Decrease in REM latency and changes in sleep quality parallel serotonergic damage and recovery after MDMA: a longitudinal study over 180 days

Abstract

The recreational drug ecstasy [3,4-methylenedioxymethamphetamine (MDMA)], has been found to selectively damage brain serotonin neurons in experimental animals, and probably in human MDMA users, but detailed morphometric analyses and parallel functional measures during damage and recovery are missing. Since there is evidence that serotonin regulates sleep, we have compared serotonergic markers parallel with detailed analysis of sleep patterns at three time-points within 180 d after a single dose of 15 mg/kg MDMA in male Dark Agouti rats. At 7 d and 21 d after MDMA treatment, significant(30-40%), widespread reductions in serotonin transporter (5-HTT) density were detected in the cerebral cortex, hippocampus, most parts of the hypothalamus, and some of the brainstem nuclei. With the exception of the hippocampus, general recovery was observed in the brain 180 d after treatment. Transient increases followed by decreases were detected in 5-HTT mRNA expression of dorsal and median raphe nuclei at 7 d and 21 d after the treatment. Significant reductions in rapid eye movement (REM) sleep latency, increases in delta power spectra in non-rapid eye movement sleep and increased fragmentation of sleep were also detected, but all these alterations disappeared by the 180th day. The present data provide evidence for long-term, albeit, except for the hippocampus, transient changes in the terminal and cellular regions of the serotonergic system after this drug. Reduced REM latency and increased sleep fragmentation are the most characteristic alterations of sleep consistently described in depression using EEG sleep polygraphy.

Recovery and aging of serotonergic fibers after single and intermittent MDMA treatment in dark agouti rat

“…Different long-term recovery capacities of serotonergic fibers in MDMA 31 and MDMA 34 treated rats Our findings on the initial reduction in serotonergic axon density and on subsequent region-dependent recovery after the single dose of MDMA are in agreement with previous studies that investigated the long-term consequences of MDMA treatment based on 5-HTT immunohistochemistry (Kirilly et al, 2008), 5-HT and 5-HIAA measurements, or paroxetine-binding or radioligand binding to 5-HTT (Scanzello et al, 1993;Lew et al, 1996;Sabol et al, 1996). All recovery studies emphasize the particular vulnerability of the hippocampus to MDMA (Stone et al, 1987;Molliver et al, 1990;Scanzello et al, 1993;Fischer et al, 1995;Lew et al, 1996;Sabol et al, 1996;Kirilly et al, 2008).…”

“…Tph immunohistochemistry is an early and sensitive method of demonstrating vulnerability caused by MDMA, reflecting the morphology of serotonergic axons as well as the actual level of Tph protein (Adori et al, 2006;Xie et al, 2006;Kovacs et al, 2007). Moreover, the Tph immunohistochemistry results are in agreement with findings from densitometry analysis of 5-HTT immunoreactivity, which is another marker of the damage to serotonergic fibers after MDMA treatment (Kovacs et al, 2007;Kirilly et al, 2008;Ando et al, 2010). …”

“…All recovery studies emphasize the particular vulnerability of the hippocampus to MDMA (Stone et al, 1987;Molliver et al, 1990;Scanzello et al, 1993;Fischer et al, 1995;Lew et al, 1996;Sabol et al, 1996;Kirilly et al, 2008). At the same time, by the senescent age (22 months after the treatment, at the age of 24 months), even the hippocampal CA1 shows complete recovery of Tph-IR axon density, similar to other brain areas examined.…”

Equivalent effects of acute tryptophan depletion on REM sleep in ecstasy users and controls

“…Decreased stage 2 sleep (Allen et al 1993;, decreased total sleep time (Allen et al 1993), increased stage 1 sleep and trends toward decreased REM onset latency (ROL) (Allen et al 1993;) have been recorded in two relatively large samples of ecstasy users. Decreased ROL, increased sleep fragmentation and reductions in 5-HT transporter densities were found in rats 21 days after a single large dose of MDMA (Kirilly et al 2008) but these changes were no longer significant after 180 days.…”

Ultrastructural characterization of tryptophan hydroxylase 2-specific cortical serotonergic fibers and dorsal raphe neuronal cell bodies after MDMA treatment in rat

“…We applied a single 15 mg/kg intraperitoneal MDMA treatment in adolescent male Dark Agouti rats. This treatment protocol and similar models of MDMA neurotoxicity have already been characterized extensively in many aspects by our group and others (Ando et al 2010;Balogh et al 2004;Kirilly et al 2008;Kovacs et al 2007;O'Shea et al 1998;Quate et al 2004).…”