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

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 highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.

Major depression is a highly prevalent mood disorder with chronic debilitating effects. Additional to a rising rate in incidence, depression is highly co–morbid with other psychiatric disorders, but also chronic cardiometabolic illnesses that present with an inflammatory component. The exact aetiology of depression is still unknown, being multifactorial in its possible aetiology. Various hypotheses have attempted to shed light on both endogenous and exogenous risk factors as well as the underlying pathology that may lead to the development of the disease. This has led to a wide range of mediators being implicated, including biogenic amines, the HPA–axis, neurotrophic factors, inflammatory agents, the cholinergic system and circadian rhythm, to name a few. The mechanisms of action of current treatment strategies, except for a few atypical and novel treatment approaches, are limited to interactions with monoamines and are at best only 65% effective. Many of these are also plagued by troubling side–effects, relapse and recurrence. It has therefore become imperative to explore novel targets for the treatment of depression that may produce more rapid, robust and lasting antidepressant effects with a less daunting side–effect profile. The strong co–morbidity between depression and various cardiometabolic disorders, including cardiovascular disease, atherosclerosis, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has led to the proposal that a metabolic disturbance may be a vital component that drives inflammatory and immunological dysfunction in depression. Supporting of this is evidence for a role of inflammatory cytokines and neurotrophic factors in the pathogenesis of depression. It has also been demonstrated that a link exists between insulin– and nitric oxide (NO)– mediated pathways in the brain, which further highlights the role of oxidative stress and cell damage. Furthermore, evidence supports a role for oxidative stress and NO in T2DM and/or insulin resistance. Insulin has also been implicated in various physiological processes in the central nervous system (CNS) and may also influence the release and reuptake of neurotransmitters. Preclinical and clinical evidence has provided support for the antidepressant–like effects of insulin–sensitizing peroxisome proliferator activated receptor (PPAR)– agonists, such as rosiglitazone and pioglitazone. In preclinical studies, however, these effects are limited to acute treatment with pioglitazone or sub–chronic (5 days) treatment with rosiglitazone. It is well–recognized that such findings need to be confirmed by chronic treatment paradigms. The aim of the current study was therefore to further investigate the proposed antidepressant–like effects of pioglitazone in a genetic animal model of depression, the Flinders sensitive line (FSL) rat, using a chronic treatment protocol. The FSL rat model was reaffirmed as presenting with inherent depressive–like behaviour compared to its more resilient counterpart, the Flinders resistant line (FRL) rat. Moreover, imipramine demonstrated a robust and reliable antidepressant–like effect in these animals using the forced swim test (FST), thus confirming the face and predictive validity of the FSL rat model for depression. In contrast to previous preclinical studies, acute dose–ranging studies with pioglitazone in Sprague Dawley rats delivered no significant anti–immobility effects in the FST, whereas results similar to that seen in the dose–ranging studies were observed following chronic treatment using FSL rats. Since altered pharmacokinetics could possibly influence the drug’s performance, another route of administration, viz. the subcutaneous route, was utilized as an additional measure to exclude this possibility. The results of the subcutaneous study, however, were congruent with that observed after oral treatment. In order to confirm an association between altered insulin sensitivity and antidepressant action and demonstration by recent studies that thiazolidinediones may augment the efficacy of existing antidepressants, we therefore investigated whether concomitant treatment with gliclazide (an insulin releaser and insulin desensitizer) or pioglitazone (an insulin sensitizer) may alter the antidepressant–like effects evoked by chronic treatment with imipramine. Pioglitazone did not positively or negatively affect the antidepressant effect of imipramine, although gliclazide tended to decrease the anti–immobility effects induced by this antidepressant. Taken together and considering the current available literature, this finding supports evidence linking the insulin–PPAR pathway to depression. However, further explorative studies are required to delineate the role of insulin sensitivity and glucose homeostasis in depression and antidepressant response. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2012.