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Thesis (Ph.D. (Pharmacology))--North-West University, Potchefstroom Campus, 2007. There have been various attempts to develop animal models of obsessive compulsive disorder (OCD) in the hope that they may provide a means to better understand and treat this disorder. Given that the aetiology of OCD most likely involves the interaction of multiple genetic and environmental factors, animal models in which the behavioural pathology develops spontaneously may be particularly useful. With this in mind, the present study has set out to evaluate the predictive, construct and face validity of naturalistic stereotypic behaviour in the deer mouse (Peromyscus maniculatus bairdii). The diversity of stereotypy in deer mice, and its separation into different degrees of stereotypy in different animals, was validated by comparison to C57B1 mice, an animal not known to engage in stereotypy under standard laboratory conditions. Given the selective response of OCD to serotonin reuptake inhibitors (SRIs) compared to noradrenaline reuptake inhibitors (NRIs), behavioural response to chronic administration of a SRI and a NRI was investigated. Validation studies were initiated by comparing untreated stereotypic deer mice to non-stereotypic C57B1 mice. Deer mice engaged in clear, stereotypic behavioural patterns such as backward somersaulting, repetitive jumping, and patterned running. Deer mice executed stereotypic behaviour to different extents within the population and could be classified as low stereotypic (LSB), high stereotypic (HSB ), or non-stereotypic mice. C57B1 did not perform any stereotypic behaviour and comparison of the two mouse strains not only highlights the stereotypic behaviour of deer mice, but also contributes to the face validity of the model. Given the dose-specific therapeutic effects of SRI's in OCD, predictive validity was evaluated by administering fluoxetine and desipramine to stereotypic deer mice at either low (10 mg/kg) or high (20 mg/kg) doses for 21 days. In view of the important role of serotonin (5-HT) and dopamine in the neurobiology of OCD, the response to 5-HT and doparnine receptor agonists, and whether the resulting behaviours can be modified by chronic fluoxetine or desipramine treatment was also studied. Subacute challenge studies with the 5-HT2A/C agonist, meta-chlorophenylpiperazin (mCPP) and the D2 agonist, quinpirole (QNP) were administered at doses of 2 mg/kg and 5 mg/kg respectively for 4 days with and without high-dose (20mg/kg) SRI or NRI treatment. High and low dose fluoxetine, but not desipramine, significantly reduced stereotypic behaviour compared to vehicle-treated animals in stereotypy animals, providing predictive validity. Subacute mCPP and QNP challenges evoked significant suppression of stereotypic behaviours, while high dose fluoxetine, but not desipramine, reversed the suppressive effects of mCPP and QNP in LSB and HSB mice. This distinct involvement of dopamine D2 and 5- HT2A and 5-HT2c receptors in stereotypic behaviour in deer mice confers noteworthy construct validity to the model. OCD has been associated with disturbances in signalling of the cyclic adenosine 3', 5'- cyclic monophosphate (CAMP) cascade. To this end, molecular data collected in the study have focussed on striatal and prefrontal cortex measurement of cAMP and the expression of phosphodiesterase 4 (PDE4) enzymes. Importantly, the degree of stereotypy could be linked to cAMP under basal conditions. High stereotypic mice had the highest cAMP levels compared to low and non-stereotypic and C57B1 mice. High stereotypy was also characterised by low PDE4 activity. Analysis of protein expression found an increase in PDE 4A1, 4A5, 4A8, and 4D1 in the prefrontal cortex of HSB mice as well as the striatum of LSB mice. The negative correlation between PDE4 and cAMP levels provides definitive confirmation for altered states of the cAMP signalling cascade in the corticostriatal- thalamic-cortico (CSTC) circuit of these animals. Differences in regional expression of PDEs are explained by the need of each region to express its own compliment of functionally relevant PDE4 isoforms. Darpp-32 is an important protein and marker for activity along the Dl/& receptor pathway. The study has described the differential regulation of Darpp-32 phosphorylation on Thr34 and Thr75 and suggests an imbalance along the D1/D2 pathway in the CSTC circuit of deer mice. Construct validity of the model was explored by examining distinct molecular parameters linked to drug treatment. Chronic drug treatment and subacute challenges noticeably highlight the disparity between LSB and HSB mice. This discrepancy is seen at the molecular levels in HSB mice where the cAMP pathway is down-regulated following drug treatment or challenge. Accordingly, the severity of pre-existing behavioural and/or neurochemical abnormalities is not only a factor to be utilized for behavioural classification, but is also the basis for differential molecular responses. In conclusion, the present study provide behavioural and pharmacological evidence that spontaneous stereotypic behaviour in the deer mice presents with significant face, predictive and construct validity as an animal model of OCD. Doctoral |
