Increased serotonin transporter availability in the brainstem of migraineurs

Abstract

For decades, serotonin has been speculated to play a major role in migraine pathophysiology. The central serotonergic system is located in the raphe nuclei and the adjacent reticular formation in the brainstem. Recently, radioligands targeting the brain serotonin transport protein (SERT) have been developed. We used the highly specific SERT-radioligand (123)I-ADAM [2-((2-((dimethylamino) methyl)phenyl)thio)-5-iodophenylamine] to test the hypothesis of the mesopontine serotonergic system being involved in the pathophysiology of migraine. Nineteen migraine patients and 10 healthy, age- and sex-matched controls were enrolled. The neuroimaging study was performed interictally during the pain-free interval. Single Photon Emission Computed Tomography (SPECT)-images were coregistered with MRI-scans. Region of interest (ROI)-analysis revealed a highly significant increase of (123)I-ADAM uptake in the mesopontine brainstem of migraineurs (p < 0.001). In contrast, (123)IADAM uptake in the thalamus did not differ significantly between migraineurs and controls. Our study demonstrates for the first time a significant increase of brainstem SERT-availability in migraineurs, suggesting a dysregulation of the brainstem serotonergic system. It remains to be elucidated whether the altered SERT-availability is causally related to migraine pathophysiology or whether it reflects secondary pathophysiological mechanisms.

PET Imaging of Serotoninergic Neurotransmission with [11C]DASB and [18F]altanserin after Focal Cerebral Ischemia in Rats

“…Likewise, these findings are in agreement with the increase in the serotonin availability observed in the brainstem of migraineurs as a response to altered endogenous 5-HT levels. 35 Despite the increase in [ 11 C]DASB binding in the ipsilateral midbrain, a lack of changes in both SERT and 5-HT 2A availability has been observed in the contralateral hemisphere after ischemia. These results stand in contrast to the increased D 2 dopaminergic receptor availability observed in the contralateral hemisphere after 2-hour MCAO, which could have a key role in the functional recovery after cerebral ischemia.…”

Increased Brainstem Serotonergic Transporter Availability in Adult Migraineurs: an [18F]FP-CIT PET Imaging Pilot Study

“…SERT modulates serotonin neurotransmission by removing serotonin from the synaptic cleft back to the presynaptic neuron. An imaging study that used a more SERTselective radioligand [ 123 I]ADAM also demonstrated significantly increased brainstem SERT availability in migraineurs than in healthy subjects [13]. Increased brainstem SERT availability together with low serotonin synthesis rate [14] and increased serotonin turnover [15,16] during headache-free phase reflect low synaptic serotonin concentration.…”

“…In-house PET template was made from 12 healthy subjects. Posterior part of the midbrain was chosen because approximately 80 % of the serotonergic neurons reside within the raphe nuclei [13]. ROIs did not include the anterior part of the midbrain which is abundant in DATs.…”

Nitroglycerin increases serotonin transporter expression in rat spinal cord but anandamide modulated this effect

“…These observations are in line with previous neuroimaging and molecular biology studies. By using neuroimaging methods (SPECT-images coregistered with MRI-scans) (Schuh-Hofer et al, 2007) it was shown that there is an increased availability of 5-HTT in brainstem in migraine patients during the interictal period. The recent PET-study also confirms that the 5-HTT availability is crucial in the pathomechanisms of migraine (Park et al, 2016).…”

“…In a neuroimaging study increased 5-HTT availability in the mesopontine brainstem of migraineurs has been detected (Schuh-Hofer et al, 2007). Data show that the vast majority of 5-HTT is localized on the axolemma, in the vicinity of the synapses, and along the axons as well.…”