Abstract
Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders with a lifetime prevalence as high as 13%. Currently more than 20 different drugs are approved to treat depression, but half of these compounds have been available for decades and the majority can be grouped into two classes
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based on their pharmacological mechanism. Of these the selective serotonin reuptake inhibitors (SSRIs) are currently one of the mainstays in the treatment of MDD. Based on the efficacy of these antidepressants, considerable clinical evidence has been found that serotonin (5-HT) containing pathways in the central nervous system play a significant role in the pathophysiology of MDD. Animal models of depression might be helpful in understanding the pathophysiology of MDD. The olfactory bulbectomy (OBX) in rats is an animal model that meets most of the criteria of a valid model for depression and as such may help to gain more insight in the etiology of depression and the development of novel antidepressants.
The present research describes a range of alterations following bilateral removal of the olfactory bulbs in rats. Basal levels of 5-HT, but not of 5-HIAA, NE and DA, were decreased in both the dorsal hippocampus (DH) and basolateral amygdala (BLA) two weeks after bulbectomy. Measurements in the DH five months after surgery revealed that this effect was long-lasting. Local administration of fenfluramine and fluvoxamine revealed that OBX caused an attenuated increase in 5-HT levels, while administration of NSD-1015, a decarboxylase inhibitor, suggested a lower rate of synthesis under basal conditions in bulbectomized animals. Systemic administration of a high dose of L-TRP resulted in a similar increase in 5-HTP accumulation in SHAM and OBX animals, suggesting that the capacity of the system to synthesize 5-HT is not affected.
Local administration of different concentrations of fluvoxamine into the DH showed a parallel increase in 5-HT levels, the basal level and maximum increase being smaller in OBX animals than in SHAM operated controls. The most likely explanation for the smaller increase in 5-HT following SSRI administration in OBX animals is the lower efflux of 5-HT. The parallelism of the of the dose-response curves suggests that the efficacy of the 5-HT transporter has not changed. In the presence of fluvoxamine, 1 μM CP 9129, a selective 5-HT1B receptor agonist, was infused locally in the DH to assess the functionality of the 5-HT1B receptor. Both SHAM and OBX animals showed a significant decrease in 5-HT levels, indicating the presence of a functional 5-HT1B receptor. When the total amount of decrease was related to the basal levels of 5-HT, there was no difference in relative effect between the two groups, indicating that the sensitivity of the terminal 5-HT1B receptor has not changed. To assess the effects of bulbectomy on functioning of the somatodendritic 5-HT1A receptor, flesinoxan, a HT1A receptor agonist, was infused locally into the median raphe nucleus (MR). SHAM operated animals showed a significant decrease in 5-HT levels after flesinoxan administration. However, in the OBX group, no significant effect of flesinoxan was found, indicating that HT1A receptors in the MR are desensitized in OBX rats. Systemic administration of fluvoxamine to OBX animals resulted in an increase in 5-HT levels similar to the increase seen in SHAM operated controls, despite the fact that basal extracellular levels are significantly lower after bulbectomy. When WAY 100.635, a HT1A receptor antagonist, was co-administered with fluvoxamine, levels of 5-HT increased significantly in SHAM animals compared to administration of fluvoxamine alone. However, in OBX animals, no extra increase in 5-HT levels after co-administration of WAY was seen, supporting the previous findings that olfactory bulbectomy leads to desensitization of somatodendritic HT1A receptors. 24-h corticosterone measurement showed no difference between SHAM and OBX. qPCR showed a decrease in expression of GABA-Aα1 subunit mRNA and an increase of MAO-A mRNA expression in the amygdala and an increase of postsynaptic HT1A receptor mRNA in the hippocampus.
Chronic dietary tryptophan supplementation was found to enhance serotonergic neurotransmission in normal animals and to normalize basal extracellular 5-HT levels and somatodendritic HT1A receptor function in bulbectomized animals. Interestingly, this normalization at the level of 5-HT release was not reflected in the open field, suggesting a dissociation between neurochemical and behavioral endpoint.
The research described in this thesis supports the validity of the olfactory bulbectomized rat as an intriguing model for affective processes in the brain. Further investigation of the neurochemical, behavioral, endocrine and immune alterations, and their interactions and correlations in bulbectomized animals may help to gain more insight into the etiology and treatment of major depressive disorder.
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