Abstract
3,4-Methylenedioxymethamphetamine (MDMA), also known as “Ecstasy”, is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI). Rats were injected subcutaneously six times with MDMA (5 mg/kg) or saline once daily. Eight days after the last injection, manganese ions (Mn2+) were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB), and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum.
Highlights
3,4-Methylenedioxymethamphetamine (MDMA), sold under the street name “Ecstasy”, is an illicit recreational drug of abuse
region of interest (ROI) were drawn for the ventral tegmental area (VTA), medial forebrain bundle (MFB), and striatum based on the Mn2+-enhanced T1-weighted images (T1WIs) at different time points, because the period of optimal signal enhancement differed between different regions
The temporal evolutions of the averaged Mn2+ relative SI (rSI) of each group in the VTA/interpeduncular nucleus (IP) and the MFB pathway are quantitatively expressed in the figure as a function of time and are fitted with sigmoid curves
Summary
3,4-Methylenedioxymethamphetamine (MDMA), sold under the street name “Ecstasy”, is an illicit recreational drug of abuse. There is evidence from light- and electronmicroscopy autoradiography studies that ascending serotoninergic axons pass through and terminate within the ventral tegmental area (VTA) [17] These long projection pathways extend for 10–11 mm within the rat brain, which makes in vivo investigation of the axonal integrity difficult using traditional neuroscience techniques. Mn2+ enters cells via voltage-gated Ca2+ channels, is transported along axon trajectories to the nerve terminal, and is released into the synapse, where it is selectively taken up by the neurons that are subsequently activated in the brain circuit [25] These features render MEMRI a powerful tool for in vivo investigations of functional connections in complex brain systems, as well as for visualizing dysfunction of long nerve projections [19]. Immunohistological staining of SERT was carried out at the end of the MEMRI experiment to confirm the MDMA-induced effect on serotonergic terminals in the striatum
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