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Ordway, Gregory A. "Molecular Pharmacology of Antidepressants." Digital Commons @ East Tennessee State University, 2006. https://dc.etsu.edu/etsu-works/8657.
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Wang, Haiyan. "Manipulation of ion channel function and its effects on the neuropharmacology of 5-hydroxytryptamine." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279930.
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Maurya, Manisha. "The effect of antidepressants on rodent brain glucocorticoid systems." Thesis, Open University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368872.
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Janger, Darren S. "The Collective Overuse of Antidepressants as a Psychological Defense Inhibiting Soul Opportunities." Thesis, Pacifica Graduate Institute, 2018. http://pqdtopen.proquest.com/#viewpdf?dispub=10750296.
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<p> It is not the existence of depressive symptomology, but understanding the function and effect that should be central in how to best support patients. Even in cases of milder depression, phase-of-life issues, or adjustment-related depressive episodes, the myth of a magical pill, here an antidepressant, appeals to the human desire for cessation of whatever unpleasantness may be arising. As a collective, clinicians may be placating clients’ psychological defenses and natural desire to suppress or dissociate at the expense of allowing a soulful opportunity to work through and resolve challenges. Utilizing a primarily hermeneutic approach, the author contemplates various studies supporting psychotherapy, psychopharmacology, and combined therapies. Ultimately, the case is made for decision-making processes that place higher value on the greater context of potential soul opportunities for resolution and healing as well as individuation and growth.</p><p>
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Nomikos, George Goulielmos. "In vivo neurochemical effects of antidepressant treatments studied by microdialysis." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/31076.
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The present experiments investigated the effects of different antidepressant treatments on dopamine (DA) transmission by employing in vivo microdialysis in the nucleus accumbens (NAC) and the striatum of freely moving rats. The treatments were: a) the tricyclic antidepressant desipramine (DMI), b) the novel antidepressant drug bupropion, and c) electrically induced seizures (ECS). The following results were obtained:
1) Neither acute (5 mg/kg), nor chronic (5 mg/kg, b.i.d. X 21) DMI influenced basal interstitial concentrations of DA in the NAC or the striatum. Chronic DMI did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. In contrast, d-amphetamine (1.5 mg/kg, s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC (not in striatum) of the chronic DMI group. d-Amphetamine-induced hypermotility was also enhanced in the chronic DMI group.
2) Bupropion (10, 25 and 100 mg/kg, i.p.) increased extracellular striatal DA concentrations in a dose-, time-, and action potential-dependent manner. Bupropion produced similar responses in the NAC. The in vivo neurochemical effects of bupropion were compared with the effects of other DA uptake inhibitors such as d-amphetamine, GBR 12909, cocaine, nomifensine, methylphenidate, and benztropine by direct administration of the drugs to the striatum via the perfusion fluid in increasing concentrations (1 to 1000 μM). The rank order of potency of these drugs as determined by the increases in extracellular DA produced by 10 or 100 μM (following correction for dialysis efficiency of the test compounds in vitro) was: GBR 12909> benztropine> amphetamine= nomifensine= methylphenidate> cocaine> bupropion. Simultaneous in vivo microdialysis in the NAC and striatum was employed to investigate the effects of chronic (10 mg/kg, b.i.d. X 21) bupropion treatment on bupropion (25 mg/kg, i.p.)-induced increases in extracellular DA concentrations. The effect of the challenge bupropion injection was significantly enhanced in the NAC (not in striatum) of
the chronic bupropion group. Bupropion-induced hyperlocomotion was also enhanced in the chronic bupropion group.
3) Following a single ECS (150 V, 0.75 sec) interstitial concentrations of DA in the NAC and striatum increased sharply to 130% and 300%, respectively. The ECS-induced DA increase in the striatum was Ca⁺⁺-sensitive, partially TTX-independent, and was not influenced by barbiturate-induced anaesthesia. Seizure activity induced by flurothyl did not influence dialysate DA concentrations from the striatum, but increased dialysate DA from the NAC to 150%. These results suggest that the ECS-induced DA release in the striatum (not in the NAC) is related to the passage of current and not to the seizure activity. A course of ECS (8 treatments, one every second day) did not influence basal extracellular DA concentrations in the striatum or the NAC, while it significantly increased the DA metabolites in the striatum. Chronic ECS did not influence apomorphine (25 μg/kg, s.c.)-induced decreases in extracellular DA in the NAC. d-Amphetamine (1.5 mg/kg s.c.)-induced increases in extracellular DA were significantly enhanced in the NAC of the chronic ECS group. d-Amphetamine-induced hypermotility was also enhanced in the chronic ECS group.
These results provide in vivo neurochemical confirmation that chronically administered DMI or ECS do not produce DA autoreceptor subsensitivity. They also demonstrate that chronic DMI- or chronic ECS-induced increases in the locomotor stimulant effects of d-amphetamine are accompanied by a potentiation of its effects on interstitial DA concentrations in the NAC. Moreover, these results demonstrate that chronic bupropion-induced behavioral sensitization is accompanied by a selective potentiation of its effects on interstitial DA concentrations in the NAC. Taken together, the present data provide direct neurochemical evidence that these antidepressant treatments can increase the functional output of the meso-accumbens dopaminergic system.<br>Medicine, Faculty of<br>Graduate
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Slamon, Noreen Deborah Louise. "Studies on the toxicological and protective responses of cultured astrocytes to antidepressants." Thesis, University of Salford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313910.
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Berggård, Cecilia. "Transcription Factor AP-2 in Relation to Personality and Antidepressant Drugs." Doctoral thesis, Uppsala University, Department of Neuroscience, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4638.
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<p>The CNS monoaminergic systems are considered as the head engine regulating neuropsychiatric functions and personality. Transcription factor AP-2 is known to be essential for the development of the brainstem including the monoaminergic nuclei, and has the ability to regulate many genes in the monoaminergic systems. The ability of transcription factors to regulate specific gene expression, has lately made them hot candidates as drug targets. In this thesis, results indicating a role of AP-2 in the molecular effects of the antidepressant drugs citalopram and phenelzine, are presented. </p><p>A polymorphism in the second intron of the gene encoding AP-2ß has previously been associated with anxiety-related personality traits as estimated by the Karolinska Scales of Personality (KSP). In this thesis, results confirming this association, gained by using a larger material and several different personality scales, are presented. Furthermore, data is presented showing an association between the activity of platelet monoamine oxidase, a trait-dependent marker for personality, and the genotype of the AP-2ß intron 2 polymorphism. </p><p>The functional importance of the AP-2ß intron 2 polymorphism has not yet been elucidated. Included in this thesis are results showing that the AP-2ß intron 2 polymorphism is not in linkage disequilibrium with the only other described polymorphism in the AP-2ß gene, i.e. in the AP-2ß promoter (-67 G/A). Introns have in several studies been shown to include binding sites for regulatory proteins, and thus, to be important in transcriptional regulation. Results are presented demonstrating that one human brain nuclear protein binds only to the long variant of the AP-2ß intron 2 polymorphism. If this protein is involved in the regulation of the AP-2ß gene, it would affect the expression levels of the AP-2ß protein. </p><p>In general, this thesis further establishes the role of transcription factor AP-2 as a regulatory factor of importance for personality and monoaminergic functions.</p>
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Damberg, Mattias. "Transcription Factor AP-2 in Relation to Serotonergic Functions in the Central Nervous System." Doctoral thesis, Uppsala University, Pharmacology, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2532.
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<p>Eukaryotic gene transcription plays a regulatory role in mammalian developmental processes. It has been shown that transcriptional control is an important mechanism for specification of neurotransmitter phenotypes. In the mammalian central nervous system, the transcription factor AP-2 family is one of the critical regulatory factors for neural gene expression and neuronal development. It has been shown that several genes in the monoaminergic systems have AP-2 binding sites in regulatory regions, suggesting a regulatory role of AP-2 also in the adult brain. Brainstem monoamines are implicated in the expression of personality traits and imbalances in these systems may give rise to psychiatric disorders. </p><p>The gene encoding AP-2β includes a polymorphic region consisting of a tetranucleotide repeat of [CAAA]<sub>4-5</sub> in intron 2. Studies on AP-2β genotype in relation to personality and platelet MAO activity, a trait-dependant marker for personality, are presented in this thesis. Furthermore, correlations between brainstem levels of AP-2α and AP-2β and monoamine turnover in projection areas in rat forebrain are reported. These results strengthen the notion that the AP-2 family is important regulators of the monoaminergic systems in the adult brain. Furthermore, two studies are presented in this thesis with analyses indicating a role for AP-2 in the molecular mechanism of antidepressant drugs.</p><p>Altogether, this thesis presents data supporting our notion that the transcription factor AP-2 family is involved in the regulation of the monoaminergic systems both pre- and postnatally, and, therefore, might be involved in the pathophysiology of neuropsychiatric disorders.</p>
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Gurgel, Josà Alves. "AvaliaÃÃo dos efeitos antiinflamatÃrios dos antidepressivos clomipramina, amitriptilina e maprotilina." Universidade Federal do CearÃ, 2002. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=1187.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior<br>No presente estudo avaliou-se os efeitos dos antidepressivos, amitriptilina (amt), clomipramina (clm) e maprotilina (mpt) em reaÃÃes inflamatÃrias. Ratos machos Wistar, 150-200g, foram divididos em cinco grupos (n=6), em experimentos de edema de pata (EP) e migraÃÃo de neutrÃfilos (MN) em bolsas de ar subcutÃnea. Amt, mpt (v.o.) e clm (i.p),10, 30 e 90mg/kg, foram administradas previamente ao estÃmulo inflamatÃrio (EI), carragenina (Cg-500 Â g/pata), fMLP (10â6M) ou dextran (Dx-300 Âg/pata). O edema foi aferido por hidropletismometria (Ugo Basile 7140), imediatamente antes (âtempo zeroâ) e 1, 2, 3 e 4h apÃs a aplicaÃÃo de Cg ou Dx. O aumento no volume da pata (volume do edema) foi calculado pela diferenÃa do volume apÃs a injeÃÃo do EI. Os dados demonstraram uma inibiÃÃo dose-dependente nos edemas de pata induzidos por Cg e Dx, na presenÃa dos antidepressivos. Amt, na maior dose, inibiu o EP induzido por Cg em 51,34% (p<0,05), e em 49% (p<0,05) o EP induzido por Dx. Clm, na maior e menor doses, reduziu o EP da Cg em 100% (p<0,001) e 42,45% (p<0,05), respectivamente, e em 97,26% (p<0,001) e 36% (p<0,05) o EP do Dx, respectivamente. A mpt inibiu o EP por Cg, em 60,9% (p<0,05) para a maior dose, e em 57,49% (p<0,01) e 34,42% (p<0,05) nas duas maiores doses, em ordem decrescente, no EP por Dx. Adicionalmente, amt e clm inibiram de forma dose-dependente a MN, na sexta hora, apÃs administraÃÃo de Cg. Amt na maior dose inibiu a MN induzida por Cg em 49,19% (p<0,05) e em 96,31% (p<0,001) a MN induzida por fMLP. A mpt (40 mg/kg, i.p.) inibiu a MN por Cg em 49,26% (p<0,001), e em 92,38% (p<0,001) a migraÃÃo induzida por fMLP. Do mesmo modo, a clm nas doses de 90. 30 e 10 mg/kg (i.p.), inibiu a MN por Cg em 76,46% (p<0,001), 64,4% (p<0,01) e 49,13% (p<0,05), respectivamente, e em 100% (p<0,001) a MN induzida por fMLP, na maior dose. Na avaliaÃÃo do efeito dos AD na degranulaÃÃo de mastÃcitos, observamos que a clm (90 mg/kg/i.p.) e a mpt (40 mg/kg/i.p.) reverteram em 100% a degranulaÃÃo induzida pelo composto 48/80. Amt (90 mg/kg/v.o.) tambÃm reverteu significativamente a degranulaÃÃo de mastÃcitos, alcanÃando 90,19% (p<0,001) de inibiÃÃo. Tais dados sugerem que amt, clm e mpt possuem significativa atividade antiinflamatÃria evidenciada por seus efeitos inibitÃrios na MN e edema<br>In the present study it was evaluated the effects of antidepressants amitriptiline (amt), clormipramine (clm) and maprotiline (mpt) in the inflammatory reaction. Male Wistar rats, 150-200g, were divided into five groups (n=6) in experiments of hind paw edema (HE) and neutrophils migration (NM) in subcutaneous air pouches. Amt, mpt (v.o.) and clm (i,p), 10, 30 and 90 mg/kg, were administrated before the inflammatory stimulus carragenin (Cg-500 Âg/paw), fMLP (10 â6M) or dextran (Dx-300 Âg/paw). Paw edema was measured with a hydroplethysmometer (Hugo Basile 7140 Plethysmometer) immediately before ( time equal zero ) and 1, 2, 3 and 4 h after the Cg or Dx challenges. The increase in paw volume (edema volume) was obtained by subtracting the paw volume measured before stimulus injection. The results demonstrate that the antidepressants induce a dose dependent reduction in the HE induced by Cg and Dx. Amt in largest dose used, inhibited the Cg-induced HE by 51,34% (p< 0,05), and the Dx-induced HE by 49% (p<0,05). Clm, in biggest and smallest dose, inhibited Cg-induced HE by 100% (p<0,001) and 42,45% (p< 0,05), respectively, and by 97,26% (p< 0,001) and 36% (p<0,05) the Dx-induced HE, respectively. The largest dose of mpt inhibited the Cg-induced HE by 60,9% (p<0,05) and at the two greatest dose, in decreasing order, inhibited the Dx-induced HE, by 57,49% (p<0,01) and 34,42% (p<0,05), respectively. Additionally, amt e clm inhibited the MN in a dose-dependently manner, in the sixth hour after Cg administration. Amt in largest dose (90 mg/kg/v.o.) inhibited the Cg-induced NM by 49,19% (p<0,05) and by 96,31% (p<0,001) the fMLP-induced NM. The mpt (40 mg/kg/i.p.) inhibited the Cg-induced NM by 49,26% (p<0,001), and by 92,38% (p<0,001) the fMLP-induced NM. In the same way, clm at the dose 90, 30 e 10 mg/kg (i.p.) inhibited Cg-induced NM by 76,46% (p< 0.001), 64,4% (p<0,01) and 49,13% (p<0,05), respectively, but the fMLP-induced NM was inhibited just by the biggest dose by 100% (p<0,001). We observed that clm (90 mg/kg/i.p.) and the mpt (40 mg/kg/i.p) completely reverted the mast cell degranulation induced by the compound 48/80. Amt (90 mg/kg/v.o.) also significantly reverted the mast cell degranulation by 90,19% (p<0,001). These data suggest that amt, clm e mpt have a significant antiinflammatory activity demonstrated by their inhibitory effects on NM and edema
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Peters, Eric James. "Pharmacogenetics of antidepressant response." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2007. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3251935.
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Harries, C. M. "Antidepressant activity of N-desmethylclomipramine." Thesis, Cardiff University, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370790.
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Mann, Catherine. "Mechanisms of action of antidepressant drugs: Presynaptic and postreceptor mechanisms." Thesis, University of Ottawa (Canada), 1992. http://hdl.handle.net/10393/10600.
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The etiology of clinical depression is unknown, but thought to be related to an impairment in brain transmission of monoamines. Depression is treated with antidepressant drugs which, regardless of classification, ultimately result in increased efficacy of aminergic transmission. Tricyclic antidepressants are known to inhibit the presynaptic uptake of amines. [3H]Imipramine, the prototype tricyclic antidepressant and a potential biological marker in depression, binds to both high- and a low-affinity sites in the brain. The high-affinity binding of [3H]imipramine to its binding site on the serotonin (5-HT) neuronal transporter has been shown to be a sodium-dependent process. However, that of [3H]paroxetine, a novel and selective 5-HT uptake inhibitor, has not yet been investigated. Because of a discrepancy between the onset of uptake-blocking effect and alleviation of depressive symptoms, the blockage of uptake is probably not the only pharmacological action of antidepressants underlying their clinical effect. Recent studies have reported decreases in beta-adrenoceptor and 5-HT2 receptor numbers following long-term treatment with antidepressants, and suggested that an adaptive change in amine receptors may be more relevent for the clinical effect. However, not all 5-HT uptake inhibitors elicit this downregulation. Recent research has thus centred on elucidating changes in the signal transduction apparatus of aminergic neurons. The 5-HT2 receptor in the brain is coupled to the phosphoinositide turnover cascade and protein kinase C (PKC) activity. The subcellular distribution of PKC following chronic antidepressant treatment has not yet been investigated. This study was undertaken (1) To compare the sodium dependence of [3H]paroxetine binding and [3H]5-HT uptake in rat diencephalon in order to confirm whether paroxetine binds to the 5-HT recognition site on the transporter, and (2) to investigate the effects of both acute and chronic antidepressant treatment on PKC location and activity (both basal and 5-HT2 receptor agonist (DOI)-challenged) in rat cortex and hippocampus. Results indicate that, antidepressant drugs induce differing but significant effects on PKC activity in the subcellular fractions of neurons both after acute and chronic treatment. These changes in PKC activity may alter transduction of cellular signals evoked by the binding of 5-HT to receptors. (Abstract shortened by UMI.)
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Longmore, J. "Investigation of the pharmacology of autonomically innervated human tissue in situ with special reference to the effects of some novel antidepressant drugs." Thesis, University of Manchester, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377654.
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Béïque, Jean-Claude. "The serotoninergic and noradrenergic systems : their involvement in the antidepressant effect." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0034/NQ64512.pdf.
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Kraft, Jeffrey Brian Jr. "Antidepressant pharmacogenetics: Searching for genetic determinants of treatment response." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3311330.
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Mongeau, Raymond. "The serotonergic and noradrenergic systems of the hippocampus : their interactions and the effects of antidepressant treatments." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28856.
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Since the formulation of the monoaminergic hypotheses of depression, several investigations have established that the serotonin (5-HT) as well as the noradrenaline (NA) systems are altered by antidepressant treatments. In the last few years, several studies have indicated that interactions between these two systems might also be important in the mechanism of action of antidepressant drugs. We have thus undertaken: (1) to elucidate the nature of some interactions between the 5-HT and NA systems in the rat hippocampus using in vivo electrophysiology and in vitro superfusion techniques; and (2) to determine whether antidepressant treatments alter these interactions. It was found that NA tonically inhibits 5-HT neurotransmission via $ alpha sb2$-adrenergic heteroreceptors. In addition, the presence of 5-HT$ sb3$ receptors facilitating the release of NA was also documented in this brain region. These receptors were shown to be activated by elevated levels of endogenous 5-HT, but did not appear to be activated by basal levels of this neurotransmitter. Long-term administrations of antidepressant drugs commonly known to increase the synaptic concentration of NA, i.e. monoamine oxidase and NA reuptake inhibitors, were found to desensitize the $ alpha sb2$-adrenoceptors that inhibit the release of 5-HT. This effect was also produced by atypical antidepressant drugs that have $ alpha sb2$-adrenergic antagonist properties (e.g. mianserin and idazoxan), but not by other antidepressant treatments, (e.g. selective 5-HT reuptake inhibitors or electroconvulsive shocks). In contrast to $ alpha sb2$-adrenergic heteroreceptors, 5-HT$ sb3$ receptors that enhance the release of NA did not become desensitized following long-term treatments with drugs that elevate the synaptic concentration of their endogenous neurotransmitter. Rather, the responsiveness of these 5-HT$ sb3$ receptors became blunted following an antidepressant treatment (desipramine) that caused a large increase in the r
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Piñeyro, Graciela. "Autoregulatory properties of 5-HT neurons and their modification by antidepressant treatments : focus on 5-HT release and uptake." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=42118.
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The present research project was designed to analyse some of the mechanisms implicated in the autoregulation of serotonin (5-HT) function in rats and mice. It focuses on (i) the study of 5-HT reuptake activity following the long-term administration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine and the tricyclic drug tianeptine, and (ii) autoreceptor-mediated control of 5-HT release at the cell body level and its modifications following long-term antidepressant treatments.<br>The adaptative properties of the 5-HT transporter were assessed using a combined methodological approach of in vivo binding studies as well as $ rm lbrack sp3H rbrack$5-HT uptake assays. Such an approach indicated that long-term administration of an SSRI: (a) reduced the efficacy of paroxetine to prolong the time for recovery of firing activity of CA$ sb3$ pyramidal neurons following the suppression induced on this parameter by microiontophoretic application of 5-HT, (b) reduced the amount of $ rm lbrack sp3H rbrack$5-HT captured by hippocampal and midbrain raphe slices, and (iii) reduced the number of 5-HT transporters in hippocampus and cortex. From these results, it was concluded that prolonged administration of paroxetine down-regulated 5-HT transporters. On the other hand, the sustained administration of the tricyclic drug tianeptine, which enhances 5-HT uptake activity, did not induce any long-lasting changes either in hippocampal 5-HT uptake activity, or in the efficacy of 5-HT synaptic transmission in this terminal projection field.<br>A second series of studies was then undertaken to assess how is extracellular availability of somatodendritic 5-HT regulated in in vivo electrophysiological and voltammetric experiments. The non-selective 5-HT agonist TFMPP inhibited 5-HT release in the dorsal raphe nucleus, independently of the firing activity of 5-HT neurons. In vitro superfusion experiments, using midbrain raphe slices from rats and mice (wild type and 5-HT$ rm sb{1B}$ knock-out) were then used to assess pharmacological and functional properties of this non-5-HT$ rm sb{1A}$ receptor. It was concluded that G$ rm sb{i/o}$-coupled 5-HT$ rm sb{1D}$ autoreceptors negatively regulate 5-HT release in midbrain raphe nuclei of rats and mice, and that these receptors desensitise following prolonged administration of SSRI's and monoamine oxidase inhibitors (MAOI's).
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Haddjeri, Nasser. "Auto- and heteromodulation of the rat brain 5-HT system : involvement in the mechanism of action of antidepressant drugs." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ36978.pdf.
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Sinei, Kipruto Arap. "The effect of antidepressant drugs on the circadian rhythm of 5-hydroxytryptamine synthesis in the central nervous system." Thesis, University of Bath, 1987. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.375335.
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Szabo, Steven T. "Interactions between serotonergic and noradrenergic systems : their involvement in antidepressant treatment of anxiety and affective disorders." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37658.
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Pertubations in serotonergic (5-HT) and noradrenergic (NA) function are implicated in the pathophysiology of anxiety and affective disorders. This is strengthened by all antidepressants regardless of targeting these monoamines produce specific alterations in one or both of these systems after a prolonged administration. These alterations are congruent to their delayed onset of action in anxiety and affective disorders and may be of relevance. Using in vivo electrophysiological paradigms in the rat, the present research endeavor was undertaken to investigate whether antidepressant drugs inhibiting one monoaminergic reuptake transporter can induce an alteration in the other system. More specifically, impact of 5-HT and adrenergic receptors on the regulation of monoaminergic and hippocampal activity after acute and sustained antidepressant treatments was assessed.<br>Long-term, but not subacute administrations of selective 5-HT reuptake inhibitors (SSRIs) attenuate the spontaneous firing activity of locus coeruleus (LC) NA neurons. On the other hand, subacute and sustained treatment regimens with NA reuptake inhibitors (NRIs) induce a robust and sustained decrease on NA firing without altering that of 5-HT. Interestingly, sustained SSRI and NRI treatments both abolished 5-HT1A receptor augmentations of LC firing, but left inhibitory 5-HT2A receptor responses normal or slightly desensitized. The SSRI induced dampening on LC firing is reversed by 5-HT2A receptors blockade. Thus, an overactivation of 5-HT 2A receptors during chronic SSRI administration results from desensitization of 5-HT1A receptors in the presence of 5-HT transporter reuptake inhibition.<br>Antagonism of 5-HT1A receptors attenuates LC NA firing, but is completely reversed by 5-HT2A receptors blockade. 5,7-DHT experiments indicate that these receptors in the LC are postsynaptic to 5-HT neurons, but the 5-HT1A effects are dependent on intact 5-HT neurons. This served as the impetus to a proposed neuronal circuitry detailing the mechanism by which these 5-HT receptors, and SSRI induce adaptations thereof, alter the NA system. This complex circuitry implicates other neurotransmitters being supported further by iontophoretic data demonstrating 5-HT1A receptor effects involve alterations in glutamate and 5-HT to mediate 5-HT2A receptor activation and regulate GABA release in the LC.<br>Given the abovementioned results, it was striking that a subacute treatment with YM992 (SSRI and 5-HT2A antagonist) attenuated NA firing to a similar extent as reported with NRIs. This was concluded to be due to overactivation of presynaptic alpha2-adrenoceptors. In contrast to NRIs, a 21-day treatment with YM992 desensitized this receptor subtype and is responsible for normalization of LC firing.<br>Reboxetine produces similar effects on 5-HT and NA neuron firing and reuptake blockade on CA3 pyramidal neurons in the hippocampus as the TCA desipramine. Unlike desipramine, reboxetine is able to alter 5-HT reuptake function and 5-HT2A receptors mediated responses by DOI after a prolonged administration and did not induce a sensitization of hippocampal 5-HT1A receptors. Thus, for the first time, experimental evidence supports that this latter effect is due to TCA structure and not NA reuptake blockade.<br>These results are extrapolated to the beneficial and side effects produced by antidepressants with hopes of expanding upon the former while reducing the latter in the treatment of anxiety and affective disorders.
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Xu, Wanning. "The effects of antidepressant drugs on the risk of colorectal cancer : a population-based case-control study." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=80898.
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Background. Experimental studies suggested that tricyclic antidepressants (TCAs) would increase the risk of cancer, whereas selective serotonin reuptake inhibitors (SSRIs) would protect against colorectal cancer.<br>Objectives. This study was carried out to examine the following hypotheses: (1) The use of TCAs increases the risk of colorectal cancer. (2) In particular, the use of genotoxic TCAs increases the risk of colorectal cancer as compared to non-genotoxic TCAs. (3) The use of (SSRIs) decreases the risk of colorectal cancer.<br>Methods. A population-based nested case-control study was carried out using as source population who individually participate in the Saskatchewan Prescription Drug Plan (SPDP) aged 5--82.5 years from 1981--2000 with no previous history of cancer since 1967. 6544 histologically proven invasive colorectal cancer cases were identified from the Saskatchewan Cancer Registry (SCR). For each case, 4 eligible non-cancer controls matched on age, gender and calendar time were randomly selected. The effects of antidepressant use on the risk of colorectal cancer were examined by conditional logistic regression, considering dosage, duration and timing of antidepressant use. (Abstract shortened by UMI.)
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Thelen, Connor. "Sex Differences in the Behavioral and Neuromolecular Effects of the Rapid-Acting Antidepressant Drug Ketamine in Mice." University of Dayton / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1575964990455656.
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Rousse, Isabelle. "The effect of acute and chronic antidepressant treatment on cognitive processes of a transgenic mouse model with impaired type II glucocorticoid receptor function." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp01/MQ44329.pdf.
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Hojati, Ashkhan. "Pharmacologic profiling of novel compounds via fluorometric analyses of monoamine transporter responses." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5983.
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In humans and other organisms, monoaminergic systems are crucial in neuronal function and behavior. The monoamine transporters (MATs), which can be found on the presynaptic plasma membrane of neurons in the central nervous system (CNS), are crucial in the regulation of neurotransmitter concentration in the synaptic cleft. As the duration and concentration of neurotransmitters in the cleft affect further downstream signaling responses, these proteins are important targets for both understanding neuronal physiology and compounds of interest. Multiple theories exist proponing the contribution of MATs to a variety of mental and neurological disorders, including depression. This theory establishes that depression is caused by imbalances in monoamine neurotransmitters. Compounds such as Fluoxetine (FLX) are classified as selective serotonin reuptake inhibitors (SSRIs), these drugs selectively block the reuptake of neurotransmitters at the serotonin transporter (SERT). Since differences in MAT selectivity of inhibitory compounds are influential to selecting efficacious antidepressant treatments, we utilized a unique fluorescent analysis technique to explore three therapeutic compounds of interest (in-vitro) which contain structural similarity to FLX. Our results confirm the selectivity of FLX at SERT, and classify the novel compounds studied into different potential categories of reuptake inhibitors. We hope these compounds will be studied further to elucidate their potentially therapeutic roles and mitigation of undesired side effects seen in other medications.
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Richer, Maxime. "Characterization of the serotonergic and noradrenergic systems in mice lacking the 5-HTA receptor and its relevance to the mechanism of action of antidepressant drugs." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=33831.
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The implication of central noradrenergic and serotonergic systems in the control of mood has been known for forty years. Indeed, the different classes of molecules prescribed in the treatment of major depression directly interfere with the transmission mediated by these amines, either at the level of the synthesis, the release, the stimulation of receptors, the reuptake or the degradation. According to the leading theory in the field, the increase in serotonergic transmission is the final convergence point of currently prescribed antidepressant drugs.<br>Pharmacological and electrophysiological studies have shown the essential role of the somatodendritic 5-HT1A autoreceptor in the control of dorsal raphe 5-HT neuronal firing frequency and release; these characteristics make this receptor an extremely interesting target for adjuvant drugs that potentiate or even accelerate the effect of actual antidepressants molecules. In fact, augmentation of synaptic levels of 5-HT, thought to be necessary for the beneficial action of antidepressants in mood, does not immediately occur subsequent to acute administration of those molecules but depends on the desensitization of 5-HT1A somatodendritic autoreceptors located in the dorsal raphe, a phenomenom temporally correlated with the onset of action of all antidepressant classes.
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Shaikh, Aamir. "Levels of PARP1-immunoreactivity in the Human Brain in Major Depressive Disorder." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/honors/547.
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MDD is a severe and debilitating disorder that is associated with a growing global economic burden due to reduced workplace productivity along with increased healthcare resource utilization. Furthermore, depression markedly enhances the risk for suicide, mortality that is especially worrisome given that 30% of depressed individuals have an inadequate response to current antidepressants. This inadequacy of antidepressants necessitates the discovery of a better understanding of the pathobiology of MDD. Most current antidepressants work through monoamine neurotransmitters, and their relative efficacy in depression led to the now dated monoamine-deficiency hypothesis. The limited usefulness of antidepressants has led to a reinvigorated search for other pathologies in depression that might yield clues for the development of better drug treatments. In this regard, a strong association has been found between oxidative stress and MDD. Our lab recently found increased DNA oxidation and elevated poly(ADP)ribose polymerase (PARP1) gene expression in the brain from donors that had MDD at the time of death. Besides DNA damage repair, PARP1 mediates several downstream inflammatory effects that may contribute to pathology in MDD. In fact, our lab has demonstrated that PARP-1 inhibition produces antidepressant-like effects in rodents, suggesting that PARP-1 inhibitors hold promise as a novel antidepressant drug. While our lab had previously demonstrated elevated PARP1 gene expression in the frontal cortex in MDD, whether PARP1 protein levels were also increased in depression had not been verified. My thesis research was performed to determine whether PARP1 protein expression was also elevated in the brain in MDD. I studied primarily the hippocampus because it is part of the limbic (mediating emotion) system of the brain and because previous research has shown numerous other pathologies in the hippocampus. My study was carried out simultaneously as others in our lab were measuring PARP1 protein levels in frontal cortex in MDD. This latter work was important since the lab’s previous work had observed elevated PARP1 gene expression in the frontal cortex, rather than in the hippocampus which was not previously studied. Hippocampal and frontal cortical brain sections were cut from frozen blocks of both MDD and psychiatrically normal control brain donors for these studies. PARP1 protein levels were estimated by assisted-imaging software. The findings herein demonstrate that levels of PARP1 immunoreactivity are significantly elevated in the frontal cortex of MDD donors as compared to control donors. However, there was no change in PARP1 immunoreactivity in the hippocampus in MDD.
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Lafaille, Francine. "Characterization of [125I]7-amino-8-iodo-ketanserin binding and comparative effects of long-term treatment with anxiolytic and antidepressant drugs on serotonin type 2 and beta-adrenergic receptors in rat brain." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=60548.
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Changes to 5-HT$ sb2$ receptors in rat brain following antidepressant and anxiolytic treatment were investigated. The B$ sb{ rm max}$ of ($ sp{125}$I) AMIK was found to be decreased significantly in rat fronto-parietal cortex after 21 days administration of antidepressant drugs including desmethylimipramine (30%), buspirone (47%) and adinazolam (17%). The anxiolytic drug, diazepam, which is devoid of intrinsic antidepressant action, did not significantly change the binding parameters. In comparison to 5-HT$ sb2$ receptors, the beta-adrenoceptors labelled by ($ sp{125}$I) cyanopindolol in membrane binding were decreased only by desmethylimipramine, with a 17% reduction in B$ sb{ rm max}$. Data from in-vitro quantitative autoradiography suggests that ($ sp{125}$I) AMIK binding to 5-HT$ sb2$ receptors is decreased in frontal and parietal cortices following 21 days administration of DMI, amitryptiline, gepirone and adinazolam. The results from the present study strongly suggest that the 5-HT$ sb2$ receptor is involved in depressive disorders. Since some of the antidepressant drugs tested possess anxiolytic activity after prolonged administration, 5-HT$ sb2$ receptors may also be important in anxiety disorders.
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Franceschelli, Anthony Albert. "Sex Differences in the Rapid and the Sustained Antidepressant-like Effects of Ketamine in Stress-naive and “Depressed” Mice Exposed to Chronic Mild Stress." University of Dayton / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=dayton1429197481.
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O'Brien, Lisa. "Critical Determinants of the Risk-benefit Assessment of Antidepressants in Pregnancy: Pharmacokinetic, Safety and Economic Considerations." Thesis, 2009. http://hdl.handle.net/1807/24518.
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Untreated depression in pregnancy may result in adverse health outcomes to both the mother and her unborn child. Pharmacotherapy with antidepressants is the most common treatment option for depression; however, the decision to treat with medication becomes complicated by pregnancy. Risk benefit assessments are critical tools to guide the treatment decision. Factors that should be included in these analyses include the pharmacokinetics and pharmacodynamics of antidepressants in pregnancy and their maternal and fetal safety. The economic cost of untreated maternal depression is also important to keep in mind.
When the pharmacokinetics of the antidepressants venlafaxine and bupropion were studied in pregnancy it was found that the apparent oral clearance rate of bupropion was increased in late pregnancy when compared to early pregnancy (p = 0.03). There was a trend for lower area under the curve for these medications when the third trimester was compared to the first trimester. When the metabolism of antidepressants was investigated using hair analysis it was found that there was increased metabolism in pregnancy when compared to the postpartum period for citalopram (p = 0.02) but not venlafaxine (p = 0.77).
Follow up of depressive symptoms throughout pregnancy identified that depression scores were highest in the first trimester of pregnancy, which may be due to concurrent nausea and vomiting of pregnancy. A meta-analysis of paroxetine use in early pregnancy demonstrated that there was no increased risk for cardiac malformations; case-control studies had an odds ratio of 1.18 (CI95: 0.88 – 1.59) while a weighted average difference of 0.3% was found in case-control studies (CI95: -0.1 – 0.7%, p = 0.19) The direct medical costs incurred by the Ontario government due to discontinuation of antidepressant medications in pregnancy was estimated to exceed $20,000,000 CAD.
The management of depression in pregnancy with pharmacotherapy is an important and complex issue. My study documents the advantages of conducting risk benefit assessments for vulnerable populations such as pregnant women with depression.
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Kruegel, Andrew Carry. "Chemical and Biological Explorations of Novel Opioid Receptor Modulators." Thesis, 2015. https://doi.org/10.7916/D8V1242F.
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This report describes the synthesis, chemical derivation, and pharmacological and behavioral characterization of several unique classes of opioid receptor modulators. In chapter one, a general overview of opioid receptor history, signaling biology, and therapeutic applications is provided. Also reviewed are several topics of high current interest, including, biased signaling, opioid receptor splice variants/heteromers, and applications of opioid modulators in the treatment of mood disorders. This introduction aims to frame the work that follows, and emphasize to the reader the untapped potential of the opioid receptor system, particularly in the realm of therapeutics development.
Chapter two discusses the development of several new C-H activation reactions to provide rapid access to the core molecular scaffold of alkaloids from Tabernanthe iboga. The methods described permit the expedient construction of structurally diverse ibogamine analogs via a modular approach. In chapter three, this work is extended by applying the new reaction methodologies to explore a novel class of oxaibogamine analogs, which act as opioid receptor agonists and antagonists. The thorough exploration of structure-activity relationships within this skeleton is described, along with the pharmacological characterization of several select analogs as biased agonists at both the kappa- and mu-opioid receptors. This section concludes with a discussion of potential therapeutic applications for the synthesized compounds as new analgesics and antidepressants, and future goals and plans for this structural class.
In chapter four, the isolation and pharmacological study of several alkaloids of Mitragyna speciosa is presented. Mitragynine, the primary natural alkaloid in this plant, is isolated, along with several naturally occurring analogs, and the modulatory activity of these compounds at the opioid receptors is fully characterized. Further, preliminary results are presented suggesting activity of these alkaloids at several other classes of central nervous system targets, including serotonin and adrenergic receptors. Also discussed are the preparations of semi-synthetic and fully synthetic mitragynine derivatives, including a total synthesis of mitragynine itself. These novel analogs are applied to explore key structure-activity relationships in this unusual opioid-active scaffold. Again, potential applications of Mitragyna alkaloid analogs in the treatment of pain and depression are discussed.
In the final chapter, I describe our discovery that tianeptine, a clinically used atypical antidepressant of previously unknown mechanism of action, acts as an agonist of both the mu- and delta-opioid receptors. Activation of the mu-opioid receptor is thus proposed as the initial molecular-level event responsible for eliciting the beneficial therapeutic effects of this agent. This hypothesis is integrated with the large body of literature describing this compound, and mechanistic theories connecting the opioid activity of tianeptine to previous observations are described, with a particular emphasis on indirect modulation of glutamate signaling. Behavioral studies in mice employing both genetic knockout and pharmacological inhibition are then used to confirm the involvement of the opioid receptors in tianeptine's mechanism of action. Also described are thorough explorations of opioid structure-activity relationships within the tianeptine scaffold, and the design and synthesis of novel analogs having improved pharmacokinetic properties. It is hoped that these derivatives may one day serve as new therapeutic options for patients suffering from treatment-resistant depression.
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Hutchinson, Ashley Nicole. "Monoaminergic Regulation of MeCP2 Phosphorylation in Mouse Models of Psychiatric Disease." Diss., 2011. http://hdl.handle.net/10161/5033.
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<p>Activation of monoaminergic receptors is essential to the mechanism by which psychostimulants and antidepressants induce changes in behavior. Although these drugs rapidly increase monoaminergic transmission, they need to be administered for several weeks or months in order to produce long-lasting alterations in behavior. This observation suggests that it is likely that molecular mechanisms downstream of receptor activation contribute to the effects of psychostimulants and antidepressants on behavior. </p><p>Recently, we and others have demonstrated that the methyl-CpG-binding protein 2 (MeCP2) contributes to both neural and behavioral adaptations induced by repeated psychostimulant exposure (Deng et al, 2010, Im et al, 2010). Psychostimulants induce rapid and robust phosphorylation of MeCP2 at Ser421 (pMeCP2), a site that is thought to modulate MeCP2-dependent chromatin regulation (Cohen et al, 2011), and this phosphorylation event is selectively induced in the GABAergic interneurons of the nucleus accumbens (NAc). In order to understand the signaling pathways that contribute to the pattern of pMeCP2 we observe, I characterized the monoaminergic signaling pathways that regulate pMeCP2. I found that activation of dopamine (DA) and serotonin (5-HT) transmission is sufficient to induce pMeCP2. The novel finding that drugs that activate serotonergic signaling induce pMeCP2 suggests that pMeCP2 may be involved in serotonergic mediated behaviors.</p><p>To determine the requirement of pMeCP2 in serotonergic mediated behaviors, I utilized mice that bear a knockin (KI) mutation that converts serine to alanine at 421 (S421A) (Cohen et al, 2011). After characterizing the behavioral phenotype of these mice, I conducted tests to assess anxiety- and depression-like behavior. I found that the KI mice do not display heightened anxiety in several assays. However, the KI mice exhibit depression-like behavior in the forced swim and tail suspension but show no differences compared to wild-type (WT) littermates in the sucrose preference test, suggesting that pMeCP2 may be implicated in the behavioral response to stressful stimuli. </p><p>Because we are interested in examining the role of pMeCP2 in the behavioral adaptations to chronic monoaminergic signaling, I then put the KI mice and their WT littermates through chronic social defeat stress, a behavioral paradigm in which repeated exposure to aggressive mice causes social avoidance that is reversed by chronic but not acute antidepressant treatment. Although the WT mice show an increase in social interaction following chronic imipramine treatment, the KI mice fail to show a behavioral response to chronic treatment. These data suggest that pMeCP2 may be implicated in the antidepressant action of chronic imipramine. Finally, investigation of the brain regions in which pMeCP2 may be contributing to the behavioral response to chronic imipramine treatment revealed that chronic but not acute imipramine treatment induces pMeCP2 in the lateral habenula (LHb), a brain region involved in the behavioral response to stress and reward. Together, these data implicate a novel role for pMeCP2 in depression-like behavior and the behavioral response to chronic antidepressant treatment.</p><br>Dissertation
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Gallardo, Alexis. "Antidepressivos e sua relação com o bruxismo." Master's thesis, 2018. http://hdl.handle.net/10284/7310.
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O bruxismo é uma parafunção oral que pode ocorrer durante a vigília e/ou durante o sono e que pode apresentar características patológicas ou apenas ser considerado um comportamento oral. Devido à etiologia multifatorial, dificuldade de caracterização e diagnóstico, a sua definição tem sofrido múltiplas alterações e ainda não há um consenso universalmente aceite.
Nas situações de depressão, ansiedade crónica associada a distúrbios do pânico e quadros dolorosos crónicos são muitas vezes utilizados medicamentos antidepressivos, tendo sido frequentemente associado a aparecimento de bruxismo secundário a este grupo terapêutico.
Este trabalho consiste numa revisão bibliográfica narrativa sobre a caracterização bruxismo, bem como, sobre a sua etiologia, nomeadamente na avaliação da sua correlação com a toma de medicamentos antidepressivos.
Muitos medicamentos antidepressivos têm sido fortemente associados à indução de bruxismo a nível individual, mas poucos a nível populacional, no entanto, tem-se apontado, para estas situações, uma relação causa-efeito bidirecional em relação ao bruxismo.<br>Bruxism is an oral parafunction that can occur during wakefulness and / or during sleep and that can present pathological characteristics or only be considered as an oral behavior. Due to the multifactorial etiology, difficulty in characterization and diagnosis, its definition has undergone multiple changes and there is still no universally accepted consensus. In situations of depression, chronic anxiety associated with panic disorders and chronic painful pictures, antidepressant medications are often used, and has frequently been associated with the appearance of bruxism as a secondary effect. This work consists of a narrative bibliographical review about the characterization of bruxism, as well as its etiology, namely in the evaluation of its correlation with the intake of antidepressant drugs. Many antidepressant medications have been strongly associated with the induction of bruxism at the individual level, but few at the population level, however, it has been pointed out, for these situations, a bidirectional cause-effect relationship in relation to bruxism.
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Romeas, Thomas. "Changements dans le circuit de la récompense suite à la bulbectomie olfactive : une nouvelle approche pour étudier des antidépresseurs." Thèse, 2009. http://hdl.handle.net/1866/2975.
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La dépression est une maladie chronique, récurrente et potentiellement mortelle qui affecte plus de 20 % de la population à travers le monde. Les mécanismes sous-jacents de la dépression demeurent incompris et la pharmacothérapie actuelle, largement basée sur l’hypothèse monoaminergique, fait preuve d’une efficacité sous optimale et d’une latence thérapeutique élevée. Par conséquent, la recherche est amenée à élaborer de nouveaux traitements pharmacologiques. Pour détecter leur action, il est avant tout nécessaire de développer des outils expérimentaux adéquats. Dans cette optique, notre but a été de mesurer l’anhédonie, un symptôme cardinal de la dépression, chez le rat de laboratoire. L’anhédonie a été définie comme une réduction de la récompense et a été mesurée avec le test de consommation de sucrose et la technique d’autostimulation intracérébrale. En vue d’induire l’anhédonie, nous avons effectué une bulbectomie olfactive, une procédure qui entraîne divers changements biochimiques, cellulaires et comportementaux similaires à ceux de l’état dépressif et qui peuvent être renversés par un traitement antidépresseur chronique. Nos résultats montrent que la bulbectomie olfactive produit également l’anhédonie, reflétée par une réduction durable de la consommation de sucrose et par une réduction de l’efficacité de l’amphétamine dans le test d’autostimulation intracérébrale. Ces effets ont été présents jusqu’à trois à quatre semaines suivant la chirurgie. La bulbectomie olfactive a aussi été associée à une augmentation de l’élément de réponse liant l’AMPc dans le striatum, un index moléculaire associé à l’anhédonie. Ces découvertes suggèrent que l’anhédonie peut être produite et étudiée de façon fiable dans le modèle de bulbectomie olfactive et que le circuit de récompense pourrait constituer une cible cohérente pour de nouvelles drogues en vue du traitement de la dépression.<br>Depression is a chronic, recurrent and potentially deadly disorder that affects over 20 % of the population worldwide. The mechanisms underlying depression are still not understood and current pharmacotherapy, based largely on monoaminergic hypotheses, is plagued by suboptimal efficacy and delayed therapeutic latency. This has lead to a search for novel pharmacological treatments. To achieve this, it is first necessary to develop adequate experimental tools. With this in mind, we aimed to measure anhedonia, a cardinal symptom of depression, in laboratory rats. We defined anhedonia as a reduction in reward, and measured it with the sucrose intake test and in the intracranial self-stimulation paradigm. In order to induce anhedonia, we surgically removed the olfactory bulbs, a procedure that results in a host of behavioral, cellular and biochemical changes that are qualitatively similar to those observed in clinical depression. These changes are long-lasting and reversed by chronic antidepressant treatment, validating olfactory bulbectomy as an animal model of depression. Our results show that olfactory bulbectomy also produces anhedonia, reflected by a stable and long-lasting reduction in sucrose intake as well as a reduction in the rewarding effectiveness of amphetamine in the self-stimulation paradigm. These effects were present even after three to four weeks post-surgery. Olfactory bulbectomy was also associated with increased striatal cAMP response element binding, a molecular index associated with depressive-like behaviour. These findings suggest that anhedonia can be reliably produced and studied within the olfactory bulbectomy model and that reward circuitry may comprise a logical target for novel drugs to treat depression.
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Younes, Stephane Y. "Les récepteurs 5-HT4b adoptent différentes conformations ligand-spécifique ayant des propriétés de signalisation et de régulation distinctes." Thèse, 2012. http://hdl.handle.net/1866/8906.
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Les antidépresseurs actuels sont très similaires au niveau de leur mécanisme d’action et sont plus ou moins efficaces. Un des problèmes majeurs est leur long temps de latence à fournir une action thérapeutique dû aux adaptations des sites pré et post synaptiques. Dans un modèle animal, nous avons récemment découvert que l’agoniste RS67333 des récepteurs 5-HT4 était en mesure de produire en trois jours les mêmes effets antidépresseurs qui normalement prennent de deux à trois semaines à apparaître avec les antidépresseurs actuellement disponibles. De plus, nous avons constaté que les effets antidépresseurs de cet agoniste possédaient une résistance à la tolérance. Il y a d’autres agonistes du même récepteur, tel que le prucalopride qui ne produit pas d’effets antidépresseurs comme RS67333. Étant donné que l’efficacité du Prucalopride à stimuler les 5-HT4Rs est similaire sinon plus grande que celle de RS67333, nous avons énoncé l’hypothèse que le récepteur 5-HT4 pourrait adopter différentes conformations actives suite à son activation par différents agonistes. Nous avons ainsi décidé d’explorer les principales réponses fonctionnelles des récepteurs 5-HT4B en observant leurs propriétés de régulation et de signalisation.
Nous avons montré que l’isoforme B du récepteur 5-HT4, étant hautement exprimé dans le système limbique, détient une signalisation et une régulation différentes dépendant du ligand activateur. Nos résultats indiquent que chacun des agonistes testés (5-HT, RS67333, ML10302, Zacopride, Prucalopride) modulent distinctivement la production d’AMPc et l’internalisation du récepteur. Les résultats nous ont clairement permis de déterminer que les agonistes possèdent une efficacité et ou puissance différentes les uns par rapport aux autres. De plus, l’ordre d’efficacité des agonistes à moduler la voie de l’AMPc était (Prucalopride > Zacopride = ML10302 = 5-HT > RS67333) et est différente de leur ordre d’efficacité à induire la régulation du récepteur par internalisation (5-HT > Zacopride > Prucalopride > ML10302 = RS67333). Ainsi, nous avons montré que les 5-HT4Rs adoptent des conformations qui sont ligand-spécifiques.
Cela implique que la sélectivité fonctionnelle serait un facteur important à considérer dans les mécanismes d’action antidépresseur des agonistes de ce récepteur.<br>Antidepressants currently available are very similar toward their mechanism of action and are more or less effective. One major problem is their long latency to provide a therapeutic effect due to adaptations of pre and post synaptic locations. In an animal model, we recently discovered that the agonist RS67333 of the 5-HT4 receptors was able to produce in three days the same antidepressant effects that normally take two to three weeks to appear with the currently available antidepressants. In addition, we found that the antidepressant effects of this agonist had a resistance to tolerance. There are others agonists of the same receptor such as prucalopride, which does not produce antidepressant effects as RS67333. Since the effectiveness of prucalopride to stimulate 5-HT4Rs is similar if not greater than RS67333, we stated the hypothesis that the 5-HT4 receptor could adopt different active conformations following its activation by various agonists. We decided to explore the major functional responses of 5-HT4B by observing their regulatory and signaling properties.
We showed that the B isoform of the 5-HT4, being highly expressed in the limbic system, has a different signaling and regulation depending on the ligand. Our results indicate that each of the agonists tested (5-HT, RS67333, ML10302, Zacopride, Prucalopride) distinctively modulate cAMP production and receptor internalization. The results have clearly identified that agonists differed in potency and efficacy. Moreover, the order of effectiveness of agonists to modulate the cAMP pathway was (prucalopride> zacopride = 5-HT = ML10302> RS67333) different from their order of effectiveness in inducing receptor regulation by internalization (5-HT> Zacopride> Prucalopride> RS67333 = ML10302). Thus, we have shown that 5-HT4Rs adopt conformations that are ligand-specific. This implies that functional selectivity is an important factor in the mechanisms of antidepressant action of this receptor agonists.
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Lu, Jennifer. "Characterization of the membrane transporter OATP1A2 activity towards different classes of drugs." Thèse, 2016. http://hdl.handle.net/1866/19272.
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Les transporteurs membranaires sont des éléments importants dans le devenir, l’efficacité, et la toxicité du médicament. Ils influencent la pharmacocinétique et la pharmacodynamie de ces derniers. Plusieurs interactions médicamenteuses observées cliniquement sont attribuables à la fois aux enzymes responsables du métabolisme des médicaments et aux transporteurs membranaires. Il est connu qu’une variabilité existe entre différents individus dans la réponse à un médicament et les polymorphismes génétiques retrouvés dans les gènes codant pour les transporteurs membranaires peuvent partiellement expliquer cette variabilité.
OATP1A2 est un transporteur membranaire exprimé sur des organes importants, comme le cerveau et le rein. Plusieurs médicaments utilisés en clinique sont des substrats d’OATP1A2 et l’expression localisée de ce transporteur suggère un rôle important dans le devenir du médicament. Donc, mon projet de doctorat consistait à caractériser l’activité d’OATP1A2 en relation avec ses substrats et inhibiteurs, et de plus, à évaluer l’impact de différents variants génétiques d’OATP1A2 sur leur transport.
Dans le premier article, la rosuvastatine a été utilisée comme substrat-type pour étudier le transport d’OATP1A2. Les expériences ont été menées en introduisant la rosuvastatine en compétition avec différent β-bloqueurs, une classe de médicaments rapportée dans la littérature comme substrats d’OATP1A2. Parmi les β-bloqueurs évalués, le carvédilol était l’inhibiteur le plus puissant. Dans la deuxième partie de l’étude, des médicaments ayant une structure similaire au carvédilol, tels que les antidépresseurs tricycliques, ont été évalués quant à leur potentiel d’inhibition sur OATP1A2. Une relation structure-activité a été définie à l’aide de ces données. Nous avons démontré que des composés tricycliques avec une courte chaîne aliphatique pouvaient inhiber OATP1A2.
Dans le deuxième article, OATP1A2 a été étudié en considérant son expression et son rôle au sein de la barrière hémato-encéphalique (BHE). Des études précédentes ont démontré qu’OATP1A2 est exprimé sur la membrane luminale des cellules endothéliales formant la BHE. Nos données démontrent que les triptans, une classe de médicaments couramment utilisées pour traiter la crise migraineuse, sont des substrats d’OATP1A2 et que les composés tricycliques identifiés comme inhibiteurs d’OATP1A2 dans nos études précédentes peuvent inhiber le transport des triptans par OATP1A2. Ces résultats sont importants puisque: 1) il a été suggéré que les triptans peuvent agir au niveau du système nerveux central en se liant aux récepteurs trouvés sur les neurones centraux; 2) comme les triptans sont des molécules hydrophiles, un mécanisme de transport facilité est nécessaire pour qu’ils pénètrent la BHE et OATP1A2 pourrait être l’élément clé; 3) l’inhibition d’OATP1A2 par les composés tricycliques pourrait limiter l’accès des triptans à leur site d’action.
Le troisième article caractérise l’activité associée à deux variants génétiques d’OATP1A2 (OATP1A2*2 et *3). Leur capacité à transporter les triptans et leur potentiel d’inhibition par les médicaments tricycliques ont été évalués. Des résultats supplémentaires caractérisant OATP1A2, mais sans liens directs avec les trois articles, seront présentés en annexe.
Dans l’ensemble, les résultats présentés dans cette thèse servent à caractériser le transporteur membranaire OATP1A2 en relation avec ses substrats et inhibiteurs, et en fonction de ses variants génétiques.<br>Drug transporters are important determinants in drug disposition, efficacy, and toxicity. They influence the pharmacokinetics and pharmacodynamics of drugs. Several clinically-observed drug-drug interactions are mediated through drug metabolizing enzymes and drug transporters. It is well known that there is an interindividual variability in the response to medications and polymorphisms found in genes encoding for drug transporters partially account for it.
OATP1A2 is a membrane drug transporter expressed on important organs, such as the brain and the kidney. A wide spectrum of drugs used in the clinic are substrates of OATP1A2. Its localisation suggests an essential role in drug disposition. Thus, my PhD project consisted of characterizing the activity of OATP1A2 in regards to its substrates, inhibitors, and different protein variants due to genetic polymorphisms.
In the first article, rosuvastatin was used as the probe substrate to study OATP1A2 transport activity. Experiments were conducted by putting rosuvastatin in competition with different β-blockers, a class of drugs known in the literature to be transported by OATP1A2. One of the drugs evaluated, carvedilol, inhibited OATP1A2 with much more potency than the others. In the second part of the study, drugs with a structure similar to carvedilol, such as tricyclic antidepressants, were tested for their potential to inhibit OATP1A2. A structure-activity relationship was defined using the data. It was demonstrated that drugs composed of a tricyclic ring with a short aliphatic amine chain were potent OATP1A2 inhibitors.
In the second article presented, OATP1A2 was studied in the context of its localization at the blood-brain barrier (BBB). OATP1A2 expression at the luminal membrane of the endothelial cells making up the BBB was demonstrated in the literature. Our article showed that triptans, a class of commonly used anti-migraine drugs, were OATP1A2 substrates. The tricyclic drugs previously evaluated were shown to potently inhibit triptan transport through OATP1A2. These findings are important for three reasons: 1) it has been postulated that triptans may act at the central nervous system by binding to receptors found on central neurons; 2) as triptans are hydrophilic molecules, a facilitated transport mechanism is required for them to penetrate the BBB and OATP1A2 may be the key player; and 3) the inhibition of OATP1A2 by the tricyclic drugs may limit the entrance of triptans to their site of action.
The third article characterized the transport activity of two OATP1A2 protein variants (OATP1A2*2 and *3). Their capacities to transport triptans and their potential of being inhibited by tricyclic drugs were evaluated. Additional data characterizing OATP1A2 but considered out of the scope of the three articles will be presented in appendices.
In overall, the central theme of this thesis looks into the characterization of the OATP1A2 membrane drug transporter in regards to its substrates, inhibitors, and proteins variants.
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Trottier, Giacomo. "The biasing of the 5-HT4 receptor as an antidepressant target." Thèse, 2017. http://hdl.handle.net/1866/18903.
Full textAbstract:
La dépression majeure peut être très dommageable pour le 8% des Nord-Américains qui en souffriront au moins une fois durant leur vie. Les traitements actuels de la dépression ont été créés grâce à la compréhension de l'hypothèse de la monoamine; où les transporteurs de la sérotonine ou les enzymes sont bloqués ou inhibés afin de maintenir le neurotransmetteur (NT) dans la fente synaptique. Sur une période de plusieurs semaines, cette augmentation de NT encourage la plasticité synaptique, ce qui augmente la sensibilité de réponse de 5-HT dans la fente synaptique. Cette forme de traitement est efficace chez 40% des patients, tandis que les 60% restants ont une réponse partielle ou nulle. Dans les modèles de dépression chez la souris des changements dans les niveaux de phosphorylation de CREB sont corrélés aux effets antidépresseurs (AD). Dans le cas RS67333, des effets AD apparaissent après 2 à 3 jours de traitement. Les effets anti-anhédoniques sont démontrés par la réponse au traitement. RS67333 est un agoniste spécifique du récepteur 5-HT4, un récepteur couplé à la protéine G (GPCR) qui est généralement situé, après synapses, dans les régions du système limbique. Il existe d'autres ligands qui sont également spécifiques au récepteur 5-HT4: 5-HT, Zacopride, Prucalopride et ML10302, mais les mêmes effets anti-anhédoniques constatés lors de RS67333 n’ont pas été observés. Comment RS67333 est-il différent des autres en termes de signalisation? Nous avons utilisé le transfert d’énergie par résonnance de bioluminescence (BRET) pour étudier les interactions 5-HT4R avec les sous-unités, α β γ de la protéine G et nous avons comparé ces associations avec d'autres agonistes connus de 5-HT4. Nous avons constaté que RS67333 est un agoniste partiel et qu’il active un changement conformationnel de la protéine Gαs, mais n’active pas un changement conformationnel de la protéine Gαo. Prucaloride, 5-HT et Zacopride induisent aussi un changement de conformation du complexe Gαs, mais pas ML10302. Pour la formation de Gαo, Prucalopride, ML10302 et 5-HT agissent comme des agonistes, mais pas zacopride ni RS67333. Nous avons utilisé un test de dosage immuno-enzymatique sur support solide (ELISA) pour mesurer l’intériorisation induite par les ligands pour étudier la régulation des récepteurs. Nous avons constaté que RS67333 et ML10302 n’induisent pas l'internalisation du récepteur, tandis que zacopride, prucalopride et 5-HT sont très efficaces. L'efficacité sous-optimale des ADs actuels met l’accent sur la nécessité de développer des médicaments avec d'autres mécanismes d'action. RS67333 a des effets persistants anti-anhédoniques après une courte période de temps, et d'autres études de ses propriétés de signalisation pourraient donner lieu à une nouvelle génération d’antidépresseurs rapides de longue durée d’action.<br>Major Depression can be very damaging on the 8% of North Americans that will have it at least once within their lifetime. Current treatments of depression have been developed through the understanding of the monoamine hypothesis; whereby serotonin (5-HT) transporters or enzymes are blocked or inhibited in order to maintain the neurotransmitter in the synaptic cleft. Over a period of several weeks this increase in NT induces synaptic plasticity which increases the response sensitivity of 5-HT in the synaptic cleft. This form of treatment is effective on 40% of patients, while the remaining 60% have partial or no response. In mouse models of depression, changes in phosphorylation levels of CREB correlated to antidepressants (AD) effects. In the case of RS67333 AD effects appear within 2-3 days of treatment. The response can be evidenced as anti- anhedonic. RS67333 is specific agonist for 5-HT4 receptor, a G protein coupled receptor (GPCR) that is typically located post synaptically, in limbic regions. There are other ligands that are also specific to receptor 5-HT4: 5-HT, Zacopride, prucalopride and ML10302, but have not been observed to have the same anti-anhedonia effects of RS67333. How does RS67333 differ from the others in terms of signaling? We used bioluminescence resonance energy transfer (BRET) to study the interactions of 5-HT4R with the α β γ subunits of the G protein and we compared these associations with other known 5-HT4 agonists. We found that RS67333 was a partial agonist and activated a conformational change of the Gαs protein but did not activate a conformational change of Gαo protein. Prucaloride, 5-HT and Zacopride also induced a conformational change of the Gαs complex but not ML10302. For the formation of Gαo, Prucalorpide, ML10302 and 5-HT acted as agonists, but not Zacopride. We used an ELISA assay to measure ligand induced internalization to study receptor regulation. We found that RS67333 and ML10302 did not induce receptor internalization, while Zacopride, Prucalopride and 5-HT were very effective. The suboptimal efficacy of current ADs stresses the need to develop drugs with other mechanisms of action. RS67333 has persistent anti-anhedonia effects after a short period of time and further studies of its signalling properties may open up a new generation of fast and long acting antidepressants.