The effects of short- and long-term neuroplastic adaptations in the human serotonin system assessed via neuroimaging

Abstract

Serotonin (5-hydoxytryptamine [5-HT]) is an important neuromodulatory agent in the brain. Serotonergic projection fibers originate in the raphe nuclei and influence signal transmission throughout the brain. This thesis applied magnetic resonance techniques in humans to evaluate the effects of acute and chronic 5 HT modulation on functional connectivity, white matter integrity, and major neurotransmitter levels. Numerous pathological conditions are associated with disturbances in the 5-HT system. However, non invasive evaluation of 5-HT system alterations in humans is challenging. The first study therefore assessed two human models of 5-HT modulation. Short-term 5-HT stimulation was investigated with an acute drug challenge using lysergic acid diethylamide (LSD), a selective 5 HT1A/5 HT2A receptor agonist. In addition, chronic 3,4 Methylenedioxymethamphetamine (MDMA, “Ecstasy”) consumption was used to examine long-term changes in the 5-HT system. MDMA is a potent 5-HT-releasing agent and repeated use in humans has been associated with long-term 5-HT depletion as well as altered 5-HT transporter and receptor levels. Functional magnetic resonance imaging (fMRI) results indicated that measuring the resting-state network of the raphe nuclei (i.e., dorsal and median raphe) facilitates the non invasive assessment of both short- and long-term changes in the human 5-HT system. In animals, long-term alterations in the 5-HT system in response to chronic MDMA exposure include degradation of axons and nerve terminals. To test whether this also occurs in human MDMA users, diffusion tensor imaging (DTI) and neurofilament light chain levels in blood (a biomarker for axonal pathology) were evaluated in the second study. However, results provided no evidence for MDMA induced axonal injury in humans. To examine whether chronic changes in the 5-HT system of regular MDMA users also affect glutamate and γ-aminobutyric acid (GABA) levels, proton magnetic resonance spectroscopy (MRS) was applied in the third study. Glutamate levels in the left striatum were elevated in MDMA users, but GABA concentrations were not altered. This thesis provides evidence that raphe nuclei functional connectivity facilitates non-invasive assessment of 5-HT system alterations in humans, relevant for the future examination of 5-HT disturbances in neurological or psychiatric patients. Moreover, the consequences of long-term 5-HT alterations in MDMA users were assessed to improve understanding of neurophysiological mechanisms underpinning cognitive deficits commonly observed in chronic MDMA users.