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.

Die grundlegenden neurobiologischen Mechanismen für das Zusammenwirken eines pathologisch erhöhten Körpergewichts und der gewichts-assoziierten emotionalen Belastung sind bisher noch wenig erforscht. Die vorliegende Arbeit untersucht gezielt Abweichungen der regionalen Transporter-Verfügbarkeiten mittels Positronen-Emissions-Tomographie (PET) mit hochselektiven Marker für den Noradrenalin- (NET) sowie den Serotonin-(5-Hydroxytryptamin-)transporter (5-HTT) und funktioneller Magnetresonanztomographie (fMRT) sowie damit verbundene Alterationen der neuronalen Ruhe-(resting-state-)Aktivität konnektierter Hirnregionen. Die Ergebnisse der kombinierten PET/fMRT Analyse wurden mit zwei neuropsychologischen Scores zur Erfassung allgemeiner und gewichtsabhängiger emotionaler Veränderungen korreliert. Insgesamt 48 Teilnehmer (Body-Mass-Index [BMI]: 19 - 50 kg/m2) erhielten eine fMRT und eine PET mittels NET-selektivem [11C]MRB (n = 20) beziehungsweise 5-HTT-selektivem [11C]DASB (n = 28). Die PET ergab im Hypothalamus eine tendentielle, BMI-abhängig verminderte Verfügbarkeit des NET, nicht jedoch des 5-HTT. Zusätzlich fand sich bei steigendem BMI innerhalb beider Neurotransmitternetzwerke in Abhängigkeit zur jeweiligen Transporter-Verfügbarkeit eine teils geschlechtsspezifisch verstärkte funktionelle Konnektivität zwischen dem Hypothalamus und Hirnregionen der Verarbeitung und Bewertung von Nahrungsreizen. Korrelationen der lokalen resting-state Aktivitäten mit den neuropsychologischen Scores lassen vermuten, dass diese Regionen zudem auch mit langfristigen, negativen Veränderungen des gewichtsabhängigen emotionalen Wohlbefindens assoziiert sind. Insgesamt spielen diese beiden zentralen Neurotransmitter-Systeme eine wichtige Rolle in der Modulation von Netzwerken zur Regulation des gewichtsabhängigen emotionalen Wohlbefindens und könnten somit wichtige Anhaltspunkte für neue pharmakologische Ansätze bereitstellen.