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.

This thesis extends the understanding of the neural and neurochemical contributions to two forms of behavioural adaptation, reversal learning and contingency degradation, in which stimulus/action-reward contingencies are altered. The results are interpreted within the psychological framework of the compulsivity construct, and their implications for the pathological behaviour of obsessive-compulsive-disorder (OCD) are considered. The orbitofrontal cortex (OFC) and striatum are key brain structures involved in reversal learning, as are the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) within those respective regions. However, there has been little empirical evidence of how these two structures and neurochemical systems interact, especially in the functional context of reversal learning. In Chapter Three, the impact of experimentally-induced reductions of 5-HT in the anterior OFC on monoamine levels in subcortical structures such as the striatum and amygdala was determined, DA being found to be significantly up-regulated in the amygdala. Functionally, 5-HT depletion of the OFC has previously been shown to induce deficits in reversal learning. To determine the possible causal significance of amygdala dopamine up-regulation for said reversal learning deficit, the effects of blocking the upregulation with the infusion of intra amygdala DA receptor antagonists following bilateral OFC 5-HT depletion were investigated in a reversal learning paradigm. In Chapter Four, the differential roles of regions of striatum were examined in visual reversal learning. Two recent investigations in non-human primates highlighted the role of the striatum in reversal learning,but pinpointed the critical region to be either the ventromedial caudate or the putamen. Marmosets were trained on a serial reversal task that allowed multiple acute neural manipulations, and the ventromedial caudate and putamen were then reversibly inactivated using the GABAA agonist muscimol. Results indicated dose-related impairments specifically in reversal learning within the putamen, with sparing of discrimination retention. By contrast, similar reversible inactivation of the caudate nucleus produced marked deficits in visual discrimination performance (retention). In Chapter Five, the neural basis of action-outcome contingency knowledge was investigated by inactivating distinct regions of the PFC, the perigenual ACC (pgACC; area 32) and the anterior OFC, and determining response sensitivity to the degradation of action-outcome contingencies. In previous work, excitotoxic lesions of either the pgACC or the OFC had been found to induce insensitivity to contingency degradation in marmosets. However, the design of that experiment did not allow specification of whether stimulus- or action-outcome associations were disrupted, and a precise neural locus could not be determined for the behavioural effects as the OFC lesions included parts of the lateral and medial OFC. I therefore developed a novel contingency degradation paradigm that distinguished between stimulus- and action-outcome associations to enable the study of acute pharmacological manipulations in both brain regions. The pgACC and OFC were reversibly inactivated using GABAA-GABAB agonists (muscimol-baclofen). Whereas the pgACC inactivation produced selective deficits in sensitivity to action-outcome contingency degradation, OFC inactivation reduced the suppressive effect of noncontingent reward on responding more generally but left intact sensitivity to degradation of the contingencies. These results are discussed in terms of different theories of the functions of the pgACC and OFC. In the final discussion the findings on the neural substrates of reversal learning and contingency degradation are drawn together in terms of their significance for theories of PFC involvement in cognitive control, and for the understanding of OCD and other neuropsychiatric disorders.

本研究旨在探討「健康、性格、習慣量表(HPH)」的臨床效度。HPH最初是由柯永河教授(民84)編製，後來廣泛使用在國內臨床場域中。發展至今已有中上程度的信效度支持，但過去較缺乏臨床上區辨與構念效度的研究，因此本研究旨在探討HPH區辨不同疾患的能力，以及以臨床疾患為受試時量尺之構念效度。 本研究回顧國內外類似測驗─MMPI、KMHQ、MCMI─的發展軌跡，並參照前人作法來進行HPH的臨床區辨效度研究。初步以臨床場域中常見的精神分裂症、重鬱症、低落型情感疾患、焦慮疾患，共257名患者為受試。先以共變數分析(ANCOVA)探討控制人口與臨床變項後，不同疾患組別在HPH的A、B、D類量尺的影響。再進一步使用羅吉斯迴歸(logistic regression)探討哪些量尺及其組合可以區辨兩兩疾患間的差異。最後，本研究也進行HPH的探索性因素分析(exploratory factor analysis)，以檢驗其臨床上的因素結構。 本研究發現，精神分裂症(A1)、躁症傾向(A2)、憂鬱自殺類(A3、B4、A4)、心理功能與健康(D1、D3、D4、D5、D6)量尺在共變數分析上的差異情形與假設大致相符，後續討論分析也支持強迫症(B5)量尺效度。羅吉斯迴歸中，A1、A3、B4、B5能在兩兩疾患間區辨有顯著預測力。其中A1能在精神分裂症與其他三組疾患的兩兩區辨中預測，A3能在重鬱症與另外兩組(精神分裂症、焦慮症)的兩兩區辨中預測，B4能在低落型情感與精神分裂症的兩兩區辨中預測，B5能在強迫症與其他疾患間的兩兩區辨中預測。但是在重鬱症與低落型情感疾患間，以及低落型情感與焦慮疾患間，沒有量尺能在兩者的區辨中有顯著預測力。而各兩兩疾患間整體區辨效果有中至高度的關聯性，分類正確率也多有七成以上，顯示HPH量表在臨床上的區辨效度獲得支持。 構念效度部分，A、D類量尺因素結構與當初編製的每個量尺構念相近，B類量尺構念雖與原量尺略有不同，但仍不違背原量尺編製架構，因此構念效度亦獲得支持。不過各量尺仍有值得編修之處，討論一節中針對結果提出HPH後續編修之建議。 最後，本研究也將此結果之臨床實務應用於討論一節中詳述，以供後續研究與實務者參考。 / The purpose of this study is to examine the clinical validity of the Health, Personality, and Habit Test (HPH). The HPH was developed by Dr. Yung-Ho Ko in 1995, and has been widely used in clinical settings. The HPH has demonstrated appropriate reliability and validity, but little research has been done on its differential and construct validity in the clinical settings. Therefore, the aim of this study is to explore the HPH’s ability to differentiate between disorders and its construct validity in clinical context. This research reviewed the developments of similar tests, such as MMPI, KMHQ, and MCMI, and examined validity of the HPH with the same methods. Subjects were 257 patients who suffered from common disorders in clinical settings, including schizophrenia, major depression, dysthymia, and anxiety disorders. ANCOVA was first used to explore whether different disorders have an effect on category A, B, and D scales after controlling demographic and clinical variables. Next, logistic regression was used to clarify which scales and combinations can differentiate between two of four disorders. Finally, exploratory factor analysis was conducted to examine the structure of HPH in clinical setting. The results of ANCOVA showed that the differences of schizophrenia scale (A1), manic scale (A2), depression/suicide scales (A3, B4, & A4), obsessive-compulsive disorder (OCD) scale (B5), and psychological function and health scales (D1, D3, D4, D5, D6) were partly consistent with assumptions, supporting the differential validity of HPH. The results of logistic regression analysis also supported the validity of A1, A3, B4, and B5 scales. More specifically, A1 was able to differentiate schizophrenia from any other three disorders, A3 was able to differentiate MDD from schizophrenia and anxiety disorders, B4 was able to differentiate dysthymia from schizophrenia, and B5 was able to differentiate OCD from other disorders. However, none of the scales was able to differentiate MDD from dysthymia, nor were they able to differentiate dysthymia from anxiety disorders. Moreover, each of the logistic regression functions showed moderate to high correlations, and most of them achieved high overall hit rates (above 70%), providing support for the clinical differential validity of the HPH. As for construct validity, these factors in category A and D scales were essentially similar to original scales. Similarly, factors in category B scales were compatible to original scales though difference was found. In sum, these results lent support to the construct validity of the HPH in the clinical settings. However, refining of the scales is needed and suggestions are discussed. Finally, the practical uses of the findings were also discussed.