Assessment of Serotonergic Function by Radioligands and Microdialysis: focus on stress-related behaviour and antidepressant efficacy

Serotonin is a signaling compound, or neurotransmitter, in the brain and is involved in the regulation of mood, e.g. in stress and depression. Most antidepressants increase serotonin concentrations in the human brain, but these therapeutic drugs do not have the desired effect in a large number of patients. The exact cause of this lack of efficacy is not clear. Therefore, it is of great importance to measure what happens with serotonin signaling during stress, in depression, and after treatment with antidepressants. Positron Emission Tomography (PET) is a non-invasive technique which may be employed to answer these questions.
The studies described in this thesis concern the validation of radiolabeled substances, or PET tracers, that are capable of measuring serotonin synthesis ([11C]5-HTP) and 5-HT2A receptor binding ([11C]MDL 100907). The latter compound appeared to be suitable. Using this tracer, we showed that 5-HT2A receptors don’t play a crucial role in the reaction of animals to social defeat stress or the development of a certain coping style under baseline conditions.
In addition, we investigated if the efficacy of antidepressants can be improved by combining a selective serotonin reuptake inhibitor (SSRI) with a 5-HT2C receptor antagonist. This combination proved capable of increasing the levels of both serotonin and dopamine, a neurotransmitter involved in motivation.
We conclude that PET can be used to assess various components of serotonin neurotransmission. Future research may be aimed at the validation of additional serotonergic ligands, study of the impact of chronic stress on the serotonergic system and assessment of positive effects of the SSRI/ 5-HTC blocker combination on behavior and mood.