=14,08; p<0,001). In contrast, isolation induced a decrease in the total number of rearings (F1,22=0,27; p=0,05), mainly in the center of the arena (58%, F1,22=12,48; p<0,01), in the first 15 minutes of test and significant on the 1st and 3rd blocks of time (BT1 e BT3). In the periphery isolation induced a significant increase in the number of rearings in BT2 and BT3. The time spent in both center and periphery of the arena by the rats reared in isolation was, respectively, decreased (54%; F1,22=11,11; p<0,01) and increased (65%; F1,22=11,20; p<0,01) when compared to grouped rats. The expression of EAAC1 was significantly increased by isolation in PFC (38%, t = 2,730, p = 0,017). In contrast, no change was found in EC (t = 1,892, p = 0,081). Isolation rearing did not induce alterations in the number of immunopositive cells for GLT1 in PFC (t= -1,28; p = 0,21). However, fluorescent labeling of GLT1 was seen associated to both glial cells and neuronal cells. The behavioral results suggest: i) Wistar rats reared in social isolation present hyperactivity in a novel environment; ii) the hyperactivity is only detectable after periods longer than 5 minutes; iii) the pattern of exploration showed by the animals demonstrate clear preference for the periphery of the arena. The molecular results provide evidence for the involvement of glutamate transporters on the reduction of glutamatergic neurotranmission in PFC of rats reared in isolation from weaning.

No description available.

Made available in DSpace on 2015-02-24T20:13:54Z (GMT). No. of bitstreams: 1 JoaoMGR_DISSERT.pdf: 11548329 bytes, checksum: b018f7ac6bfdefc0440cb7355ab6ae06 (MD5) Previous issue date: 2011-12-08 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / The circadian behavior associated with the 24 hours light-dark (LD) cycle (T24) is due to a circadian clock , which in mammals is located in the hypothalamic suprachiasmatic nucleus (SCN). Under experimental conditions in which rats are espoused to a symmetric LD 22h cycle (T22) the two SCN regions, ventrolateral (vl) and dorsomedial (dm), can be functionally isolated, suggesting that each region regulates distinct physiological and behavioral components. The vl region regulates the locomotor activity and slow wave sleep (SWS) rhythms, while the dm region assures the body temperature and paradoxical sleep (PS) rhythms regulation. This research aimed to deepen the knowledge on the functional properties of circadian rhythmicity, specifically about the internal desynchronization process, and its consequences to locomotor activity and body temperature rhythms as well as to the sleep-wake cycle pattern in rats. We applied infrared motion sensors, implanted body temperature sensors and a telemetry system to record electrocorticogram (ECoG) and electromyogram (EMG) in two rat groups. The control group under 24h period LD cycle (T24: 12hL-12hD) to the baseline record and the experimental group under 22h period LD cycle (T22: 11hL- 11hD), in which is known to occur the uncoupling process of the circadian locomotor activity rhythm where the animals show two distinct locomotor activity rhythms: one synchronized to the external LD cycle, and another expressed in free running course, with period greater than 24h. As a result of 22h cycles, characteristic locomotor activity moment appear, that are coincidence moments (T22C) and non coincidence moments (T22NC) which were the main focus or our study. Our results show an increase in locomotor activity, especially in coincidence moments, and the inversion of locomotor activity, body temperature, and sleep-wake cycle patterns in non coincidence moments. We can also observe the increase in SWS and decrease in PS, both in coincidence and non coincidence moments. Probably the increases in locomotor activity as a way to promote the coupling between circadian oscillators generate an increased homeostatic pressure and thus increase SWS, promoting the decreasing in PS / O comportamento circadiano associado ao ciclo di?rio de 24 horas deve-se ? a??o de um rel?gio circadiano que em mam?feros se localiza nos n?cleos supraquiasm?ticos do hipot?lamo (NSQs). Sob condi??es experimentais em que ratos s?o submetidos a um ciclo claro-escuro (CE) sim?trico de 22h (T22) as regi?es ventrolateral (vl) e dorsomedial (dm) dos NSQs podem ser separadas funcionalmente, sugerindo que cada regi?o regula vari?veis fisiol?gicas distintas. A regi?o vl regula os ritmos de atividade e sono de ondas lentas (SOL), enquanto a regi?o dm ? respons?vel pelo ritmo da temperatura corporal e sono paradoxal (SP). A investiga??o desenvolvida no presente trabalho visou aprofundar o conhecimento sobre as propriedades funcionais da ritmicidade circadiana, mais especificamente sobre o processo da dessincroniza??o interna e as suas implica??es no ritmo de atividade locomotora, temperatura corporal e padr?o do ciclo sono-vig?lia em ratos. Com este objetivo, foram utilizados sensores de movimentos por infravermelho e implantados sensores para temperatura corporal, al?m disso o sistema de telemetria foi utilizado para o registro de par?metros fisiol?gicos de eletrocorticograma (ECoG) e eletromiograma (EMG), em dois grupos de animais. O grupo controle sob ciclo claro-escuro com per?odo de T24 (12h claro: 12h escuro), para o registro basal das vari?veis em an?lise; e o grupo experimental sob ciclo claro-escuro com per?odo de T22 (11h claro: 11h escuro), no qual se sabe que ocorre o desacoplamento do ritmo circadiano de atividade locomotora e os animais apresentam dois componentes distintos de atividade: um sincronizado ao ciclo claro-escuro; e outro que se expressa em livre curso, com per?odo maior que 24h. Em decorr?ncia do protocolo de dessincroniza??o for?ada, surgem momentos caracter?sticos no perfil de atividade locomotora: momentos de coincid?ncia (T22C) e de n?o coincid?ncia (T22NC), que foram o foco principal do nosso estudo. Podemos observar o aumento de atividade locomotora principalmente em momentos de coincid?ncia, e a invers?o do padr?o de atividade locomotora, temperatura corporal e ciclo sono-vig?lia em momentos de n?o coincid?ncia. Podemos ainda observar o aumento do SOL e diminui??o do SP, tanto em momentos de coincid?ncia como em momentos de n?o coincid?ncia. ? prov?vel que o aumento da atividade locomotora como forma de facilitar o acoplamento entre os osciladores circadianos gere um aumento da press?o homeost?tica e com isso aumento de SOL, e diminui a dura??o de SP

O estresse por isolamento social aplicado em ratos a partir do desmame e mantido durante o desenvolvimento encefálico tem sido utilizado como um modelo experimental de desordens psiquiátricas como a esquizofrenia. Tem sido demonstrado que o isolamento induz alterações morfológicas, comportamentais (como hiperatividade em um novo ambiente) e neuroquímicas semelhantes àquelas que ocorrem em humanos esquizofrênicos. Evidências sugerem que as sinapses glutamatérgicas sejam o sitio primário das anormalidades que ocorrem na esquizofrenia, sendo as alterações dopaminérgicas secundárias às glutamatérgicas. Nesse sentido, alterações nos mecanismos de regulação desta neurotransmissão pelos transportadores de glutamato podem contribuir para o desenvolvimento e/ou manutenção da esquizofrenia. Neste estudo analisamos o padrão de atividade locomotora e a expressão de transportadores de glutamato (EAAC1 e GLT1) no córtex pré-frontal e córtex entorrinal de ratos criados em isolamento a partir do desmame. Ratos Wistar machos (PND21) foram aleatoriamente alocados em 2 grupos (n=11-12): controle (agrupados, 3 animais/caixa) ou isolados (1 animal/caixa) por 10 semanas. Os animais foram testados no campo aberto (arena) durante 20 min. e registrados: números de cruzamentos (exploração horizontal), número de levantamentos (exploração vertical) e tempo despendido, tanto no centro como na periferia da arena. Os grupos foram comparados utilizando ANOVA ou teste t de Student (significante quando p 0.05). Os animais foram anestesiados (uretana-Sigma, 25%, 5ml/kg), perfundidos e os encéfalos retirados, congelados e posteriormente utilizados nos experimentos de imunoistoquímica. Secções (40m) do córtex pré-frontal (CPF) e córtex entorrinal (CE) foram utilizadas para o estudo da expressão de EAAC1 e GLT1. A criação em isolamento induziu hiperatividade, com um aumento no número total de cruzamentos em relação aos animais agrupados (F1,22=0,38; p<0,05), sendo mais consistente na periferia da arena e após 5 minutos de teste (73%, (F1,22=14,08; p<0,001). Em contraste, o isolamento induziu redução no número total de levantamentos (F1,22=0,27; p=0,05), principalmente no centro da arena (58%, F1,22=12,48; p<0,01), nos primeiros 15 minutos de teste e significante no 1° e 3° blocos de tempo (BT1 e BT3). Na periferia o isolamento induziu aumento significante no número de levantamentos em BT2 e BT3. O tempo despendido no centro e na periferia da arena pelos animais criados em isolamento foi, respectivamente, reduzido (54%; F1,22=11,11; p<0,001) e aumentado (65%; F1,22=11,20; p<0,01) quando comparados aos animais agrupados. A expressão de EAAC1 foi significantemente aumentada pelo isolamento no CPF (38%, t= 2,730, p=0,017). Em contraste, nenhuma diferença foi encontrada no CE (t= 1,892; p= 0,081). O isolamento não induziu alteração no número de células imunopositivas para GLT1 no CPF (t=-1,28; p=0,21). Entretanto, marcação fluorescente de GLT1 foi observada associada a células gliais e neuroniais do CPF e CE. Os resultados comportamentais sugerem: i) ratos Wistar criados em isolamento social apresentam hiperatividade em novo ambiente; ii) a hiperatividade locomotora somente é detectável após períodos maiores que cinco minutos de exposição a um novo ambiente; iii) o padrão de exploração apresentado pelos animais demonstra clara preferência pela periferia da arena. Os resultados moleculares fornecem evidências para a participação dos transportadores de glutamato na redução da neurotransmissão glutamatérgica no CPF de ratos criados em isolamento a partir do desmame. / Isolation rearing of rats from weaning has been used as an experimental model of psychiatric disorders like schizophrenia. It has been demonstrated that isolation induces morphological, behavioral (like hyperactivity in a novel environment) and neurochemical changes similar to those reported for humans with schizophrenia. Evidence suggest that glutamatergic synapses might be the site of primary abnormalities in this disorder with the dopaminergic changes being secundary to the glutamatergic ones. In this context, changes on the mechanisms of regulation of the glutamatergic neurotransmission through glutamate transporters may contribute to the development and/or maintenance of schizophrenia. In this study we analyzed the pattern of locomotor activity and the expression of glutamate transporters (EAAC1 and GLT1) in prefrontal cortex and entorhinal cortex of rats reared in social isolation from weaning. Male Wistar rats (PND 21) were randomly allocated in 2 groups (n=11-12): control (grouped, 3 animals/cage) or isolated (1 animal/cage) for 10 weeks. The animals were tested in the open field (arena) for 20min. and recorded: number of crossings (horizontal exploration), number of rearings (vertical exploration) and time spent either at the center or at the periphery of the arena. The groups were compared using ANOVA or Sudents \"t\" test (significance level was set at p 0.05). The animals were anesthetized (urethane-Sigma, 25%, 5ml/kg), perfused and the brains removed, frozen and further used on the experiments of immunohistochemistry. Sections (40m) of the prefrontal córtex (PFC) and entorhinal córtex (EC) were used for studying the expression of EAAC1 and GLT1. Isolation rearing induced hyperactivity, with an increase in the number of crossings related to grouped animals (F1,22=0,38; p<0,05), being more consistent at the periphery of the arena and after 5 minutes of test (F1,22=14,08; p<0,001). In contrast, isolation induced a decrease in the total number of rearings (F1,22=0,27; p=0,05), mainly in the center of the arena (58%, F1,22=12,48; p<0,01), in the first 15 minutes of test and significant on the 1st and 3rd blocks of time (BT1 e BT3). In the periphery isolation induced a significant increase in the number of rearings in BT2 and BT3. The time spent in both center and periphery of the arena by the rats reared in isolation was, respectively, decreased (54%; F1,22=11,11; p<0,01) and increased (65%; F1,22=11,20; p<0,01) when compared to grouped rats. The expression of EAAC1 was significantly increased by isolation in PFC (38%, t = 2,730, p = 0,017). In contrast, no change was found in EC (t = 1,892, p = 0,081). Isolation rearing did not induce alterations in the number of immunopositive cells for GLT1 in PFC (t= -1,28; p = 0,21). However, fluorescent labeling of GLT1 was seen associated to both glial cells and neuronal cells. The behavioral results suggest: i) Wistar rats reared in social isolation present hyperactivity in a novel environment; ii) the hyperactivity is only detectable after periods longer than 5 minutes; iii) the pattern of exploration showed by the animals demonstrate clear preference for the periphery of the arena. The molecular results provide evidence for the involvement of glutamate transporters on the reduction of glutamatergic neurotranmission in PFC of rats reared in isolation from weaning.

Bien que la neurotransmission glutamatergique joue un rôle pivot dans le développement et l’expression de la sensibilisation comportementale aux amphétamines, le rôle spécifique de certaines structures glutamatergiques qui projettent sur l’aire tegmentale ventrale et/ou le noyau accumbens n’est pas encore bien caractérisé. Nous montrons que l’hippocampe dorsal, la partie prélimbique du cortex préfrontal et l’amygdale basolatérale joue un rôle prépondérant dans les réponses locomotrices induites par l’administration aiguë (développement de la sensibilisation) et chronique (expression de la sensibilisation) d’amphétamines, suggérant les réponses locomotrices aux amphétamines impliquent un ensemble de structures glutamatergiques corticolimbiques. Par la suite, nous nous sommes intéressés au rôle de la neurotransmission glutamatergique associée aux récepteurs NMDA dans le noyau accumbens, qui est considéré comme le noyau clé de l’expression de la sensibilisation, sur le développement à court terme de la sensibilisation aux amphétamines. De plus, nous montrons le développement de la sensibilisation à court terme aux amphétamines requiert l’activation concomitante de certains récepteurs NMDA au glutamate et nicotiniques à l’acétylcholine dans le noyau accumbens. De plus, l’activation concomitante de ces récepteurs sous tend également la libération de dopamine induite par les amphétamines dans le noyau accumbens. L’ensemble de ces données montre que la neurotransmission glutamatergique, et les structures glutamatergiques qui projettent sur l’aire tegmentale ventrale et/ou le noyau accumbens, joue un rôle majeur dans la sensibilisation comportementale à court terme aux amphétamines. / Although it is well admitted that the glutamatergic neurotransmission plays a pivotal role in the development and expression of behavioral sensitization to amphetamine, the specific role of glutamatergic structures that project to the ventral tegmental and/or the nucleus accumbens is less well studied. We showed that the dorsal hippocampus, the prelimbic part of the prefrontal cortex and the basolateral amygdala play a critical role in both acute (development of sensitization) and chronic (expression of sensitization) locomotor responses induced by amphetamine, suggesting that behavioral responses to amphetamine are mediated by circuitry of corticolimbic glutamatergic structures. Next, we investigated the role of glutamatergic NMDA receptors contained in the nucleus accumbens, which is seen as the key structure for the expression of sensitization, in the development of short term sensitization to amphetamine. Interestingly, we showed that, contrasting with the current dichotomous thinking that has attributed specialized functions to the ventral tegmental area and the nucleus accumbens, respectively in the development and the expression of behavioral sensitization, concomitant activation of certain types of NMDA and nicotinic receptors in the nucleus accumbens is also required for the development of short term sensitization. Furthermore, we showed that concomitant activation of these receptors sustained the amphetamine-induced dopamine release in the nucleus accumbens. All these data show that glutamatergic neurotransmission, and glutamatergic structures which project onto mésoaccumbens system, plays a major role in short-term behavioral sensitization to amphetamine.

<p>Anti-psychotic drug (APD) administration can induce movement disorders including tardive dyskinesia (TD), characterized by abnormal movements of the oro-facial region and occasionally the trunk and limbs. The most widely accepted model of TD is the APD-induced vacuous chewing movement (VCM). While the mechanism of induction of TD remains unclear, there are two prevailing hypothesis: oxidative stress and dopamine supersensitivity. Currently available APDs antagonize dopamine D2 receptors (D2R) which can result in excessive dopamine accumulation and oxidation which was demonstrated to induce striatal neurodegeneration and increased oxidative stress. The dopamine supersensitivity hypothesis proposes that APD treatment causes an up-regulation of high affinity D2Rs to compensate for D2R antagonism. Curcumin, a derivative of turmeric, has been demonstrated to affect dopamine levels and hold significant anti-apoptotic potential. Thus, the goal of this study was to investigate curcumin’s potential to prevent haloperidol-induced behavioural and biochemical abnormalities. Four groups of rats were treated daily: control; haloperidol (at 2mg/kg intra-peritoneally); curcumin (at 200mg/kg orally in jello) and curcumin plus haloperidol. VCMs, catalepsy and locomotor activity were assessed. Animals were sacrificed and tissues removed for qPCR, immunoblot, receptor binding, and UPLC assessments. At day14 there was a significant increase in VCMs and catalepsy following haloperidol treatment, which was prevented by curcumin treatment. However, curcumin did not alter locomotor activity. Curcumin was demonstrated to increase the expression of the anti-apoptotic molecule BclXL and to increase striatal D2Rs. These investigations support the potential of curcumin in the prevention of TD and provide insight into the complex pathophysiology of this disorder.</p> / Doctor of Philosophy (Medical Science)