The discovery of stem and progenitor cells capable of ongoing neurogenesis in the adult mammalian brain has raised hope that we will one day be able to harness their intrinsic regenerative capacity following injury. Development of such therapeutic strategies relies on a comprehensive understanding of the underlying regulation of the neurogenic process. To this end, I show, in this thesis, that cultured post-natal hippocampal neural progenitor cells (NPCs) express a specific repertoire of connexins (Cx), a family of channel forming proteins critical for communication prior to the development of functional chemical synapses. I show that this pattern of Cx expression, specifically Cx43 and Cx45, is modulated by interaction with the extracellular matrix component laminin providing evidence of extracellular matrix-cell interaction in the regulation of intrinsic Cx expression and function in postnatal NPCs. In adult brain, I show, for the first time, that Cx45 localizes to all cell types of the neuronal lineage with the exception of the type 3 doublecortin (DCX)-positive NPCs. Using a loss of function approach, I show that this expression is required for the normal proliferation of type 1 nestin and glial fibrillary acidic protein-positive stem like NPCs but not for the differentiation or survival of their progeny in the adult hippocampus. With respect to exogenous pharmacological cues that influence hippocampal neurogenesis, this thesis also demonstrates that chronic treatment with a sub-set of selective serotonin reuptake inhibitor antidepressants, fluoxetine and escitalopram, increases the proliferation but not the survival of adult NPCs in healthy, non-depressed mice. Further, standard post-operative analgesia with the opiate buprenorphine inhibits the proliferation of DCX-positive adult NPCs and increases the survival of their progeny. Finally, over the course of the research for this thesis, it became clear that exposing research animals to even very subtle environmental changes can influence the basal neurogenic process. Ultimately this work further highlights the exquisite sensitivity of the regulation of what is already recognized to be a highly dynamic process and provides important insight into the neurogenic process that can be used to inform future therapeutic development and application.

Although extensive evidence suggests antidepressants are a non-effective treatment for the majority of depressive cases where they are prescribed and despite other developed countries taking steps to provide alternative treatments, Canada's prescription rates continue rising and no state action is being taken. The primary purpose of this study is to explore whether the media in English-speaking Canada, represented by its "newspaper of record," The Globe and Mail, has been performing its essential role in informing Canadians about the controversy surrounding antidepressants and the pharmaceutical system that that has made them central to treating depression. Data was collected in the form of newspaper articles from between 2000 and 2015 in order to analyze media coverage to ensure the essential facts were reported and to qualify to what degree a patient advocacy role challenging the norms of contemporary treatment has been adopted. / February 2017

The development of new solid forms of active pharmaceutical ingredients (API) is relevant both from fundamental as well as industrial perspectives. To this end, Crystal Engineering plays an ever-increasing important role in pharmaceutical sciences. Among the crystal engineering strategy, salt formation is the most important and implemented approach. The salt forms of API could be used to modulate and tuned the solubility and stability of API to provide optimal practical uses. Herein, we report pharmaceutical salts of two Selective Serotonin Reuptake Inhibitor antidepressants used in the treatment of depression and anxiety disorders, Paroxetine (PRX) and Fluoxetine (FLX). For this purpose, salt formers, supramolecular synthesis and crystallization protocols have been driven by the systematization of structural and supramolecular data of molecules and analogues from the Cambridge Structural Database. Paroxetine bromide hemihydrate ((PRXBr)0.5H2O), Paroxetine Nitrate hydrate (PRXNO3H2O) and two polymorphs of Fluoxetine Nitrate (FLXNO3) have obtained. All were characterized by a combination of techniques including Single Crystal X-ray Diffraction, Differential Scanning Calorimetry (DSC), Thermogravimetry analysis (TGA), Hot Stage Microscopy, Fourier transform infrared spectroscopy (IR) and solubility measurements. Since the hydration/dehydration process in APIs induces phase transitions that compromise its efficiency, the structural characterization of (PRXBr)0.5H2O help to understand its reversible dehydration process. Also, this study has implication in the understating of dehydration of isostructural PRX hydrochloride salt. Additionally, the (PRXNO3)H2O have shown the conformational flexibility and supramolecular diversity of PRX. On the other hand, the chirality of FLX is related to two nitrate salt polymorphs. A racemate and a non-centrosymmetric structure with independent enantiomers in the asymmetric unit were obtained for FLXNO3. Their packing have shown the existence of different racemic motifs, resulting in different enantiomer orientations The rare occurrence of racemic systems in non-centrosymmetric space groups becomes this event a noteworthy case. By their physicochemical properties, the polymorphs were monotropically related. The scientific contributions of this thesis show the diversity of the solid forms and define candidates to new antidepressants APIs solid formulations. / O desenvolvimento de novas formas sólidas de ingredientes farmacêuticos ativos (API) é relevante tanto numa perspectiva fundamental como industrial. Para tal, a Engenharia de cristais tem desempenhado um papel importante nas ciências farmacêuticas. Dentre as estratégias, a formação de sais é a abordagem mais importante e implementada. Os sais de APIs são capazes de modular e ajustar a solubilidade e a estabilidade, a fim de proporcionar uso prático. Nesta tese, são reportados sais de dois fármacos Inibidores Seletivos de Recaptação de Serotonina, consolidados no tratamento da depressão e distúrbios de ansiedade, a Paroxetina (PRX) e a Fluoxetina (FLX). Brometo de Paroxetina hemiidratado ((PRXBr)0.5H2O), Nitrato de Paroxetina hidratado (PRXNO3H2O) e polimorfos de Nitrato de Fluoxetina (FLXNO3), síntese e protocolos de cristalização foram cuidadosamente delineados, com base na sistematização de dados estruturais e supramoleculares das moléculas e seus análogos, depositados no Cambridge Structural Database. Todos os sais foram caracterizados por Difração de Raios-X por Monocristal, Calorimetria Explanatória Diferencial (DSC), Análise termogravimétrica (TGA), Termomicroscopia, Espectroscopia vibracional na região do infravermelho (IR) e solubilidade. Considerando que a hidratação/desidratação induz mudanças de fases que comprometem a eficiência do API, a caracterização do (PRXBr)0.5H2O auxiliou no entendimento do processo de desidratação reversível que ocorre para esse fármaco. Estas mudanças de fase resultam também em implicações sobre a compreensão do processo de desidratação do sal isoestrutural de cloreto de PRX hemiidratado. Além disso, por meio da elucidação estrutural do (PRXNO3)H2O, foi possível analisar a diversidade conformacional e supramolecular da PRX. Quanto à FLX, verificou-se que sua quiralidade está relacionada com seu polimorfismo. Um racemato e uma estrutura não centrossimétrica com dois enatiômeros independentes na unidade assimétrica foram obtidos para o FLXNO3. A comparação destas estruturas permitiu mostrar a existência de arranjos supramoleculares racêmicos, constituídos por diferentes orientações de enatiômeros. A rara ocorrência de sistemas racêmicos em grupos espaciais não-centrossimétricos tornou este evento um caso notável. A partir das propriedades físico-químicas, os polimorfos puderam ser monotropicamente relacionados. Os resultados desta tese trazem importantes contribuições científicas para diversidade de formas sólidas e também define novas formulações sólidas para utilização como antidepressivos.

Background: Selective serotonin reuptake inhibitor (SSRI) antidepressants prevent serotonin (5-HT) uptake by the serotonin transporter (SERT). Since blood platelets express SERT, SSRIs may modify platelet function and the risk of cardiovascular disease. However, the beneficial or adverse effects of SSRIs on arterial thrombosis are poorly characterised and detailed in vitro experimental data is limited. The SSRI citalopram is a racemate, the (S)-isomer being the more potent SERT inhibitor. Although citalopram has been shown to inhibit platelets in vitro, it is unclear whether this is mediated via SERT blockade. Aim: To determine if citalopram inhibits platelet function via SERT blockade, or through a novel mechanism of action. Findings: 5-HT uptake into platelets was blocked by both citalopram isomers at concentrations that had no apparent effect on platelet function. Despite the (S)-citalopram isomer being the more potent SERT inhibitor, (R)-citalopram was equally potent at inhibiting other platelet functions. These findings strongly suggest that inhibition of platelet function by citalopram in vitro is not mediated by blocking SERT. Subsequent experiments identified two putative mechanisms for citalopram-mediated platelet inhibition: 1) citalopram did not inhibit calcium store release induced by the platelet agonist U46619, despite blocking subsequent Rap1 activation. A credible target for this inhibitory mechanism is the calcium and diacylglycerol guanine nucleotide exchange factor-1 (CalDAG-GEFI): 2) citalopram suppressed early protein phosphorylation within the GPVI pathway, resulting in the inhibition of subsequent platelet responses. Further experiments show that other commonly used antidepressants also inhibit platelets. As with citalopram, inhibition was only observed at concentrations above those required to block SERT, suggesting that alternative inhibitory mechanism(s) are responsible. Conclusions: Data presented in this thesis support two novel putative mechanisms of citalopram-induced platelet inhibition. These findings demonstrate that citalopram and other antidepressants inhibit platelets independently of their ability to block SERT-dependent 5-HT transport. The identification of thesemechanisms provides a pharmacological approach to develop novel antiplatelet agents based on current antidepressants.

The development of new solid forms of active pharmaceutical ingredients (API) is relevant both from fundamental as well as industrial perspectives. To this end, Crystal Engineering plays an ever-increasing important role in pharmaceutical sciences. Among the crystal engineering strategy, salt formation is the most important and implemented approach. The salt forms of API could be used to modulate and tuned the solubility and stability of API to provide optimal practical uses. Herein, we report pharmaceutical salts of two Selective Serotonin Reuptake Inhibitor antidepressants used in the treatment of depression and anxiety disorders, Paroxetine (PRX) and Fluoxetine (FLX). For this purpose, salt formers, supramolecular synthesis and crystallization protocols have been driven by the systematization of structural and supramolecular data of molecules and analogues from the Cambridge Structural Database. Paroxetine bromide hemihydrate ((PRXBr)0.5H2O), Paroxetine Nitrate hydrate (PRXNO3H2O) and two polymorphs of Fluoxetine Nitrate (FLXNO3) have obtained. All were characterized by a combination of techniques including Single Crystal X-ray Diffraction, Differential Scanning Calorimetry (DSC), Thermogravimetry analysis (TGA), Hot Stage Microscopy, Fourier transform infrared spectroscopy (IR) and solubility measurements. Since the hydration/dehydration process in APIs induces phase transitions that compromise its efficiency, the structural characterization of (PRXBr)0.5H2O help to understand its reversible dehydration process. Also, this study has implication in the understating of dehydration of isostructural PRX hydrochloride salt. Additionally, the (PRXNO3)H2O have shown the conformational flexibility and supramolecular diversity of PRX. On the other hand, the chirality of FLX is related to two nitrate salt polymorphs. A racemate and a non-centrosymmetric structure with independent enantiomers in the asymmetric unit were obtained for FLXNO3. Their packing have shown the existence of different racemic motifs, resulting in different enantiomer orientations The rare occurrence of racemic systems in non-centrosymmetric space groups becomes this event a noteworthy case. By their physicochemical properties, the polymorphs were monotropically related. The scientific contributions of this thesis show the diversity of the solid forms and define candidates to new antidepressants APIs solid formulations. / O desenvolvimento de novas formas sólidas de ingredientes farmacêuticos ativos (API) é relevante tanto numa perspectiva fundamental como industrial. Para tal, a Engenharia de cristais tem desempenhado um papel importante nas ciências farmacêuticas. Dentre as estratégias, a formação de sais é a abordagem mais importante e implementada. Os sais de APIs são capazes de modular e ajustar a solubilidade e a estabilidade, a fim de proporcionar uso prático. Nesta tese, são reportados sais de dois fármacos Inibidores Seletivos de Recaptação de Serotonina, consolidados no tratamento da depressão e distúrbios de ansiedade, a Paroxetina (PRX) e a Fluoxetina (FLX). Brometo de Paroxetina hemiidratado ((PRXBr)0.5H2O), Nitrato de Paroxetina hidratado (PRXNO3H2O) e polimorfos de Nitrato de Fluoxetina (FLXNO3), síntese e protocolos de cristalização foram cuidadosamente delineados, com base na sistematização de dados estruturais e supramoleculares das moléculas e seus análogos, depositados no Cambridge Structural Database. Todos os sais foram caracterizados por Difração de Raios-X por Monocristal, Calorimetria Explanatória Diferencial (DSC), Análise termogravimétrica (TGA), Termomicroscopia, Espectroscopia vibracional na região do infravermelho (IR) e solubilidade. Considerando que a hidratação/desidratação induz mudanças de fases que comprometem a eficiência do API, a caracterização do (PRXBr)0.5H2O auxiliou no entendimento do processo de desidratação reversível que ocorre para esse fármaco. Estas mudanças de fase resultam também em implicações sobre a compreensão do processo de desidratação do sal isoestrutural de cloreto de PRX hemiidratado. Além disso, por meio da elucidação estrutural do (PRXNO3)H2O, foi possível analisar a diversidade conformacional e supramolecular da PRX. Quanto à FLX, verificou-se que sua quiralidade está relacionada com seu polimorfismo. Um racemato e uma estrutura não centrossimétrica com dois enatiômeros independentes na unidade assimétrica foram obtidos para o FLXNO3. A comparação destas estruturas permitiu mostrar a existência de arranjos supramoleculares racêmicos, constituídos por diferentes orientações de enatiômeros. A rara ocorrência de sistemas racêmicos em grupos espaciais não-centrossimétricos tornou este evento um caso notável. A partir das propriedades físico-químicas, os polimorfos puderam ser monotropicamente relacionados. Os resultados desta tese trazem importantes contribuições científicas para diversidade de formas sólidas e também define novas formulações sólidas para utilização como antidepressivos.

This thesis aims to review if there is an association between antidepressants and caries in children and adolescents. Previous established evidence exhibits that adults prescribed tricyclic antidepressants have an increased risk of caries. Simultaneously, a global trend of increased prescriptions of antidepressant medications is seen. In Sweden during 2018, 0–17-year old’s on antidepressant medication represented 1,6% percent of the total population. It is of utmost relevance to investigate the association between antidepressants and caries as the increasing population of medicating children may lead to an increased caries prevalence. A systematic literature review was performed in accordance with PRISMAs guidelines. The title-abstract and keywords searches were conducted in the following seven bibliographic databases: PubMed, EMBASE, CINAHL, Scopus, Web of Science, PsycINFO and MedLine. The search consisted of blocks based on “caries”, “children” and “antidepressants”. Unique articles were reviewed from title and abstract. Articles that met the criteria were reviewed in full text. The search generated 1829 unique articles, 1891 were excluded from the predefined criteria. 10 articles were reviewed in full text. None of the articles were eligible within the criteria of inclusion. The conclusion is that further research is needed in this area to assess the possible association between antidepressants and caries in children and adolescents. / Uppsatsen syftar till att sammanställa forskningsläget för sambandet mellan antidepressiv medicinering och karies hos barn och ungdomar. Tidigare evidens visar att vuxna som medicinerar med tricykliska antidepressiva har ökad kariesrisk. Samtidigt kan man globalt se en generell förskrivningsökning av antidepressiva. I Sverige under 2018, utgjorde användarna av antidepressiva i åldersgruppen 0–17 år 1,6% av totalpopulationen. Det är av högsta relevans att undersöka om det finns en potentiell association mellan antidepressiva och karies finns då den ökande populationen av medicinerande barn kan medföra ökad kariesprevalens. En systematisk litteraturöversikt genomfördes enligt PRISMAs riktlinjer. Titel- sammanfattnings och nyckelordssökningen utnyttjade följande sju elektroniska databaser: PubMed, EMBASE, CINAHL, Scopus, Web of Science, PsycINFO och MedLine. Sökningen utfördes i block utifrån “karies”, “barn” och “antidepressiva”. Unika artiklar granskades utifrån titel och abstrakt. Artiklar som uppfyllde förutbestämda kriterier för inklusion granskades i fulltext. Utifrån sökningen påträffades 1829 unika artiklar, varav 1819 exkluderades utifrån från titel och abstrakt. 10 artiklar granskades i fulltext och vi konstaterade att ingen artikel uppfyllde kriterierierna. Slutsatsen för studien är att fler studier och mer forskning behövs inom området. Detta för att kunna svara på om det finns ett samband mellan antidepressiva och karies hos barn.

Within the field of depression the “monoamine hypothesis” has been the leading theory to explain the biological basis of depression. This theory proposes that the biological basis of depression is due to a deficiency in one or more of three key neurotransmitter systems, namely noradrenaline, dopamine and serotonin which are thought to mediate the therapeutic actions of virtually every known antidepressant agent. Citalopram is a selective serotonin-reuptake inhibitor (SSRI) used for the treatment of depression and anxiety disorders. Citalopram is a racemic compound, in other words composed of a 50:50 mixture of two enantiomers (S-(+)-citalopram and R-(-)-citalopram) and with one of the enantiomers (S-(+)-citalopram) accounting for the inhibitory effect. At the time of introduction of citalopram the physician needed a therapeutic drug monitoring service to identify patients with interactions, compliance problems and for handling questions concerning polymorphic enzymes and drug metabolism. An achiral analytical separation method based on solid-phase extraction followed by high-performance liquid chromatography (HPLC) was developed for routine therapeutic drug monitoring (TDM) of citalopram and its two main demethylated metabolites. As the data available on citalopram were from achiral concentration determinations and to be able to further investigate citalopram enantiomers effects and distribution, a chiral method for separation of the enantiomers of citalopram and its demethylated metabolites was established. The advances within chiral separation techniques have made measurement of the concentrations of the individual enantiomers in biological fluids possible. The process behind enantioselective separation is however not fully understood and the mechanism behind the separation can be further scrutinized by the use of multivariate methods. A study of the optimization and characterization of the separation of the enantiomers of citalopram, desmethylcitalopram and didesmethylcitalopram on an acetylated ß-cyclodextrin column, by use of two different chemometric programs - response surface modelling and sequential optimization was performed. Sequential optimization can be a quicker mean of optimizing a chromatographic separation; response surface modelling, in addition to enabling optimization of the chromatographic process, also serves as a tool for learning more about the separation mechanism. Studies of the antidepressant effect and pharmacokinetics of citalopram have been performed in adults, but the effects on children and adolescents have only been studied to a minor extent, despite the increasing use of citalopram in these age groups. A study was initiated to investigate adolescents treated for depression, with respect to the steady-state plasma concentrations of the enantiomers of citalopram and its demethylated metabolites. The ratios between the S- and R-enantiomers of citalopram and didesmethylcitalopram were in agreement with studies involving older patients. The concentrations of the S-(+)- and R-(-) enantiomers of citalopram and desmethylcitalopram were also in agreement with values from earlier studies. The results indicate that the use of oral contraceptives may have some influence on the metabolism of citalopram. This might be because of an interaction of the contraceptive hormones with the polymorphic CYP2C19 enzyme. Even though the SSRIs are considered less toxic compared with older monoamine-active drugs like the tricyclic/tetracyclic antidepressants, the risk of developing serious side effects such as ECG abnormalities and convulsions has been seen for citalopram, when larger doses have been ingested. Furthermore, fatal overdoses have been reported where citalopram alone was the cause of death. Data on the toxicity of each of the enantiomers in humans have not been reported and no data on blood levels of the enantiomers in cases of intoxication have been presented. An investigation was initiated on forensic autopsy cases where citalopram had been found at the routine screening and these cases were further analysed with enantioselective analysis to determine the blood concentrations of the enantiomers of citalopram and metabolites. Furthermore the genotyping regarding the polymorphic enzymes CYP2D6 and CYP2C19 were performed. In 53 autopsy cases, we found increasing S/R ratios with increasing concentrations of citalopram. We found also that high citalopram S/R ratio were associated with high parent drug to metabolite ratio and may be an indicator of recent intake. Only 3.8 % were found to be poor metabolizers regarding CYP2D6 and for CYP2C19 no poor metabolizer was found. Enantioselective analysis of citalopram and its metabolites can provide valuable information about the time that has elapsed between intake and death. Genotyping can be of help in specific cases but the possibility of pharmacokinetic interactions is apparently a far greater problem than genetic enzyme deficiency. / On the day of the public defence the status of article IV was: Submitted.

<p>This thesis explored the epidemiology of Posttraumatic Stress Disorder (PTSD) and different aspects of the disorder. Firstly, we investigated the lifetime prevalence of traumatic experiences and PTSD in the general adult population in Sweden and evaluated the impact of different trauma types, trauma frequency, and perceived distress. The results show that traumatic experiences are common and PTSD is not rare; roughly one out of ten traumatic events results in PTSD, with a 5.6% lifetime prevalence. The female/male ratio is 2:1. The risk for PTSD increases considerably with a high trauma-associated emotional impact. The distressing impact of a given trauma appears to be higher in women than in men, indicating an increased vulnerability in women. Secondly, we hypothesized that traffic road accidents (TRA’s) are one of the most prevalent types of traumatic events in Swedish society; therefore, we examined the impact of event and response characteristics associated with TRA’s on PTSD development. The data demonstrate that of those who had experienced a TRA (n=1074, 58.9%), 6.1% reported lifetime PTSD. TRA’s associated with fatal accidents and injury to oneself and related to high distress more than double the risk for PTSD. Thirdly, we compared the relative merits of the DSM-IV’s three-factor solution for PTSD symptoms to alternative models. We found that the symptomatology is equally well accounted for using all factor analytic models as yet presented in the literature; the DSM-IV, we found, provides as good a fit to data as other models. Fourthly, we examined the neurofunctional correlates of PTSD symptoms and whether a treatment-induced (serotonin reuptake inhibitor - SSRI) reduction of PTSD symptoms is associated with altered rCBF during symptom provocation. Our results indicate that PTSD symptoms correlates with areas involved in memory, emotion, attention, and motor control and that SSRI treatment normalizes provocation-induced rCBF in these areas.</p>

This thesis explored the epidemiology of Posttraumatic Stress Disorder (PTSD) and different aspects of the disorder. Firstly, we investigated the lifetime prevalence of traumatic experiences and PTSD in the general adult population in Sweden and evaluated the impact of different trauma types, trauma frequency, and perceived distress. The results show that traumatic experiences are common and PTSD is not rare; roughly one out of ten traumatic events results in PTSD, with a 5.6% lifetime prevalence. The female/male ratio is 2:1. The risk for PTSD increases considerably with a high trauma-associated emotional impact. The distressing impact of a given trauma appears to be higher in women than in men, indicating an increased vulnerability in women. Secondly, we hypothesized that traffic road accidents (TRA’s) are one of the most prevalent types of traumatic events in Swedish society; therefore, we examined the impact of event and response characteristics associated with TRA’s on PTSD development. The data demonstrate that of those who had experienced a TRA (n=1074, 58.9%), 6.1% reported lifetime PTSD. TRA’s associated with fatal accidents and injury to oneself and related to high distress more than double the risk for PTSD. Thirdly, we compared the relative merits of the DSM-IV’s three-factor solution for PTSD symptoms to alternative models. We found that the symptomatology is equally well accounted for using all factor analytic models as yet presented in the literature; the DSM-IV, we found, provides as good a fit to data as other models. Fourthly, we examined the neurofunctional correlates of PTSD symptoms and whether a treatment-induced (serotonin reuptake inhibitor - SSRI) reduction of PTSD symptoms is associated with altered rCBF during symptom provocation. Our results indicate that PTSD symptoms correlates with areas involved in memory, emotion, attention, and motor control and that SSRI treatment normalizes provocation-induced rCBF in these areas.

Obsessive–compulsive disorder (OCD) is a psychiatric condition that is characterized by two main symptom cohorts, namely recurrent inappropriate thoughts (obsessions) and seemingly purposeless repetitive motor actions (compulsions). In 70% of cases, the condition only re–sponds to chronic, but not sub–chronic, high dose treatment with the selective serotonin reup–take inhibitors (SSRIs), such as fluoxetine and escitalopram. This indicates a role for hyposero–tonergic functioning in the primary brain areas involved in OCD, namely the components of the cortico–striatal–thalamic–cortical (CSTC) circuit which include the prefrontal cortex, the basal ganglia, and the thalamus. A number of studies have demonstrated a lower serotonin trans–porter (SERT) availability in OCD patients compared with healthy controls, supporting the hy–pothesis of a hyposerotonergic state in OCD. The current study focuses on the validation of the deer mouse (Peromyscus maniculatus bairdii) model of OCD and builds on previous work done in our laboratory. Deer mice that are bred and housed in confinement naturally develop two main forms of stereotypical behaviour, namely vertical jumping and pattern running. Furthermore, these behaviours can be catego–rized into various levels of severity, namely high (HSB), low (LSB) and non–stereotypic (NSB) cohorts. The seemingly purposeless and repetitive nature of these behaviours mimics the com–pulsions that characterize human OCD and constitutes the basis for the face validity of the model. However, although these two forms of stereotypy seem equally repetitive and persis–tent, stereotypical pattern runners do not complete the required number of cage revolutions per 30 minutes compared to the amount of jumps executed by stereotypical vertical jumpers. As only one set of criteria for the appraisal of the different topographies of deer mouse stereotypy has been applied in previous studies, the matter of whether pattern runners do in fact generate stereotypical behaviour of the same persistent and severe nature as opposed to the behaviour expressed by vertical jumpers, is problematic. Therefore, the first objective of the current study was to develop a new classification system for the appraisal of the different forms of behavioural topographies of deer mice and subse–quently to evaluate whether pattern runners can indeed be categorized into non–, low– and high stereotypical cohorts. After an eight–week behavioural assessment period, deer mice express–ing the two different behavioural topographies could be classified into non–, low– and high stereotypical cohorts (NSB, LSB, and HSB respectively), applying different criteria for each be–havioural topography. Based on the weekly mean stereotypy count generated during three 30–minute intervals of highest stereotypical behaviour over the course of a 12–hour assessment period, HSB pattern runners were found to execute on average 296 cage revolutions per 30 minutes, while HSB vertical jumpers executed an average of 3063 jumps per 30 minutes. This discrepancy between the generated numbers of the different topographies of stereotypy indi–cates that one classification system for the appraisal of both behavioural topographies is indeed inappropriate, and hence requires re–evaluation and validation. As patients with OCD present with a lower central SERT availability compared to healthy controls, the second objective of the study was to determine whether a decrease in SERT den–sity could be demonstrated in HSB animals compared to the NSB and LSB controls. After eight weeks of behavioural assessment, animals were sacrificed and frontal–cortical and striatal SERT binding was performed. HSB deer mice presented with significantly lower striatal, but not fron–tal–cortical SERT availability compared to the [NSB/LSB] control animals (p = 0.0009). As far as it concerns a lower SERT availability in HSB animals and involvement of the CSTC circuitry, this data is congruent with that demonstrated in human OCD and strengthens the construct validity of the model. Although previous studies undertaken in our laboratory demonstrated that deer mouse stereotypy is attenuated after chronic (21–day) fluoxetine administration, OCD only responds to chronic, but not sub–chronic treatment with the SSRIs. The lack of response of deer mouse stereotypy to sub–chronic treatment has not been established and therefore the third study ob–jective was to assess the behavioural effects of sub–chronic (7–day) and chronic (28–day) SSRI treatment on expression of deer mouse stereotypy. Chronic, but not sub–chronic treatment with oral escitalopram (50 mg/kg/day) significantly increased the number of intervals over a 12–hour assessment period during which no stereotypical behaviour were expressed by HSB deer mice (p = 0.0241) and decreased the number of intervals during which high–stereotypical be–haviour were executed (p = 0.0054). Neither chronic, nor sub–chronic treatment significantly affected the behaviour of animals in the [NSB/LSB] cohort. The fact that the model demon–strates a lack of response to sub–chronic treatment with high dose SSRIs, positively contributes to the predictive validity of the deer mouse model of OCD. The results from the current study therefore strengthens the construct and predictive valid–ity of the deer mouse model of OCD and confirm the model’s status as a prominent animal model of OCD. Not only is hyposerotonergic functioning in the CSTC circuitry implicated in the behaviour of HSB animals, but the model also demonstrates selective response to chronic SSRI–treatment - two core characteristics of human OCD. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.