Proefschrift Maastricht. / Met lit. opg. en samenvatting in het Nederlands.

Depression is a psychiatric disorder associated with severe impairment in physical, social and role functioning, and with higher health care utilization. Experiencing an event that causes physical or psychological stress may substantially increase a person's chances of developing depression. Coping has been defined as a response aimed at diminishing the physical, emotional and psychological burden that is associated with stressful life events. Coping is considered one of the core concepts in health psychology and is strongly associated with the regulation of emotions throughout the stress period and thus it is important that it is understood, especially in the South African context of future morbidity. The purpose of this study was to determine whether there is a relationship between coping self–efficacy strategies and depression in an African context. Participants consisted of a convenience sample of 2 198 participants from both rural and urban areas. The rural group consisted of 182 adolescent Further Education and Training (FET) students between the ages of 16 and 21 years, and the urban group consisted of another 2 016 adolescent FET students between the ages of 16 and 21 years. Participants from both groups completed measurements on coping and depression. Two self–report measures were used: the Coping Self–Efficacy Scale (CSE) to determine a person's confidence or perceived self–efficacy in performing coping behaviors when facing life challenges or threats and the Patient Health Questionnaire (PHQ9) to measure depression severity. Descriptive analysis results indicated that a relationship existed between coping selfefficacy strategies and depression and that levels of depression were very similar for both rural (9.23) and urban (9.25) groups. Coping strategies were very different in rural and urban areas; rural participants only used problem–focused coping and stop unpleasant thoughts and emotions, while urban participants used all three coping self–efficacy strategies: problemfocused coping, stopping unpleasant thoughts and emotions and support from friends and family. Rural participants did not use support from friends and family as a coping selfefficacy strategy; possibly due to the different relationships people living in rural areas have with one another, as opposed to the relationships of people living in urban areas. Rural people may not deem it socially acceptable to ask friends or family members or help when struggling with various stressors. Alternatively, rural areas may be more depleted of personal resources due to the strong urbanization process going on. It was concluded that there is an important relationship between coping strategies and level of depression, and in this study this relationship was found to be different in some ways for rural and urban groups. The results of this study have great implications for further research and clinical practice. / Thesis (M.A. (Research Psychology))--North-West University, Potchefstroom Campus, 2011.

Depression is a psychiatric disorder associated with severe impairment in physical, social and role functioning, and with higher health care utilization. Experiencing an event that causes physical or psychological stress may substantially increase a person's chances of developing depression. Coping has been defined as a response aimed at diminishing the physical, emotional and psychological burden that is associated with stressful life events. Coping is considered one of the core concepts in health psychology and is strongly associated with the regulation of emotions throughout the stress period and thus it is important that it is understood, especially in the South African context of future morbidity. The purpose of this study was to determine whether there is a relationship between coping self–efficacy strategies and depression in an African context. Participants consisted of a convenience sample of 2 198 participants from both rural and urban areas. The rural group consisted of 182 adolescent Further Education and Training (FET) students between the ages of 16 and 21 years, and the urban group consisted of another 2 016 adolescent FET students between the ages of 16 and 21 years. Participants from both groups completed measurements on coping and depression. Two self–report measures were used: the Coping Self–Efficacy Scale (CSE) to determine a person's confidence or perceived self–efficacy in performing coping behaviors when facing life challenges or threats and the Patient Health Questionnaire (PHQ9) to measure depression severity. Descriptive analysis results indicated that a relationship existed between coping selfefficacy strategies and depression and that levels of depression were very similar for both rural (9.23) and urban (9.25) groups. Coping strategies were very different in rural and urban areas; rural participants only used problem–focused coping and stop unpleasant thoughts and emotions, while urban participants used all three coping self–efficacy strategies: problemfocused coping, stopping unpleasant thoughts and emotions and support from friends and family. Rural participants did not use support from friends and family as a coping selfefficacy strategy; possibly due to the different relationships people living in rural areas have with one another, as opposed to the relationships of people living in urban areas. Rural people may not deem it socially acceptable to ask friends or family members or help when struggling with various stressors. Alternatively, rural areas may be more depleted of personal resources due to the strong urbanization process going on. It was concluded that there is an important relationship between coping strategies and level of depression, and in this study this relationship was found to be different in some ways for rural and urban groups. The results of this study have great implications for further research and clinical practice. / Thesis (M.A. (Research Psychology))--North-West University, Potchefstroom Campus, 2011.

AFRIKAANS: Die doel van hierdie studie is om te verken of die Ericksoniaanse terapiebenadering met sandspelterapie gekombineer kan word om kinders en adolessente wat depressiewe gedrag toon, te ondersteun. Die studie is uitgevoer deur middel van gevallestudies waar kinders en adolessente wat depressiewe gedrag toon, ondersteun is deur middel van die Ericksoniaanse benadering tot sandspelterapie. Die motivering vir hierdie studie hou verband met jarelange interaksie met kinders wat emosionele ontwikkelingsteurnisse ervaar het wat beperkend was met betrekking tot die bereiking van hul volle potensiaal. Ek wou dus ondersoek instel na die moontlikheid om die Ericksoniaanse terapie-benadering met sandspelterapie te kombineer in die behandeling van kinders en adolessente wat depressiewe gedrag toon. My navorsing was daarop gerig om ‘n moontlike kennisbydrae te lewer tot die gebruik van die gekombineerde benadering met kinders en adolessente wat depressie as ontwikkelingsteurnis ervaar. ‘n Teoretiese raamwerk is gebruik wat uit verskillende teorieë bestaan het as 'n lens waardeur ek data geanaliseer en interpreteer het. Die ekologiese teorie, sisteemteorie en transteoretiese model is tydens die studie as teoretiese raamwerk bespreek. ‘n Intervensiestudie gekombineer met ‘n gevalstudie as navorsingsontwerp is tydens my studie gebruik. Ek het kwalitatiewe datainsamelingstegnieke in die onderhawige studie geïmplementeer ten einde die navorsingsprobleem en bevindinge deurtastend te ondersoek en te beskryf. Die data-analisestrategieë wat in die studie geïmlementeer was, berus op Creswell (2003) en Creswell (2005) se benaderings (Sien bl. 109). In antwoord op my primêre navorsingsvraag, het ek tot die gevolgtrekking gekom dat die Ericksoniaanse benadering in kombinasie met sandspelterapie wel van waarde mag wees vir sommige kinders en adolessente wat depressie as ontwikkelingsteurnis ervaar. / ENGLISH: The aim of this study was to investigate the possibility of combining the Ericksonian method with sandplay therapy to support children and adolescents with depression as developmental disorder. The aforementioned was executed by examining case studies in which children and adolescents that showed depression was supported by the Ericksonian method to sandplay therapy. This study was motivated by the researcher’s interaction with children that showed emotional developmental disorders and where these developmental disorders delayed the attainment of their potential. One of the reasons for my research was the potential contribution of knowledge towards the use of the combined method with children and adolescents whom experience depression as developmental disorder. The echological theory, systems theory and trans-theoretical model was used as theoretical framework for my study. I made use of an intervention study combined with a case study during the research. In order to investigate and describe the research problem and findings I implemented qualitative data-collection strategies. / Thesis (PhD)--University of Pretoria, 2011. / Educational Psychology / unrestricted

Motivation - Depression is a mental disorder that has been associated with cardiovascular morbidity and mortality in the Western world. Cardiometablic mechanisms have been implicated as possible intermediating factors in the relationship between depressive symptoms and cardiovascular disease; however this has not yet been determined in black Africans (hereafter referred to as Africans). Aim - The overarching aim of this study was to investigate the relationship between depressive symptoms and cardiometabolic risk. We therefore aimed to assess cardiometabolic function, neuroendocrine responses, inflammatory and haemostatic markers in Africans with depressive symptoms compared to those without symptoms of depression. Methodology - Manuscripts presented in Chapter 2, 3 and 4 utilised data from the cross-sectional, target population multi-disciplinary “Sympathetic activity and Ambulatory Blood Pressure in Africans” (SABPA) study. The participants comprised of 200 African teachers from the Dr Kenneth Kaunda District in North-West province, South Africa. As cardiovascular disease is compromised by a positive HIV status, 19 participants were excluded from further statistical analysis. Stratification was based on the Patient Health Questionnaire 9-item (PHQ-9), which has been validated in a sub-Saharan African setting. PHQ-9 scores > 10 were used to classify participants as having signs of depressive symptoms. Subjects were further stratified by gender (Manuscript 1 and 3) and cortisol responses (Manuscript 2). Cardiometabolic health measures included 24-hour blood pressure, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], left ventricular hypertrophy (LVH),inflammatory and haemostatic markers (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Resting 12-lead ECG Cornell Product-Left ventricular hypertrophy (CP-LVH) was measured as a marker of target end-organ damage and cardiovascular dysfunction (Manuscript 1 and 2). Means and prevalence were computed through t-test and Chi-square analysis respectively. Significant differences of mean cardiometabolic measures between depressive symptom status groups were also determined by analysis of covariance (adjusted for traditional cardiovascular risk factors and additional factors as specific per manuscript). Multivariate analysis was used to demonstrate associations between left ventricular hypertrophy (LVH) and cardiometabolic markers in Africans with depressive symptoms (Manuscript 1 and 2) and a logistic regression analysis were performed to examine the association between depressive symptoms and inflammatory/haemostatic factors (Manuscript 3). All subjects who participated gave informed consent, the study was approved by the Ethics Committee of North-West University (NWU-0003607S6), in accordance with the principles outlined by the World Medical Association Declaration of Helsinki of 1975 (revised 2008). Results and conclusions of the individual manuscripts - The aim of the study was to investigate the associations between depressive symptoms and cardiometabolic function including cardiovascular dysfunction. Markers of cardiometabolic function assessed were 24 hour blood pressure measurements, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], inflammatory and haemostatic variables (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Manuscript 1, focused on LVH as a marker of cardiovascular dysfunction and metabolic syndrome components as markers of cardiometabolic function. The aim of the study was to assess the associations between LVH and metabolic syndrome (MetS) risk markers in participants with and without depressive symptoms. Results revealed that in African men with depressive symptoms the most significant determinants of LVH were systolic blood pressure (SBP) and the percentage glycosylated haemoglobin (HbA1c). While in African women (with depressive symptoms), this association was determined by low high-density lipoprotein (HDL-cholesterol). The study concluded that in black African men, independent of depressive symptoms, cardiometabolic factors (namely SBP and HbA1c) may be the driving significant factors in the development of cardiovascular diseases. Furthermore, the data showed that depressive symptoms in African women were associated with a measure of target end organ damage, and that this association was driven by a metabolic factor. Manuscript 2, the aim of this manuscript was to examine the relationship between depressive symptoms, neuroendocrine responses [with cortisol and 3-methoxy-phenylglycol (MHPG) as markers] and cardiovascular risk, i.e. LVH. The results revealed that Africans with depressive symptoms demonstrated blunted cortisol and MHPG levels in response to acute mental stress, in comparison to those without symptoms of depression. Additionally, these low cortisol and blunted MHPG responses were associated with LVH in this ethnic group. The conclusion for this manuscript was that, blunted neuroendocrine responses linked depressive symptoms and ECG left ventricular hypertrophy in Africans. When coupled to their hypertensive status, these vasoconstrictive responses (cortisol and MHPG) may underpin the increased long-term depression and vascular disease risk in urban Africans. Manuscript 3, the aim of this manuscript was to investigate the relationship between depressive symptoms and inflammatory/haemostatic markers in a cohort of urban-dwelling black African men and women. Our data demonstrated hypercoagulation vulnerability in African men with depressive symptoms. The African men with signs of depression displayed higher plasminogen activator inhibitor (PAI-1) levels and marginally elevated D-dimer levels. It was concluded that hypercoagulation may partially be the mediating factor between depressive symptoms and cardiovascular risk in African men; a situation that may be exacerbated by hyperkinetic blood pressure. In conclusion, through the assessement of cardiometabolic function and neuroendocrine responses, it seems that Africans withdepressive symptoms are at great risk for cardiovascular related morbidity and mortality, this was particulary evident in the African men (Manuscript 1 and 3). Additionally, it appears that blunted neuroendocrine responses and hypercoagulation could be seen as possible cardiovascular risk markers in Africans with depressive symptoms. / PhD (Physiology), North-West University, Potchefstroom Campus, 2014

Methamphetamine (MA) is a well-known, easily accessible and powerful psychostimulant, and its abuse has become a global problem. MA abuse affects millions of people worldwide and places an enormous burden on public healthcare resources. Documented consequences of MA abuse include cardiotoxic, neurotoxic and teratogenic effects, as well as long-term consequences of chronic abuse including affective disorders such as schizophrenia and major depressive disorder (MDD). MDD is a highly prevalent mood disorder in both adults and children, documented to contribute to approximately 850 000 suicides annually. This disorder is projected to become the 2nd leading disease of global burden by 2020, preceded only by ischemic heart disease. Depressive-like behaviour is documented as a symptom of chronic MA abuse and particularly during extensive MA withdrawal. Also, MA abuse during pregnancy is documented to cause neurodevelopmental changes that persist into later life. However, current understanding thereof is limited and warrants further investigation of the effects of early-life exposure to MA on outcome in adulthood, particularly in terms of mood disorders. The aim of the current study was to determine the effect of chronic exposure to MA on the depressive-like behaviour later in life in stress-sensitive (Flinders Sensitive Line) and control (Flinders Resistant Line) rats. Rats were exposed during one of the following natal day (ND) age groups: prenatal (ND-13 to ND+02), postnatal (ND+03 to ND+18), prepuberty (ND+19 to ND+34) or puberty (ND+35 to ND+50). These age groups represent different stages in neurodevelopment, as also seen in humans. For prenatal exposure, pregnant dams received 5 mg/kg daily subcutaneously (s.c.), and pups from postnatal, prepuberty and puberty age groups received an escalating dose regimen to simulate “binge-dosing” commonly seen in humans abusing MA. After MA exposure, rats were housed normally until behavioural testing on postnatal day 60 (ND+60), which included the novel object recognition test (NOR), open field test (OFT) and forced swim test (FST), measuring cognitive function, locomotor activity and depressive-like behaviour respectively. The FST data showed increased immobility behaviour of saline-treated FSL rats relative to that of FRL rats, in line with previous data validating FSL rats as a genetic rodent model of depression. Practically significant MA-induced increases in immobility behaviour were observed in all FSL and FRL treatment groups in the FST, reaching statistical significance in prenatally treated FRL rats, and in postnatally, prepuberty and puberty treated FSL rats. The data suggest that early-life MA exposure may alter neurodevelopment to predispose the rats to display depressive-like behaviour in early adulthood, and suggests that this detrimental effect of MA may be more expressed in stress-sensitive rats. Furthermore, all FSL groups plus prenatally and puberty treated FRL rats revealed practically and statistically significant decreases in swimming behaviour in the FST, whereas decreases in swimming behaviour in prepuberty treated FRL rats were practically significant but did not reach statistical significance. These data suggest that MA-induced depressive-like behaviour in FSL rats may be related to impaired serotonergic neurotransmission, and that this appears to be more robust in FSL rats. Climbing behaviour in the FST was generally not altered by early-life MA exposure, with a notable exception being a practically and statistically significant increase in puberty treated FRL rats. These data suggest that in general early-life MA exposure does not affect noradrenergic neurotransmission in early adulthood, except when normal rats were treated at puberty. The reason for the latter observation is not clear. The data from the NOR test revealed no discernible trends of MA-induced effects on memory and cognition, except for a small albeit practically significant increase in exploration time in prepuberty treated FRL rats and a practically and statistically significant decrease in exploration time in puberty-treated FRL rats. Lastly, locomotor activity in the OFT was mostly unaffected by MA treatments, except for practically significant decreases in locomotor activity in postnatally-and prepuberty-treated FRL rats and practically and statistically significant decreases in locomotor activity of prepuberty treated FSL rats. Altered locomotor activity is therefore not expected to explain any of the immobility results of the FST. In final conclusion, the study confirms that early-life MA exposure results in a depressogenic effect later in life in stress-sensitive (FSL) and control (FRL) rats, but appears to be more robust in stress-sensitive animals. Furthermore the data suggest that long-lasting MA-induced depressogenic effects may relate to impaired serotonergic neurotransmission. / MSc (Pharmacology), North-West University, Potchefstroom Campus, 2014

Motivation - Depression is a mental disorder that has been associated with cardiovascular morbidity and mortality in the Western world. Cardiometablic mechanisms have been implicated as possible intermediating factors in the relationship between depressive symptoms and cardiovascular disease; however this has not yet been determined in black Africans (hereafter referred to as Africans). Aim - The overarching aim of this study was to investigate the relationship between depressive symptoms and cardiometabolic risk. We therefore aimed to assess cardiometabolic function, neuroendocrine responses, inflammatory and haemostatic markers in Africans with depressive symptoms compared to those without symptoms of depression. Methodology - Manuscripts presented in Chapter 2, 3 and 4 utilised data from the cross-sectional, target population multi-disciplinary “Sympathetic activity and Ambulatory Blood Pressure in Africans” (SABPA) study. The participants comprised of 200 African teachers from the Dr Kenneth Kaunda District in North-West province, South Africa. As cardiovascular disease is compromised by a positive HIV status, 19 participants were excluded from further statistical analysis. Stratification was based on the Patient Health Questionnaire 9-item (PHQ-9), which has been validated in a sub-Saharan African setting. PHQ-9 scores > 10 were used to classify participants as having signs of depressive symptoms. Subjects were further stratified by gender (Manuscript 1 and 3) and cortisol responses (Manuscript 2). Cardiometabolic health measures included 24-hour blood pressure, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], left ventricular hypertrophy (LVH),inflammatory and haemostatic markers (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Resting 12-lead ECG Cornell Product-Left ventricular hypertrophy (CP-LVH) was measured as a marker of target end-organ damage and cardiovascular dysfunction (Manuscript 1 and 2). Means and prevalence were computed through t-test and Chi-square analysis respectively. Significant differences of mean cardiometabolic measures between depressive symptom status groups were also determined by analysis of covariance (adjusted for traditional cardiovascular risk factors and additional factors as specific per manuscript). Multivariate analysis was used to demonstrate associations between left ventricular hypertrophy (LVH) and cardiometabolic markers in Africans with depressive symptoms (Manuscript 1 and 2) and a logistic regression analysis were performed to examine the association between depressive symptoms and inflammatory/haemostatic factors (Manuscript 3). All subjects who participated gave informed consent, the study was approved by the Ethics Committee of North-West University (NWU-0003607S6), in accordance with the principles outlined by the World Medical Association Declaration of Helsinki of 1975 (revised 2008). Results and conclusions of the individual manuscripts - The aim of the study was to investigate the associations between depressive symptoms and cardiometabolic function including cardiovascular dysfunction. Markers of cardiometabolic function assessed were 24 hour blood pressure measurements, metabolic syndrome markers, neuroendocrine markers [cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG)], inflammatory and haemostatic variables (fibrinogen, C-reactive protein, plasminogen activator inhibitor-1 and D-dimer). Manuscript 1, focused on LVH as a marker of cardiovascular dysfunction and metabolic syndrome components as markers of cardiometabolic function. The aim of the study was to assess the associations between LVH and metabolic syndrome (MetS) risk markers in participants with and without depressive symptoms. Results revealed that in African men with depressive symptoms the most significant determinants of LVH were systolic blood pressure (SBP) and the percentage glycosylated haemoglobin (HbA1c). While in African women (with depressive symptoms), this association was determined by low high-density lipoprotein (HDL-cholesterol). The study concluded that in black African men, independent of depressive symptoms, cardiometabolic factors (namely SBP and HbA1c) may be the driving significant factors in the development of cardiovascular diseases. Furthermore, the data showed that depressive symptoms in African women were associated with a measure of target end organ damage, and that this association was driven by a metabolic factor. Manuscript 2, the aim of this manuscript was to examine the relationship between depressive symptoms, neuroendocrine responses [with cortisol and 3-methoxy-phenylglycol (MHPG) as markers] and cardiovascular risk, i.e. LVH. The results revealed that Africans with depressive symptoms demonstrated blunted cortisol and MHPG levels in response to acute mental stress, in comparison to those without symptoms of depression. Additionally, these low cortisol and blunted MHPG responses were associated with LVH in this ethnic group. The conclusion for this manuscript was that, blunted neuroendocrine responses linked depressive symptoms and ECG left ventricular hypertrophy in Africans. When coupled to their hypertensive status, these vasoconstrictive responses (cortisol and MHPG) may underpin the increased long-term depression and vascular disease risk in urban Africans. Manuscript 3, the aim of this manuscript was to investigate the relationship between depressive symptoms and inflammatory/haemostatic markers in a cohort of urban-dwelling black African men and women. Our data demonstrated hypercoagulation vulnerability in African men with depressive symptoms. The African men with signs of depression displayed higher plasminogen activator inhibitor (PAI-1) levels and marginally elevated D-dimer levels. It was concluded that hypercoagulation may partially be the mediating factor between depressive symptoms and cardiovascular risk in African men; a situation that may be exacerbated by hyperkinetic blood pressure. In conclusion, through the assessement of cardiometabolic function and neuroendocrine responses, it seems that Africans withdepressive symptoms are at great risk for cardiovascular related morbidity and mortality, this was particulary evident in the African men (Manuscript 1 and 3). Additionally, it appears that blunted neuroendocrine responses and hypercoagulation could be seen as possible cardiovascular risk markers in Africans with depressive symptoms. / PhD (Physiology), North-West University, Potchefstroom Campus, 2014

Methamphetamine (MA) is a well-known, easily accessible and powerful psychostimulant, and its abuse has become a global problem. MA abuse affects millions of people worldwide and places an enormous burden on public healthcare resources. Documented consequences of MA abuse include cardiotoxic, neurotoxic and teratogenic effects, as well as long-term consequences of chronic abuse including affective disorders such as schizophrenia and major depressive disorder (MDD). MDD is a highly prevalent mood disorder in both adults and children, documented to contribute to approximately 850 000 suicides annually. This disorder is projected to become the 2nd leading disease of global burden by 2020, preceded only by ischemic heart disease. Depressive-like behaviour is documented as a symptom of chronic MA abuse and particularly during extensive MA withdrawal. Also, MA abuse during pregnancy is documented to cause neurodevelopmental changes that persist into later life. However, current understanding thereof is limited and warrants further investigation of the effects of early-life exposure to MA on outcome in adulthood, particularly in terms of mood disorders. The aim of the current study was to determine the effect of chronic exposure to MA on the depressive-like behaviour later in life in stress-sensitive (Flinders Sensitive Line) and control (Flinders Resistant Line) rats. Rats were exposed during one of the following natal day (ND) age groups: prenatal (ND-13 to ND+02), postnatal (ND+03 to ND+18), prepuberty (ND+19 to ND+34) or puberty (ND+35 to ND+50). These age groups represent different stages in neurodevelopment, as also seen in humans. For prenatal exposure, pregnant dams received 5 mg/kg daily subcutaneously (s.c.), and pups from postnatal, prepuberty and puberty age groups received an escalating dose regimen to simulate “binge-dosing” commonly seen in humans abusing MA. After MA exposure, rats were housed normally until behavioural testing on postnatal day 60 (ND+60), which included the novel object recognition test (NOR), open field test (OFT) and forced swim test (FST), measuring cognitive function, locomotor activity and depressive-like behaviour respectively. The FST data showed increased immobility behaviour of saline-treated FSL rats relative to that of FRL rats, in line with previous data validating FSL rats as a genetic rodent model of depression. Practically significant MA-induced increases in immobility behaviour were observed in all FSL and FRL treatment groups in the FST, reaching statistical significance in prenatally treated FRL rats, and in postnatally, prepuberty and puberty treated FSL rats. The data suggest that early-life MA exposure may alter neurodevelopment to predispose the rats to display depressive-like behaviour in early adulthood, and suggests that this detrimental effect of MA may be more expressed in stress-sensitive rats. Furthermore, all FSL groups plus prenatally and puberty treated FRL rats revealed practically and statistically significant decreases in swimming behaviour in the FST, whereas decreases in swimming behaviour in prepuberty treated FRL rats were practically significant but did not reach statistical significance. These data suggest that MA-induced depressive-like behaviour in FSL rats may be related to impaired serotonergic neurotransmission, and that this appears to be more robust in FSL rats. Climbing behaviour in the FST was generally not altered by early-life MA exposure, with a notable exception being a practically and statistically significant increase in puberty treated FRL rats. These data suggest that in general early-life MA exposure does not affect noradrenergic neurotransmission in early adulthood, except when normal rats were treated at puberty. The reason for the latter observation is not clear. The data from the NOR test revealed no discernible trends of MA-induced effects on memory and cognition, except for a small albeit practically significant increase in exploration time in prepuberty treated FRL rats and a practically and statistically significant decrease in exploration time in puberty-treated FRL rats. Lastly, locomotor activity in the OFT was mostly unaffected by MA treatments, except for practically significant decreases in locomotor activity in postnatally-and prepuberty-treated FRL rats and practically and statistically significant decreases in locomotor activity of prepuberty treated FSL rats. Altered locomotor activity is therefore not expected to explain any of the immobility results of the FST. In final conclusion, the study confirms that early-life MA exposure results in a depressogenic effect later in life in stress-sensitive (FSL) and control (FRL) rats, but appears to be more robust in stress-sensitive animals. Furthermore the data suggest that long-lasting MA-induced depressogenic effects may relate to impaired serotonergic neurotransmission. / MSc (Pharmacology), North-West University, Potchefstroom Campus, 2014

Major depression is a serious mood disorder affecting more than 120 million people worldwide, irrespective of their race or socio-economic status. This psychiatric disorder is predicted to become the second leading cause of disability by the year 2020, second only to heart diseases in the global population, without distinguishing differences in the incidence within defined age groups. Depression is known to affect people across all age groups, including children, adolescents, adults and geriatrics, although older age is associated with an increased susceptibility to major depression and other psychiatric conditions. Until the 1970‘s depression during childhood and adolescence was thought to be uncommon or non-existent. Recent epidemiological studies have demonstrated that there is a persistent escalation in the prevalence of depression in children and adolescents. Accordingly, the number of prescriptions for drugs to treat this disorder in juveniles has escalated significantly. With our current limited understanding of the safety and long-term effects of treatment with antidepressants, the clinician is left making decisions without sound evidence of safety. In addition, psychotropic drugs may affect neurodevelopment during childhood and adolescence and may consequently modulate susceptibility to psychiatric disorders later in life. The objective of the current study was to investigate the effects of early-life (pre-natal and postnatal) chronic treatment with venlafaxine, a dual action serotonin-noradrenalin reuptake inhibitor, during the developmental phase of the serotonin and norepinephrine pathways in stress-sensitive rats on measures of cognition, anxiety-like and depressive-like behaviour later in life. The study also investigated which age shows optimal behavioural changes later in life, following the above mentioned administration of venlafaxine. In addition we also determined the effects that the administration of venlafaxine has on the levels of monoamines l-norepinephrine (l-NE) and serotonin (5-HT) in the prefrontal cortex and the hippocampus. A number of translational animal models of psychiatric disorders have been described and validated, and is suitable for such investigations. For the current study we used stress-sensitive Flinders Sensitive Line (FSL) rats and their controls, Flinders Resistant Line (FRL) rats. Pregnant dams were injected subcutaneously for 14 days with 10 mg/kg venlafaxine or saline from pre-natal day 15 (ND-15) to ND-01. New-born pups were then injected subcutaneously with 3 mg/kg venlafaxine or saline for 14 days from postnatal day 3 (ND+03) to ND+17. These doses were determined from previous studies reported in literature. Four rat treatment groups of both FSL and FRL rats received injections during pre-natal + postnatal ages as follows: saline + saline, venlafaxine + saline, saline + venlafaxine and venlafaxine + venlafaxine. Following the drug treatments, all rat groups were housed under normal conditions until the indicated time to be subjected to a battery of behavioural tests, including the novel object recognition test (nORT), locomotor activity test (Digiscan®), elevated plus maze (EPM) and forced-swim test (FST), scheduled on either ND+35, ND+60 or ND+90. Separate treatment groups were used for each age group. After the behavioural tests animals were decapitated, the brains removed and the prefrontal cortex and hippocampus dissected out. These were analysed at a later stage using an HPLC with electrochemical detection to determine the levels of the monoamines l-NE and 5-HT. All animal procedures were approved by the Ethics Committee of the North-West University (approval number: NWU-00045-10-S5), and are in accordance with the recommendations of the National Institutes of Health guide for the care and use of laboratory animals. The data from the current study suggest that in general FRL rats were not influenced by the early-life treatment with venlafaxine, as observed in the nORT, EPM or FST on ND+35, ND+60 or ND+90. There was minimal changes seen in the immobile behaviour in the FST of FRL rats that received prenatal venlafaxine. As expected, depressive-like behaviour in the FST was significantly enhanced in FSL rats relative to corresponding FRL rat groups as observed at ND+35 and ND+60, but not ND+90. Importantly, depressive-like behaviour was reversed following pre- and postnatal treatment with venlafaxine in FSL rats at ND+60, relative to the corresponding FRL rat groups. Reversal of depressive-like behaviour in FSL rats were not observed at ND+35 or ND+90, suggesting a delayed response that is reversed later in adulthood. The data from the nORT, Digiscan® or EPM did not reveal any significant differences between the various FSL treatment groups, including at ND+60. The current study therefore demonstrated that the treatment regimen employed had a transient effect on depressive-like behaviour later in life and suggested that genetic susceptibility plays an important role in the treatment of depression. This was suggested by the venlafaxine-induced decrease in immobile behaviour exhibited by FSL rats at ND+60 in the FST, and the subsequent increase in immobile behaviour at ND+90. In general, the most significant venlafaxine-induced effects were seen in FSL rats, suggesting genetic susceptibility plays an important role. / MSc (Pharmacology), North-West University, Potchefstroom Campus, 2014

In vivo intracranial microdialysis is a valuable technique yielding novel and useful insight into normal or pathological neurochemical processes in the brain by means of sampling of interstitial fluid of cells in a living animal. It's most important advantage is that it can continuously monitor time-related changes in the concentration of neurotransmitters and their metabolites, other neuromodulators, energy substrates, as well as exogenous drugs in the extracellular fluid of specific brain areas of interest. While the development and standardization of the intracranial microdialysis technique in our laboratory was the main aim of the current study, a pilot application study was also performed during which the effect of several locally administered pharmacological agents on brain glutamate levels in a genetic rat model of depression was investigated. Abnormal neuronal glutamate levels have been implicated in various psychiatric conditions including major depressive disorder. The Flinders Sensitive Line (FSL) is a genetic line of Sprague-Dawley rat that displays various behavioral and neurochemical traits akin to that observed in depression. The Flinders Resistant Line (FRL) rat is used as the normal control. The prefrontal cortex is an important brain area involved in the neuropathology of depression. Prefrontal cortical glutamate levels in a small number of FSL and FRL rats were therefore compared at baseline and following local administration of potassium chloride (100 mM), the latter in order to study changes in evoked glutamate release. Ketamine hydrochloride (9 mM) and fluoxetine (30 μM) respectively were also administered via reverse dialysis. Prior to initiating the microdialysis studies, an HPLC-fluorescence method was developed to analyze the levels of glutamate in the microdialysate. As part of the development and standardization of the microdialysis technique, a number of validation studies were performed. This included refining the stereotaxic surgery procedure, determining the most appropriate anesthesia protocol, and standardizing the microdialysis procedure with regard to perfusion fluid, flow rate, sample volume, duration of dialysis, and anatomical verification of probe location. The HPLC-fluorescence method for the analysis of glutamate was also developed and validated. This technique proved to be sensitive and specific for the determination of glutamate with a linearity of 0.991 in the concentration range of standards tested (0.1 – 10 μM) and an intra-assay repeatability (precision value) yielding relative standard deviations of less than 10.5%, Mean elution time was between 24 and 26 minutes for glutamate in the microdialysis sample and the limit of detection and quantification was both 0.1 μM. Results from the application study indicated that baseline values of glutamate in the prefrontal cortex did not differ between FRL and FSL rats during the 1 hour period of dialysis. However, potassium chloride-evoked glutamate release was greater in FSL vs. FRL rats, although this difference was not statistically significant. Local perfusion by reverse dialysis of ketamine hydrochloride produced statistically significant increases in glutamate concentrations at certain time points in FSL rats. Although glutamate levels were also increased in FRL rats in response to ketamine, it was not statistically different compared to baseline levels. Fluoxetine perfusion did not affect glutamate release in either of the two rat groups. In conclusion, we have successfully developed and established an intracranial in vivo microdialysis procedure in our laboratory, as well as standardized and validated a sensitive method to analyze glutamate in microdialysate samples. These techniques were then applied in a small number of FSL vs. FRL rats in order to confirm their application in a typical research scenario. Although the data were too limited to make any valid conclusions about glutamate concentrations in an animal model of depression or the effect of drugs on the release thereof, these novel techniques and analyses will be valuable in future studies. / Thesis (MSc (Pharmacology))--North-West University, Potchefstroom Campus, 2013.