Distribution of temperature changes and neurovascular coupling in rat brain following 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) exposure

Abstract

(+/−)3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is an abused psychostimulant producing strong monoaminergic stimulation and whole-body hyperthermia. MDMA-induced thermogenesis involves activation of uncoupling proteins (UCP), primarily a type specific to skeletal muscle (UCP-3) and which is absent in brain, although other UCP types are expressed in brain (e.g., thalamus) and might contribute to thermogenesis. Since neuroimaging of brain temperature could provide insights of MDMA action, we measured spatial distributions of systemically-administered MDMA-induced temperature changes and dynamics in rat cortex and subcortex using a novel magnetic resonance method, Biosensor Imaging of Redundant Deviation of Shifts (BIRDS), with an exogenous temperature-sensitive probe (thulium ion and macrocyclic chelate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl-1,4,7,10-tetraacetate (DOTMA4−)). The MDMA-induced temperature rise in cortex was greater than in subcortex (1.6±0.4°C vs. 1.3±0.4°C) and occurred more rapidly (2.0±0.2°C/h vs. 1.5±0.2°C/h). MDMA-induced temperature changes and dynamics in cortex and body were correlated, although body temperature exceeded cortex before and after MDMA. Temperature, neuronal activity, and blood flow (CBF) were measured simultaneously in cortex and subcortex (i.e., thalamus) to investigate possible differences of MDMA-induced warming across brain regions. MDMA-induced warming correlated with increases in neuronal activity and blood flow in cortex, suggesting that the normal neurovascular response to increased neural activity was maintained. In contrast to cortex, a biphasic relationship was seen in subcortex (i.e., thalamus), with a decline in CBF as temperature and neural activity rose, transitioning to a rise in CBF for temperature >37°C, suggesting that MDMA affected CBF and neurovascular coupling differently in subcortical regions. Considering that MDMA effects on CBF and heat dissipation (as well as potential heat generation) may vary regionally, neuroprotection may require different cooling strategies.

Neurovascular unit alteration in somatosensory cortex and enhancement of thermal nociception induced by amphetamine involves central AT1 receptor activation

“…Indeed, neuroinflammation induced by central administered LPS elicits progressive loss of dopamine neurons and thermal hyperalgesia (Cahill et al ., ; Qin et al ., ). Moreover, pharmacological and electrical stimulation of catecholaminergic pathways elicit neurovascular coupling in the S1Bf (Polesskaya et al ., ; Coman et al ., ; Petrof et al ., ; Lecrux & Hamel, ). Considering the above mentioned evidences, the observed changes in the neurovascular components in the somatosensory cortex could result in functional alterations, thus they should not be observed with the AT 1 ‐R antagonism.…”

Imaging the intratumoral–peritumoral extracellular pH gradient of gliomas

“…BIRDS agents, similar to clinically‐used DOTA, could potentially be translated across a range of magnetic fields because the T 2 / T 1 ratio remains high and the proton shift sensitivities to the molecular event in the environment are largely unaffected. The readout of the physicochemical environment does not depend on diffusion or blood flow and BIRDS signals can be detected beyond MRI contrast (i.e., we see BIRDS signals when the MRI images are darkened by T 2 shortening) . Moreover, although the distribution of BIRDS agents may depend on vessel permeability (e.g., normal versus tumor tissue), the shift‐based reporting is independent of the agent's concentration from voxel to voxel.…”

Imaging the Transmembrane and Transendothelial Sodium Gradients in Gliomas

“….03 ppm/°C). The maximum pH difference between glioma and brain tissue is ~0.4 pH units (Coman et al, 2016;Huang et al, 2016;Maritim et al, 2017;Rao et al, 2017) whereas temperature differences of ~0.5 °C are extremely unusual in the brain (Coman et al, 2013;Coman et al, 2015;Walsh et al, 2020). Under these extreme conditions, the respective 23 Na shift variations caused by pH and temperature would be 0.1 ppm and 0.015 ppm.…”