The rising number of the population that present with major depressive disorder has intensified the need to identify and elucidate new biological markers for the diagnosis and treatment of depression. Depression presents with evidence of changes in the nitric oxide (NO) pathway. In this study, levels of various endogenous markers of the NO cascade, viz. nitrite (NO2–), asymmetrical dimethylarginine (ADMA) and arginase II activity, were investigated in the Flinders Sensitive Line (FSL) rat, a genetic animal model of depression. The aim of the current study was to determine if there are differences between these markers in the plasma of the FSL rat compared to its healthy control, the (Flinders Resistant Line) FRL rat, with the possibility of considering their use as biomarkers of depression. Nitrite was chosen as metabolite over nitrate (NO3–) because the dietary intake of nitrite and/or nitrate does not significantly affect nitrite (NO2–) levels in plasma. Although this is of no significance if applied to rats, it is an important factor to be considered when doing clinical studies. For neurochemical determination of nitrite a sensitive fluorometric reversed phase high–performance liquid chromatographic (HPLC) assay was developed to analyze nitrite in human and rat plasma. Derivatization of sample nitrite was performed with 2,3–diaminonaphthalene (DAN) followed by the quantification of the stable and highly fluorescent product, 2,3–naphthotriazole (NAT). Determination of arginase II activity was performed by measuring L–arginine and L–ornithine concentrations in the plasma, while ADMA was measured simultaneously with L–arginine and L–ornithine using liquid chromatography/tandem mass spectrometry, or LC/MS/MS. Plasma nitrite levels of FSL rats were significantly decreased compared to plasma nitrite levels in the FRL rat, but neither the levels of ADMA nor arginase II activity showed a significant difference between the FSL and FRL rat groups. From these results it is concluded that in accordance with previous studies, the NO pathway plays an important role in the pathophysiology of depression, as depicted in the differences found between plasma nitrite levels in the FSL rat compared to its healthy control. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2011.

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.

Text in Afrikaans / Die doel van hierdie ondersoek is om die verskil in effek tussen direktiewe en nie-direktiewe insette van die fasiliteerder, tydens sensitiwiteitopleiding, te bepaal deur sommige kliente voor te berei op die ervaring deur middel van 'n uitdeelstuk en ander kliente nie voor te berei nie. Die sensitiwiteitgroepe word deurgaans op ongestruktureerde wyse hanteer en met behulp van 'n kwantitatiewe meting en verwerking met t-toetse asook 'n kwalitatiewe meting word hipoteses getoets. Die instrumente wat gebruik word is die POI, Rotter, Firo-B en 'n oopvraag-tegniek. Die resultate dui daarop dat persone wat voorberei word op die ervaring 'n groter interne lokus van kontrole openbaar. / The aim of this study is to determine the difference in effect between directive and non-directive inputs by the facilitator during sensitivity training, by preparing some clients for the experience with the aid of a handout while other clients go through the same experience unprepared. The sensitivity groups are run on an unstructured basis and effects are measured with a quantatitive measurement and calculated with t-tests as well as qualitative. measurement, thereby testing the hypotheses. The instruments that are used are the POI, Rotter, Firo-B and an open question technique. The results seem to indicate that people who are prepared for the experience show a higher internal locus of control. / Industrial and Organisational Psychology / M.A. (Bedryfsielkunde)