Browsing Doctoral Degrees (Psychiatry) by Author "Fairbairn, Lorren Rosli"
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- ItemEfficacy and mechanism of action of intrahippocampalD-cycloserine in an animal model of Posttraumatic Stress Disorder (PTSD)(Stellenbosch : Stellenbosch University, 2015-03) Fairbairn, Lorren Rosli; Seedat, Soraya; Daniels, W. M. U.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Psychiatry.ENGLISH SUMMARY : Posttraumatic stress disorder (PTSD) has been described as a persistent (Bremner et al., 1996) and incapacitating (Zatzick et al., 1997; Mendlowicz &Stein 2000) psychiatric disorder which occurs after exposure to a potentially traumatic event (DSM-5, APA 2013). Exposure based therapy (EBT) is one of the most common and effective therapies for posttraumatic stress disorder (Mendes et al., 2008). The procedure involves controlled exposure to the feared stimulus in the absence of any overt danger. EBT in humans is procedurally very similar to fear extinction training in animal models of emotional learning, such as fear conditioning (Norton & Price, 2007). It has previously been shown that dysfunctional fear extinction underpins PTSD pathophysiology (Keane et al., 1985; Cohen et al., 2006; Amstadter et al., 2009). With recent studies demonstrating fear extinction as an essential process for studying putative pharmacotherapies for clinical use in PTSD treatment. One such novel pharmacological agent, D-cycloserine (DCS), has been investigated in both preclinical and clinical studies of anxiety and has been reported to facilitate extinction of learned fear in rats and to promote exposure-based therapies in humans (Walker et al., 2002; Ledgerwood et al., 2003; Davis et al., 2006; Bontempo et al., 2012). DCS is a partial agonist of the N-methyl-D-aspartate receptor (NMDAR) and exerts its effects by binding to the glycine regulatory site of the NMDA complex. In addition, these glutamatergic receptors, specifically the hippocampal NMDARs and their subsequent signalling pathways have been implicated in fear extinction. PTSD affects individuals in all sectors of society and is as much a concern with respect to children as to adults. Considering that adolescence is a period of heightened vulnerability for mood and anxiety disorders, it is crucial to observe the effects of trauma on this developmental stage. Therefore the main aim of this study was to determine whether intrahippocampal infusions of DCS could reverse the PTSD phenotype, as displayed by our animal model, in both adolescents and adults with special focus on fear extinction. In the current study, we used a fear conditioning paradigm consisting of a brief, intense electric footshock (1.5 mA) and a neutral tone (80 dB, 9 kHz) to represent the traumatic event and investigated the efficacy and molecular mechanism of action of DCS on the behaviour and neurochemistry of adolescent and adult rats. The present study was particularly interested in the effects of DCS on hippocampal brain-derived neurotrophic factor (BDNF), hippocampal NMDAR expression levels, factors downstream of the NMDA signalling pathway (i.e. neuronal nitric oxide synthase) and protein changes in the hippocampus (HC) of fear conditioned and DCS-treated animals. Our animal model generated the following key findings. Firstly, various behavioural tests demonstrated that fear conditioned rats exhibited a PTSD-like disorder as shown by their increased and sustained conditioned fear response and increased anxiety-like symptoms. These effects were reversed by intrahippocampal DCS infusions, as assessed by behavioural freezing. Secondly, an upregulation of hippocampal NMDARs was noted in fear conditioned rats, while repeated administration of intrahippocampal DCS reduced this effect. Thirdly, intrahippocampal DCS infusions enhanced dorsal hippocampal BDNF expression in DCS treated groups, with fear conditioned rats expressing the lowest BDNF levels. Fourthly, intrahippocampal DCS administration elicited similar patterns in adolescents and adults with regards to fear extinction i.e. a decreased fear response was noted in both age groups after DCS administration. Lastly, we observed that hippocampal protein expression differed between adolescent and adult rats. Most proteins were distinctly expressed in either of the two age groups. The protein, neurabin-2 was specifically expressed during the adolescent period. Furthermore, footshock led to an increase in adolescent protein expression, whereas DCS treatment led to a decrease in adolescent protein expression. Overall, this study supported and extended previous findings that DCS has a therapeutic effect on fear conditioning by enhancing extinction of anxiety-like symptoms in rodents. We were able to show that animals subjected to fear conditioning/trauma show signs of alterations in proteins involved in neuronal plasticity, calcium (Ca2+) homeostasis, cellular stress, cell cycle arrest, initiation of apoptotic mechanisms and cell signalling dysregulation. These proteins all have a role in one or more of the neurochemical parameters as examined in our PTSD model i.e. interact with the HC, BDNF, nNOS or NMDARs. Therefore, additional studies are needed to elucidate the relationship between epigenetic modifications and the resulting proteomic responses as demonstrated in our study. In addition, the role of BDNF in PTSD has to be further investigated, be it as a biomarker or as adjunctive therapy for PTSD.