Keijzer, Noa (2021) The effect of fluoxetine treatment on persistent contextual fear conditioning in post-traumatic stress disorder modulated through the serotonergic system. Bachelor's Thesis, Biology.
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Abstract
Post-traumatic stress disorder (PTSD) is a disabling psychiatric condition which is characterized by persistence of contextual conditioned fear after the exposure to a physical, physiological or sexual traumatic event due to poor fear memory extinction. The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely used in the treatment of PTSD, but the therapeutic mechanism remains poorly understood. Brain structures involved in contextual fear conditioning, including the hippocampus, amygdala, bed nucleus of the stria terminalis (BNST) and the prefrontal cortex (PFC), contain a high number of serotonin (5-HT) receptors. Furthermore, serotonergic dysfunction has been associated with PTSD, indicating that 5-HT plays an important role in contextual fear conditioning. Investigating the neurocircuitry of contextual fear conditioning and the role of 5-HT demonstrated that contextual fear conditioning processes are mainly modulated via 5-HT1, 5-HT-2 and 5-HT3 receptors. Multiple experimental animal models showed that the 5-HT1A heteroreceptor mediates a reduced fear acquisition and expression, the 5-HT2A and 5-HT3A receptors regulate fear memory extinction and the 5-HT2C receptor is involved in mediating anxiety-like behavior. Not surprising, humans carrying a genetic variation in essential genes for the development of serotonergic neurons and 5-HT signaling such as Pet1, Thp2, Vmat2 and 5-HTT displayed to be predisposed to a serotonergic dysfunction leading to PTSD-like behavior. Acute fluoxetine treatment immediately increases extracellular 5-HT levels, but worsens patients’ symptoms via the internalization and activation of 5-HT1A autoreceptors in the raphe nucleus. In contrast, chronic fluoxetine treatment leads to the deactivation of 5-HT1A autoreceptors resulting in normal 5-HT signaling. In addition, fluoxetine blocks 5-HT2C receptors leading to a reduction in anxiety-like behavior. In rodents, chronic fluoxetine treatment displayed to have beneficial effects on contextual fear conditioning. However in human PTSD patients, chronic fluoxetine treatment resulted in contradicting findings indicating that there probably exist additional underlying dysfunctions which require more research.
| Item Type: | Thesis (Bachelor's Thesis) |
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| Supervisor name: | Havekes, R. |
| Degree programme: | Biology |
| Thesis type: | Bachelor's Thesis |
| Language: | English |
| Date Deposited: | 03 Feb 2021 10:39 |
| Last Modified: | 03 Feb 2021 10:39 |
| URI: | https://fse.studenttheses.ub.rug.nl/id/eprint/23847 |
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