myo-lnositol (mIns), a natural component of the human diet and essential precursor of several signalling pathways, including that of G protein-coupled receptors, has also been shown to be effective in the treatment of psychiatric disorders such as depression, obsessive compulsive disorder and panic disorder. Most likely since mlns is a simple isomer of glucose, no serious side effects have been reported with its use, even at high oral doses of mlns. Previous studies suggest that the therapeutic action of mlns may include reduced serotonin 5HTzA and muscarinic acetylcholine receptor function. An important signal transduction system that may possibly be involved in the mechanism of action of antidepressants is phosphoinositide (PI) turnover. In this signalling system PI-phospholipase C (PLCpl), that is implicated in the in the mechanism of action of antidepressants and anxiolytics, is activated. The mechanism of action of mlns, however, still remains elusive and needs further investigation. In this study a possible modulatory role of 24-hour pre-treatment of human neuroblastoma cell line (SH-SY5Y) with mlns on mRNA levels and protein expression of phospholipase C-p1 (PLCP1) and glycogen synthase kinase 3P (GSK3p) was investigated. The effects of mlns were also compared to that of other prototype antidepressants, such as fluoxetine (a selective serotonin reuptake inhibitor), imipramine (a tricyclic antidepressant), lithium and another drug with potential antidepressant effects, sildenafil (phosphodiesterase 5-type (PDE5) inhibitor). Real-time reverse transcription Polymerase Chain Reaction (RTPCR) was performed in order to investigate the mRNA levels, while protein expression in membranes and the cytosol fraction of cells were quantified with Western blots. The expression of PLCPl was decreased after pre-treatments with imipramine or myoinositol in combination with fluoxetine. In addition, sildenafil alone or in combination with myo-inositol, also decreased the expression of membrane-bound PLCp1. However, a 24- hour pre-treatment with lithium did not alter PLCPl expression significantly. Determined mRNA levels for the expression of PLCPl were consistent in these findings, except for the inhibition of the mRNA for the expression of PLCPl also after lithium treatment. The reduced PLCpl mRNA levels after lithium pre-treatment may suggest the involvement of posttranscriptional modification (or delayed translational effects) of PLCpl after lithium treatment. The data from the current study suggest that antidepressant action may include downregulation of PLCPl expression and that modulators of the nitric oxidecGMP pathway (e.g. sildenafil as a PDE5 inhibitor) may exhibit similar properties. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

This study analyzed news coverage from the Indianapolis Star and The New York Times about the blockbuster drug Prozac® from the day it was approved on Dec. 29, 1987, until Dec. 31, 2006, to gain insights about whether the tone and prominence of news stories about Prozac changed over the duration of its 20 year lifecycle.A content analysis was used to evaluate whether stories were more favorable in tone during the first phase of Prozac's lifecycle, whether the tone of those stories became more negative as time passed, and, if it did, during which phase of Prozac's lifecycle that change in tone occurred.The findings from this study can assist public relations practitioners - particularly those who work in the pharmaceutical industry - in developing proactive and strategic media relations plans for consumer products such as prescription drugs and establishing more appropriate expectations and projected metrics. / Department of Journalism

myo-lnositol (mIns), a natural component of the human diet and essential precursor of several signalling pathways, including that of G protein-coupled receptors, has also been shown to be effective in the treatment of psychiatric disorders such as depression, obsessive compulsive disorder and panic disorder. Most likely since mlns is a simple isomer of glucose, no serious side effects have been reported with its use, even at high oral doses of mlns. Previous studies suggest that the therapeutic action of mlns may include reduced serotonin 5HTzA and muscarinic acetylcholine receptor function. An important signal transduction system that may possibly be involved in the mechanism of action of antidepressants is phosphoinositide (PI) turnover. In this signalling system PI-phospholipase C (PLCpl), that is implicated in the in the mechanism of action of antidepressants and anxiolytics, is activated. The mechanism of action of mlns, however, still remains elusive and needs further investigation. In this study a possible modulatory role of 24-hour pre-treatment of human neuroblastoma cell line (SH-SY5Y) with mlns on mRNA levels and protein expression of phospholipase C-p1 (PLCP1) and glycogen synthase kinase 3P (GSK3p) was investigated. The effects of mlns were also compared to that of other prototype antidepressants, such as fluoxetine (a selective serotonin reuptake inhibitor), imipramine (a tricyclic antidepressant), lithium and another drug with potential antidepressant effects, sildenafil (phosphodiesterase 5-type (PDE5) inhibitor). Real-time reverse transcription Polymerase Chain Reaction (RTPCR) was performed in order to investigate the mRNA levels, while protein expression in membranes and the cytosol fraction of cells were quantified with Western blots. The expression of PLCPl was decreased after pre-treatments with imipramine or myoinositol in combination with fluoxetine. In addition, sildenafil alone or in combination with myo-inositol, also decreased the expression of membrane-bound PLCp1. However, a 24- hour pre-treatment with lithium did not alter PLCPl expression significantly. Determined mRNA levels for the expression of PLCPl were consistent in these findings, except for the inhibition of the mRNA for the expression of PLCPl also after lithium treatment. The reduced PLCpl mRNA levels after lithium pre-treatment may suggest the involvement of posttranscriptional modification (or delayed translational effects) of PLCpl after lithium treatment. The data from the current study suggest that antidepressant action may include downregulation of PLCPl expression and that modulators of the nitric oxidecGMP pathway (e.g. sildenafil as a PDE5 inhibitor) may exhibit similar properties. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2005.

Fluoxetine (FLX), the active ingredient of Prozac™, is a member of the selective serotonin reuptake inhibitor (SSRI) class of anti-depressant drugs and is present in aquatic environments worldwide. Previous studies reported that FLX is an endocrine disruptor in fish, bioconcentrating in tissues including the brain. Evidence implicates that serotonin influences the activity of the hypothalamo-pituitary-interrenal (HPI) stress axis, thus exposure to FLX may disrupt the teleost stress response. This study examined in vitro cortisol production in rainbow trout (Oncorhynchus mykiss) head kidney/interrenal cells exposed to FLX and 14C-pregnenolone metabolism in head kidney microsome preparations of FLX-exposed trout. Results indicated that cells exposed in vitro to increasing concentrations of FLX had lower cortisol production and cell viability (versus control) and microsomes isolated from trout exposed to 54 μg/L FLX had higher pregnenolone metabolism versus those of control and low FLX-exposed (0.54 μg/L) trout.

Thesis (M.A.)--University of North Carolina Wilmington, 2008. / Title from PDF title page (October 20, 2008) Includes bibliographical references (59-71)

Dissertation (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2008. / Vita. Bibliography: p. 149-167.

Thesis (M. Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 1998. / Typescript. Bibliography: leaves 68-81.

Submitted by Ronildo Prado (ronisp@ufscar.br) on 2017-08-10T18:15:49Z No. of bitstreams: 1 TeseVBR.pdf: 4285837 bytes, checksum: f56f2cc3a6bc871221c45ed2a7e0ac84 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-08-10T18:15:58Z (GMT) No. of bitstreams: 1 TeseVBR.pdf: 4285837 bytes, checksum: f56f2cc3a6bc871221c45ed2a7e0ac84 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-08-10T18:16:06Z (GMT) No. of bitstreams: 1 TeseVBR.pdf: 4285837 bytes, checksum: f56f2cc3a6bc871221c45ed2a7e0ac84 (MD5) / Made available in DSpace on 2017-08-10T18:16:13Z (GMT). No. of bitstreams: 1 TeseVBR.pdf: 4285837 bytes, checksum: f56f2cc3a6bc871221c45ed2a7e0ac84 (MD5) Previous issue date: 2017-04-07 / Outra / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Canadian Institutes of Health Research (CIHR) / Serotonin (5-HT) is a neurotransmitter involved in nervous system development, being an important modulator of respiratory rhythm via activation of diverse receptors on respiratory neurons. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine act as antidepressants and are generally prescribed in depression therapy, including to pregnant women. This study investigated the effects of prenatal (E15-21) exposure to fluoxetine on the ventilatory and metabolic responses to 7% CO2 (hypercapnia) and 10% O2 (hypoxia) of male and female rats during postnatal development (P0-82). To this end, osmotic pumps were implanted subcutaneously in pregnant female rats at embryonic day (E) 15 and delivered vehicle (VEH) or fluoxetine (SSRI, 10 mg/Kg/day) during 7 days. Respiratory frequency (fR), tidal volume (Vt), ventilation (Ve ), O2 consumption (''VO2 ) and air convection requirements (Ve/VO2 ratio) of pups from these litters were studied. In P0-2 male rats, the SSRI group showed a lower Vt and a higher fR in room air conditions, whereas female rats of SSRI group showed a lower Vt in normocapnia normoxica and a higher hyperventilation induced by hypercapnia. At P6-8, male SSRI animals presented a higher fR during hypoxia together with a decrease in the number of neurons that express 5-HT in the caudal dorsal raphe (RDC). P6-8 females from ISRS group showed an attenuated fR during hypoxia. No differences were observed between male rats in the VEH and ISRS groups at P12-14 although there was an increase in the number of 5-HT neurons in the RD. SSRI females showed an attenuated hypercapnic ventilatory response. At P24-26, male SSRI animals showed a lower VEin room air conditions, a higher ventilatory response to hypercapnia and to hypoxia, together with an increase in the number of 5-HT neurons in the ROB and a higher density of TH expression in the LC area. P24-26 SSRI females displayed a lower Ve/V O2 due to a higher V O2 in room air conditions and a higher hyperventilation induced by hypercapnia. In P76-82 male rats, the SSRI group hypoventilated in room air conditions during both wakefulness and NREM sleep and showed a higher increase in Vt induced by hypoxia during wakefulness. These animals showed a higher number of 5-HT neurons in the ROB, RPA and an increase in the number of neurons that express TH in the A5 and in the LC rostral area. Finally, at P76-82, female SSRI rats showed a higher fR in room air conditions during both wakefulness and NREM sleep, an attenuated hypercapnic ventilatory response due to an attenuation of fR during NREM sleep; and an attenuated hypoxic ventilatory response during wakefulness. Also, these animals showed a decrease in the number of 5-HT neurons in the RD. Taken together, these data indicate that SSRI exposure during the prenatal period alters the development of the brainstem respiratory network and results in long lasting and sex specific changes in breathing pattern and in the ventilatory responses to respiratory challenges demonstrating that central and/or peripheric chemoreception may be disrupted in these animals. / A serotonina (5-HT) é um neurotransmissor envolvido no desenvolvimento de vários sistemas neuronais, sendo um importante modulador da ritmogênese respiratória via ativação em diversos receptores nos neurônios respiratórios. Os inibidores seletivos de recaptação de serotonina (ISRSs), como a fluoxetina, agem como antidepressivos e geralmente são prescritos na terapia da depressão, incluindo às mulheres grávidas. Este estudo investigou os efeitos de uma exposição prenatal [dia embrionário (E) 15-21] à fluoxetina nas respostas ventilatórias e metabólicas à hipercapnia (7% CO2) e hipóxia (10% O2) em ratos e ratas durante o desenvolvimento pós-natal (P0-82). Para isso, bombas osmóticas foram implantadas subcutaneamente em ratas grávidas em E15 e forneceram veículo (CTRL) ou fluoxetina (ISRS, 10 mg/Kg/dia) durante 7 dias. A frequência respiratória (fR), o volume corrente (Vt), a ventilação (V e ), o consumo de O2 (V O2) e o equivalente respiratório (V E/VO2) dessas ninhadas foram analisados. Em ratos P0-2, o grupo ISRS apresentou um Vt menor e uma fR maior em ar ambiente. Já as fêmeas do grupo ISRS apresentaram um Vt menor em normocapnia normóxica e um aumento da hiperventilação induzida por hipercapnia. Na idade P6-8, machos ISRS apresentaram uma fR maior durante a hipóxia juntamente com uma queda de 37,9% no número de neurônios que expressam 5-HT na rafe dorsal caudal (RDC), as fêmeas ISRS por sua vez, apresentaram uma fR atenuada em hipóxia em 6%. Nenhuma diferença das varíaveis respiratórias entre grupos foi observada em machos da idade P12-14, porém houve um aumento de 84,7% no número de neurônios que expressam 5-HT na rafe dorsal (RD). As ratas ISRS P12-14 apresentaram uma resposta ventilatória atenuada à hipercapnia. Na idade P24-26, os ratos ISRS demonstraram uma Ve menor em ar ambiente, uma maior resposta ventilatória à hipercapnia e à hipóxia, juntamente com um aumento de 56% no número de neurônios que expressam 5-HT na rafe obscurus (ROB) e uma maior densidade na expressão de tirosina hidroxilase (TH) na região do Locus coeruleus (LC) (16% de aumento). As fêmeas ISRS exibiram um menor V e/V O2 devido a um maior V O2 em normocapnia normóxica e uma maior hiperventilaçao induzida por hipercapnia. Nos ratos P76-82, o grupo ISRS hipoventilou em condições de ar ambiente durante vigília e sono NREM e apresentou um maior aumento no Vt induzido por hipóxia durante a vigília. Estes animais apresentaram um maior número de neurônios que expressam 5-HT na ROB, RPA e um aumento do número de neurônios que expressam TH na região A5 e na região rostral do LC. Finalmente, as fêmeas ISRS da idade P76-82 apresentaram uma maior fR em condições de ar ambiente durante a vigília e o sono NREM, uma resposta ventilatória a hipercapnia atenuada em devido a atenuação da fR durante o sono NREM; e uma resposta ventilatória a hipóxia atenuada durante a vigília. Adicionalmente, estes animais apresentaram uma redução do número de neurônios que expressam 5-HT na RD. Estes resultados, em conjunto, sugerem que uma exposição a ISRS durante o período prenatal altera o desenvolvimento da rede respiratória do tronco encefálico e promove efeitos em longo prazo e sexo específicos na respiração basal como em condições de desafios respiratórios, demonstrando que a quimiorrecepção central e/ou periférica pode estar alterada nestes animais. / CNPq: 209935/2013-8 / CNPq: 141653/2012-4 / FAPESP: 2012/15298-2 / FAPESP: 2012/19966-0

Made available in DSpace on 2014-06-11T19:32:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-01-26Bitstream added on 2014-06-13T18:44:41Z : No. of bitstreams: 1 hoshiba_ma_dr_jabo.pdf: 2741697 bytes, checksum: c38099a374c12bb742a6cd32c49e5ee4 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Fundação de Amparo à Pesquisa do Estado do Amazonas (FAPEAM) / Como estratégia para diminuir o alto índice de canibalismo na larvicultura do matrinxã, o uso do aminoácido essencial triptofano (Trp) parece promissor. O aminoácido é o precursor do neurotransmissor mono-amínico serotonina (5-hidroxitriptamina, 5-HT) e sua taxa de biossíntese no encéfalo são limitadas pela disponibilidade desse aminoácido, que parece ser uma das principais limitações para a síntese de 5-HT. A ingestão aumentada de triptofano eleva o nível do aminoácido no encéfalo, resultando em biossíntese aumentada de 5-HT no encéfalo de peixes. Esse por sua vez, é um neurotransmissor que media uma ampla variedade de comportamentos (agressão, medo e estresse em várias espécies, assim como na relação das interações sociais em muitos animais) por ação no sistema nervoso central e periférico. Assim, o presente estudo utilizou um aminoácido promotor da serotonina (triptofano), um inibidor seletivo da recaptação do neurotransmissor (fluoxetina) e um inibidor da síntese da serotonina (PCPA – paraclorofenilalanina), para verificar seu papel na mediação do comportamento agressivo e no desenvolvimento e sobrevivência larval de matrinxã no período de 1 a 12 dias após a eclosão. O triptofano foi fornecido juntamente com a ração, já a fluoxetina e a paraclorofenilalanina foram dissolvidos na água. Esse estudo foi realizado em duas condições de temperatura de cultivo, ou seja, com temperatura controlada em uma faixa de variação estreita (26-28°C) e com temperaturas variando de 19 a 31°C. Os resultados obtidos permitiram concluir que o uso do triptofano como suplemento na ração, pode ser uma alternativa viável na criação de matrinxã, pois aumentou o crescimento e a sobrevivência da prole, exceto na concentração mais alta (2,96g/100g ração). O uso de fluoxetina também aumentou a sobrevivência da prole, com redução do canibalismo, no... / The use of tryptophan as a strategy to reduce cannibalism in matrinxã hatchery seems promising. This amino acid is a precursor of the neurotransmitter serotonin (5-hidroxy-triptamine, 5-HT) whose biosynthesis rate in brain is limited by the amino acid availability. The increased intake of tryptophan by brain elevates the amino acid concentration in tissue resulting in higher serotonin production in fish. Serotonin is involved in the control of several types of behavior (aggression, fear, stress and social interaction in many animals) through effect in central and peripheral nervous systems. The present study evaluated the effect of a serotonin synthesis promoter (tryptophan), a selective inhibitor of serotonin reuptake (fluoxetine) and a selective inhibitor of serotonin synthesis (PCPA – paraclorofenilalanine) on the control of the aggressive behavior and on early development of matrinxã up to 12 days after hatching. Tryptophan was offered in the diet, and fluoxetine and PCPA in immersion solutions. The study was performed in two rearing temperatures, controlled temperature (26-28°C) and natural temperature without control (19 a 31°C). The results showed that tryptophan might be an alternative in matrinxã rearing since it promoted growth and enhanced survival of progeny, except in the highest concentration tested (2.96g/100g diet). Fluoxetine also enhanced larvae survival, with cannibalism reduction. The highest concentration (5000 ppb fluoxetine/L) reduced growth. The immunohistochemistry showed that the serotoninergig system is already developed in larvae and is similar to that of the juvenile fish of the same species. The temperature variation affected negatively the biological responses tested in this study, suggesting to be a stressor for fish. The PCPA did not show responses that could demonstrate a biological pattern

The widespread use of pharmaceutics raises an anthropogenic issue in natural environment. Selective serotonin reuptake inhibitors (SSRI) used as antidepressants, pass through most wastewater treatment plants and enter natural waters.  Their impact on personality of aquatic animals is poorly investigated, especially in invertebrates. In the current study, the impact of fluoxetine (an SSRI) on animal personality was investigated in the freshwater isopod Asellus aquaticus. To investigate responses, isopods were exposed for 1 day to fluoxetine of 10 ng L-1. Boldness, exploration, activity and escape behaviour (running and freezing) were tested on male and female isopods of two phenotypes of pigmentation (dark and light). The isopods showed consistency of behaviour responses in assays; one of the prerequisites for the existence of personality traits. Fluoxetine exposure reduced activity level, but had no effect on the other personality traits measured. This study thus provides some support for the idea that an environmentally relevant concentration of fluoxetine affects personality in A. aquaticus.