Physical activity has several advantages for health. The first objective of this research was to determine the relationship between physical activity and selected physical and psychological health components. The physical components include: diabetes risk, obesity, cholesterol and cardiovascular disease. The psychological health components include stress and depression. Secondly, this research aimed to determine the relationship between physical activity and medical costs. Medical costs were divided into pharmaceutical, general practitioners and hospital claims. A total of 9 860 employees of the same financial institution in South Africa, between the ages 18 and 64 (x̄ = 35.3 ± 18.6 years), participated in the study and participation was voluntary. No differentiation was made between race groups. The assessment of selected health risk factors and physical activity was done by using the Health Risk Assessment (HRA) methodology developed by the company, Monitored Health Risk (MHM). Assessment included a physical activity, diabetes risk and cardiovascular risk questionnaire, BMI and random blood glucose measurements, as well as stress and depression scores. The amount of days absent from work in the past six months was also determined by the questionnaire. Participants was categorised in three groups – low, moderate and high physical activity participation. Medical expenditure data was obtained from Monitored Health Risk Management Pty (Ltd). Hospital, pharmaceutical and general practitioners (GP) claims included all costs occurring during a six month period. The majority of the study group showed low physical activity participation (78.27%). The results also showed that both men and women showed an increased risk for diabetes, and high physical activity levels have a practically and statistically significant effect on the reduction of diabetes risk. In this study all the physical activity groups of both males and females showed an increased average body mass index (BMI) and therefore are considered to be an increased risk according to the classification as stipulated by the study perimeters. The average means for cholesterol in all groups are categorised as low risk. No significant differences are seen between the female groups as well as between the different male groups. The men in the study group showed higher cardiovascular risk than women. There are no statistically significant differences between the women’s groups. However, regarding the male groups, the low physically active male group showed significant differences to the high physical active male group. Thus, in this study it appears that the men participating in high levels of physical activity show the lowest risk for cardiovascular disease and therefore appear to be influenced by physical activity. The majority of the study group is shown to be in the high stress category (55.48%). It seems that work issues (82%), financial problems (74%) and family problems (69%) contribute most to the population’s high stress levels and depression experience. The Physical activity index (PAI) in relation to stress only shows practical significance in moderate and high physical women. The PAI and stress-related index reports statistically (p≤0.05; 0.001) significant and practice significant difference within the population. There was also a statistically significant (p≤0.05) relation between stress and physical activity in relation to days absent. Although high levels of stress and low levels of physical activity are present in the population, the relation become statistically significant in relation with depression. The study group was divided into two groups when the medical cost was examined. One group consisted of those individuals who do not use chronic medication and the other group, those individuals that use chronic medication. The majority of the study group (chronic and nonchronic medication use), show low physical activity participation (average of 78.80%). The results show statistically and practically significant differences between the groups that do not use chronic medication and the groups that use chronic medication. The women that use chronic medication show an increase in pharmaceutical costs with an increase in physical activity. However, when investigating the GP cost of women who use chronic medication, there is only a small difference in GP cost in the different physical activity participation categories. The data shows that men have higher pharmaceutical costs than women in all the physical activity categories. The results also indicate that men who use chronic medication, participating in low levels of physical activity do show higher pharmacy and GP costs. Medical cost associated with hospitalisation of those men whose chronic medications show an average higher medical cost (R231.72 versus R672.71). The women who are on chronic medication show about two and a half times higher hospitalisation cost (R253.97 versus R650.82) and the men an almost four times higher cost (R189.34 versus R721.71). No practically significant difference was found between the groups. The women show an increased incidence of low physical activity participation (82.38%), whereas 68.80% of the men show low physical activity participation. Women who use chronic medication and participate in moderate physical activity show lower hospital costs. The women in this study group that use chronic medication and participate in high levels of physical activity show the highest hospital cost. The men’s profile indicates that medical cost due to hospital claims rise with the higher levels of physical activity. / Thesis (PhD (Human Movement Sciences))--North-West University, Potchefstroom Campus, 2013.

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.

Physical activity has several advantages for health. The first objective of this research was to determine the relationship between physical activity and selected physical and psychological health components. The physical components include: diabetes risk, obesity, cholesterol and cardiovascular disease. The psychological health components include stress and depression. Secondly, this research aimed to determine the relationship between physical activity and medical costs. Medical costs were divided into pharmaceutical, general practitioners and hospital claims. A total of 9 860 employees of the same financial institution in South Africa, between the ages 18 and 64 (x̄ = 35.3 ± 18.6 years), participated in the study and participation was voluntary. No differentiation was made between race groups. The assessment of selected health risk factors and physical activity was done by using the Health Risk Assessment (HRA) methodology developed by the company, Monitored Health Risk (MHM). Assessment included a physical activity, diabetes risk and cardiovascular risk questionnaire, BMI and random blood glucose measurements, as well as stress and depression scores. The amount of days absent from work in the past six months was also determined by the questionnaire. Participants was categorised in three groups – low, moderate and high physical activity participation. Medical expenditure data was obtained from Monitored Health Risk Management Pty (Ltd). Hospital, pharmaceutical and general practitioners (GP) claims included all costs occurring during a six month period. The majority of the study group showed low physical activity participation (78.27%). The results also showed that both men and women showed an increased risk for diabetes, and high physical activity levels have a practically and statistically significant effect on the reduction of diabetes risk. In this study all the physical activity groups of both males and females showed an increased average body mass index (BMI) and therefore are considered to be an increased risk according to the classification as stipulated by the study perimeters. The average means for cholesterol in all groups are categorised as low risk. No significant differences are seen between the female groups as well as between the different male groups. The men in the study group showed higher cardiovascular risk than women. There are no statistically significant differences between the women’s groups. However, regarding the male groups, the low physically active male group showed significant differences to the high physical active male group. Thus, in this study it appears that the men participating in high levels of physical activity show the lowest risk for cardiovascular disease and therefore appear to be influenced by physical activity. The majority of the study group is shown to be in the high stress category (55.48%). It seems that work issues (82%), financial problems (74%) and family problems (69%) contribute most to the population’s high stress levels and depression experience. The Physical activity index (PAI) in relation to stress only shows practical significance in moderate and high physical women. The PAI and stress-related index reports statistically (p≤0.05; 0.001) significant and practice significant difference within the population. There was also a statistically significant (p≤0.05) relation between stress and physical activity in relation to days absent. Although high levels of stress and low levels of physical activity are present in the population, the relation become statistically significant in relation with depression. The study group was divided into two groups when the medical cost was examined. One group consisted of those individuals who do not use chronic medication and the other group, those individuals that use chronic medication. The majority of the study group (chronic and nonchronic medication use), show low physical activity participation (average of 78.80%). The results show statistically and practically significant differences between the groups that do not use chronic medication and the groups that use chronic medication. The women that use chronic medication show an increase in pharmaceutical costs with an increase in physical activity. However, when investigating the GP cost of women who use chronic medication, there is only a small difference in GP cost in the different physical activity participation categories. The data shows that men have higher pharmaceutical costs than women in all the physical activity categories. The results also indicate that men who use chronic medication, participating in low levels of physical activity do show higher pharmacy and GP costs. Medical cost associated with hospitalisation of those men whose chronic medications show an average higher medical cost (R231.72 versus R672.71). The women who are on chronic medication show about two and a half times higher hospitalisation cost (R253.97 versus R650.82) and the men an almost four times higher cost (R189.34 versus R721.71). No practically significant difference was found between the groups. The women show an increased incidence of low physical activity participation (82.38%), whereas 68.80% of the men show low physical activity participation. Women who use chronic medication and participate in moderate physical activity show lower hospital costs. The women in this study group that use chronic medication and participate in high levels of physical activity show the highest hospital cost. The men’s profile indicates that medical cost due to hospital claims rise with the higher levels of physical activity. / Thesis (PhD (Human Movement Sciences))--North-West University, Potchefstroom Campus, 2013.

This research was aimed at validating the PHQ–9 in an African context. This study forms part of the project of Psychosocial Health and Biomarkers in an African context (FORT3, Wissing, 2008). The Patient Health Questionnaire (PHQ–9) is a nine–item depression scale that has the potential of being a dual–purpose instrument to establish the diagnosis of a depressive disorder, as well as the grade of symptom severity (Kroenke, Spitzer & Williams, 2001). The PHQ–9 was administered with criterion related measures to a multicultural convenience sample of 2214 participants from the North West Province of South Africa, including two groups of adolescents (n1 = 1480 and n2 = 559) and an availability sample of adults (n3 = 185). Instruments to determine criterion validity were the General Health Questionnaire (GHQ), designed to detect symptoms of mental disorders; the Mental Health Continuum - Short Form for Adults (MHC–SF) which measures the degree of emotional, social and psychological well–being; and the New General Self–Efficacy Scale (NGSE) designed to measure an individual’s general self–efficacy. Descriptive statistics for the PHQ–9 including its reliability in the various groups is reported. The PHQ–9 manifested a Cronbach Alph are liability index of 0.86. Criterion–related validity was supported by significant correlations between the PHQ–9 and criterion measures. Confirmatory factor analysis for the PHQ–9 yielded a one–factor solution in all groups. The percentage variance explained ranged between 34.71% and 46.62%. Exploratory factor analyses yielded two factors in all groups with the second factor comprised of no more than 2 items and thus interpreted as a minor factor. The construct validity obtained in this research indicates that the PHQ–9 may be a valid measure to identify depression in a South African context. Based on the psychometric properties found in this study, it can be concluded that the PHQ–9 is a valid measure of depression in two of the samples selected for this study. Future studies may further validate this instrument in specific language and cultural groups, and explore the cross–cultural measurement equivalence. / Thesis (M.A. (Research Psychology))--North-West University, Potchefstroom Campus, 2011.

The mining industry in South Africa plays a significant role in the economy of the country. South Africa is rated as one of the world’s largest producers of key reserves - gold, manganese ore and platinum– and the high level of industrial and production skills in the mines also contributes to the country’s success. Although the gold mining industry’s contribution is of the utmost importance, it is also under pressure to remain competitive and cost–efficient. Old shafts, worsening health of employees, ore bodies that are not always in their prime phase, the radical increase in the annual electricity tariffs and the possibility of decreased gold prices contribute to the decline in the gold mining industry’s success. The objective of this study was to investigate the relationship between role–specific stress and physical and psychological health, and to determine whether social support has a moderating effect in this relationship for employees in a mining training academy. A cross–sectional survey design was used and a convenience sample (n=437) was taken from a South African gold mining company, where the only criterium for inclusion was to be employed by the organisation at the time the research took place. Descriptive statistics and inferential statistics were used to analyse the data. The measuring instruments used in this study were proven to be reliable. The results indicate that role stressors and physical and psychological health problems are positively related. It also shows that social support can decrease role–specific stress and that social support – especially from colleagues and supervisors – can help to reduce depression and improve the quality of sleep. Furthermore, logistic regression analyses were used to determine whether role stress and social support hold any predictive value regarding physical and psychological health. It was found that if participants’ experience role–specific stress and they receive support – especially from supervisors – it can predict their quality of sleep and the use of medication (physical viii health). The findings also indicate that role stress can predict the experience of depression with regards to psychological health. However, the moderating effect of social support between role stress and depression was not supported in this research. To conclude, recommendations for the organisation and future research are made. / Thesis (M.Com. (Industrial Psychology))--North-West University, Potchefstroom Campus, 2012.

This research was aimed at validating the PHQ–9 in an African context. This study forms part of the project of Psychosocial Health and Biomarkers in an African context (FORT3, Wissing, 2008). The Patient Health Questionnaire (PHQ–9) is a nine–item depression scale that has the potential of being a dual–purpose instrument to establish the diagnosis of a depressive disorder, as well as the grade of symptom severity (Kroenke, Spitzer & Williams, 2001). The PHQ–9 was administered with criterion related measures to a multicultural convenience sample of 2214 participants from the North West Province of South Africa, including two groups of adolescents (n1 = 1480 and n2 = 559) and an availability sample of adults (n3 = 185). Instruments to determine criterion validity were the General Health Questionnaire (GHQ), designed to detect symptoms of mental disorders; the Mental Health Continuum - Short Form for Adults (MHC–SF) which measures the degree of emotional, social and psychological well–being; and the New General Self–Efficacy Scale (NGSE) designed to measure an individual’s general self–efficacy. Descriptive statistics for the PHQ–9 including its reliability in the various groups is reported. The PHQ–9 manifested a Cronbach Alph are liability index of 0.86. Criterion–related validity was supported by significant correlations between the PHQ–9 and criterion measures. Confirmatory factor analysis for the PHQ–9 yielded a one–factor solution in all groups. The percentage variance explained ranged between 34.71% and 46.62%. Exploratory factor analyses yielded two factors in all groups with the second factor comprised of no more than 2 items and thus interpreted as a minor factor. The construct validity obtained in this research indicates that the PHQ–9 may be a valid measure to identify depression in a South African context. Based on the psychometric properties found in this study, it can be concluded that the PHQ–9 is a valid measure of depression in two of the samples selected for this study. Future studies may further validate this instrument in specific language and cultural groups, and explore the cross–cultural measurement equivalence. / Thesis (M.A. (Research Psychology))--North-West University, Potchefstroom Campus, 2011.

The mining industry in South Africa plays a significant role in the economy of the country. South Africa is rated as one of the world’s largest producers of key reserves - gold, manganese ore and platinum– and the high level of industrial and production skills in the mines also contributes to the country’s success. Although the gold mining industry’s contribution is of the utmost importance, it is also under pressure to remain competitive and cost–efficient. Old shafts, worsening health of employees, ore bodies that are not always in their prime phase, the radical increase in the annual electricity tariffs and the possibility of decreased gold prices contribute to the decline in the gold mining industry’s success. The objective of this study was to investigate the relationship between role–specific stress and physical and psychological health, and to determine whether social support has a moderating effect in this relationship for employees in a mining training academy. A cross–sectional survey design was used and a convenience sample (n=437) was taken from a South African gold mining company, where the only criterium for inclusion was to be employed by the organisation at the time the research took place. Descriptive statistics and inferential statistics were used to analyse the data. The measuring instruments used in this study were proven to be reliable. The results indicate that role stressors and physical and psychological health problems are positively related. It also shows that social support can decrease role–specific stress and that social support – especially from colleagues and supervisors – can help to reduce depression and improve the quality of sleep. Furthermore, logistic regression analyses were used to determine whether role stress and social support hold any predictive value regarding physical and psychological health. It was found that if participants’ experience role–specific stress and they receive support – especially from supervisors – it can predict their quality of sleep and the use of medication (physical viii health). The findings also indicate that role stress can predict the experience of depression with regards to psychological health. However, the moderating effect of social support between role stress and depression was not supported in this research. To conclude, recommendations for the organisation and future research are made. / Thesis (M.Com. (Industrial Psychology))--North-West University, Potchefstroom Campus, 2012.

Fluoxetine and escitalopram are the only antidepressants approved by the Food and Drug Administration of the United States of America (FDA) for treatment of major depression in children and adolescents. Both drugs are selective serotonin reuptake inhibitors (SSRIs). In recent years there has been a growing concern over the long-term developmental effects of early-life exposure to SSRIs. The current study employed male Flinders Sensitive Line (FSL) rats, a well described and validated translational model of depression, to investigate the long term effects of pre-pubertal fluoxetine exposure. First we examined the effect of such early-life exposure on the development of depressive-like behaviour, locomotor activity and anxiety-like behaviour as manifested in early adulthood. Next, the current study investigated the effect of pre-pubertal fluoxetine exposure on the acute monoaminergic stress response, as displayed later in life. Animals received either saline (vehicle control), or 10 mg/kg/day fluoxetine from postnatal day (ND+) 21 to ND+34 (pre-puberty). The treatment period was chosen to coincide with a developmental phase where the serotonergic system’s neurodevelopment had been completed, yet the noradrenergic and dopaminergic systems had not, a scenario comparable to neurodevelopment in human adolescents. Both behavioural and in vivo intra-cerebral microdialysis experiments were conducted after ND+60 (early adulthood). On ND+60 rats allocated to behavioural experiments were evaluated for depressive-like behaviour in the forced swim test (FST), locomotor activity in the open field test (OFT), and anxiety-like behaviour in the OFT. Corticosterone concentrations were shown to be significantly higher in male FSL rats exposed to a 10 minute forced swim stress when compared to male FSL rats not exposed to a forced swim stress on ND+60. In the microdialysis experiments the rats were exposed to an acute 10 minute forced swim stress and the concentrations of the monoamines and their metabolites were measured before, during, and after the acute stressor. Relative to saline-treated (control) rats, fluoxetine-treated FSL rats did not show long-term changes in immobility in the FST (i.e. no anti-depressant-like activity) on ND+60. Like-wise anxiety-like behaviour in the OFT did not change. However, a significant decrease in locomotor activity was observed in fluoxetine-treated FSL rats compared to saline-treated (control) rats. These data suggest that a long-lasting anti-depressant-like effect of fluoxetine may be masked by the effect on locomotor activity. With measurements from the microdialysis experiments a significant attenuation of the noradrenergic stress response was observed in fluoxetine-treated rats compared to saline controls. A similar picture was observed for 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin (5-HT), although the latter was not statistically significant. At baseline, before the stressor, significant increase in dopamine (DA) levels were observed in fluoxetine treated rats when compared to saline controls, suggesting that enhanced dopamine neurotransmission may comprise a long-term effect of pre-pubertal fluoxetine treatment. There were no discernible differences in homovanilllic acid (HVA) concentrations between fluoxetine-treated rats and saline controls. In conclusion significant developmental effects of pre-pubertal fluoxetine exposure were observed later in life and these findings warrant further investigation. / MPharm (Pharmacology), North-West University, Potchefstroom Campus, 2015

Methamphetamine (METH) abuse has become a fast growing drug problem that has developed into a global epidemic. In fact, METH is one of the most commonly abused substances with an estimated 35 million abusers worldwide and is said to be the second most popular illicit drug. The Western Province of South Africa has seen a dramatic increase in drug abuse in recent years where METH is the primary or secondary drug of abuse. Interestingly, more than 50% of these individuals are under the age of 20 years. The longer duration of euphoric effects of METH has attracted many users away from cocaine in favour of METH. In addition to the rapid euphoric effect of METH, the direct short-term effects include arousal, reduced fatigue, an increase in blood pressure, reduced appetite as well as sustained attention. Chronic METH abuse may result in debilitating and long-lasting effects that includes mood disorders such as depression. Studies suggest a strong relationship between exposure to adverse environmental factors early in life and the later development of a neuropsychiatric disorder, such as depression. However, these severe consequences do not seem to invoke cessation of the drug. The euphoric and addictive properties of METH causes users to abuse the drug with an increase in frequency and dose, even though it might not have been their original intention. The primary objective of this study was to investigate the effect of early-life administration of METH to stress-sensitive (Flinders Sensitive Line - FSL) and control (Flinders Resistant Line - FRL) rats on depressive-like behaviour and regional brain monoamine levels later in life. The study implemented a sixteen-day period for administration of METH or a vehicle control from postnatal day 19 (PnD19) to postnatal day 34 (PnD34). The latter developmental stage corresponds to pre-adolescence in the rat when neurological development are similar to that seen in human adolescents, and represents the stage when drug abuse is most common in humans. Chronic dosing of METH and saline was performed twice daily at 09:00 and at 15:00. The animals received a sub-cutaneous (SC) escalating dose regimen of METH during the 16 day period (mimicking binging behaviour in humans), with every dose escalating in increments of 0.2 mg/kg from 0.2 mg/kg to 6.0 mg/kg. The study then investigated whether early-life administration of METH would cause depressive-like behaviours directly after the injection period (immediate drug effects before withdrawal on PnD35) or later in life (after the withdrawal period in early adulthood on PnD60). The behavioural effects were assessed in a battery of tests and thereafter the rats were sacrificed and the frontal cortex removed and snap frozen for later analyses of altered neurochemistry. The study demonstrated that chronic METH treatment during pre-adolescence induces significant behavioural changes related to depression in humans directly after the injection period (PnD35) and later in life (PnD60). The animals displayed antidepressant-like behaviour in the forced swim test (FST) before withdrawal, yet a depressogenic effect was observed 25 days post-withdrawal. This effect also seems to be additive to the congenital depressive-like phenotype of FSL rats, suggesting a role for genetic susceptibility. This observation would be in line with the two-hit hypothesis of depression, suggesting that the manifestation of depression will result when a genetic predisposition is followed by an environmental stressor (i.e. METH) later in life. The data suggests a working hypothesis that individuals that already have a predisposition to depression may be more susceptible to developing depression when abusing METH. The fact that the FSL control rats were more immobile than FRL control rats also confirmed the face validity of the FSL genetic rat model of depression. Locomotor activity assessment indicated that METH treatment decreased locomotor activity in FSL and FRL rats compared to their vehicle controls on PnD35 but not on PnD60. It is important to note that the effects observed in locomotor activity could not have contributed to the immobility observed in the FST, confirming that the immobility in the FST indeed reflects psychomotor and not locomotor effects. The study also demonstrated that METH significantly lowers social interaction behaviour in both FRL and FSL rats, both immediately following drug treatment (PnD35) and after withdrawal (PnD60). It is therefore clear that this effect of METH is long-lasting, putatively related to neurodevelopmental effects. In addition, the rats investigated the familiar object for a greater amount of time in the novel object recognition test (nORT) on PnD35 and PnD60 and may be the result of loss of recognition memory for the familiar object. This data confirms that METH results in cognitive memory deficits probably due to sustained adverse neurodevelopmental effects. Neurochemical analyses of the frontal cortex indicated decreased serotonin (5-HT) and norepinephrine (NE) levels on PnD35. METH is widely recognised for its pro-inflammatory effects, while the reduced 5-HT levels observed may have been the result of an increase in circulating pro-inflammatory cytokines. Neurochemical analyses provided thought-provoking data concerning the role of the permissive hypotheses of depression, indicating that dopamine (DA) is most likely not responsible for the behavioural effects observed, at least under the current study conditions, whereas 5-HT is decidedly more involved than expected. The data also suggest that depletion in NE plays a role in the development of depressive-like behaviours following METH exposure. Based on these findings, we propose that disturbances in 5-HT and NE are a crucial mechanism in how METH abuse may precipitate or worsen depressive-like symptoms in individuals who abuse METH. It should be noted that this study does not discard the role of DA in the development of depression after METH exposure, although under the current study conditions it appears that DA does not play a central role. The current study demonstrated that pre-adolescent exposure to METH can reproduce most of the behavioural changes seen in depressed individuals, and that these behavioural data can be used to identify causal neurochemical factors. Environmental stressors such as METH abuse should be regarded as an additional diagnostic criterion and is relevant to an accumulative risk factor hypothesis. Furthermore, although further study is required, the data suggests that early-life exposure to METH may predispose an individual to mood disorders and behavioural abnormalities later in life. / MSc (Pharmacology), North-West University, Potchefstroom Campus, 2015