Synapse
January 1, 2000
Richard B. Rothman, Michael H. Baumann, Christina M. Dersch et al.
933 citations
Stimulants like amphetamine, MDMA, and methamphetamine are known to produce reinforcing effects in animals through the brain chemical dopamine. However, their subjective effects in humans—such as euphoria or alertness—may rely more on norepinephrine. Using lab tests, the authors measured how several stimulants affect the release of norepinephrine and dopamine. They found that all tested drugs were most potent at releasing norepinephrine. Crucially, the oral doses that produce amphetamine-like subjective effects in people correlated with the drugs' ability to release norepinephrine, not dopamine, and did not lower prolactin levels (a marker of dopamine release). These findings suggest norepinephrine may play a key role in the subjective experience of stimulants in humans.
Synapse
January 1, 1987
Pierre Blier, Claude de Montigny
428 citations
Rats given the 5-HT1A agonist gepirone for 14 days initially showed reduced firing of serotonin neurons in the dorsal raphe, which gradually returned to normal. After 14 days, the response of these neurons to intravenous LSD was markedly reduced, while responses to 8-OH-DPAT and gepirone were unchanged. Direct application of serotonin, LSD, 8-OH-DPAT, and gepirone to the neurons showed reduced responsiveness, but not to GABA. Postsynaptic hippocampal neurons remained normally responsive to serotonin and related drugs. The findings suggest that desensitization of somatodendritic 5-HT autoreceptors, combined with normal postsynaptic receptor activation, leads to increased tonic activation of postsynaptic 5-HT1A receptors, consistent with the delayed clinical anxiolytic and antidepressant effects of gepirone.
Synapse
June 1, 1998
Ursula Scheffel, Zsolt Szabó, William B. Mathews et al.
146 citations
A single baboon treated with MDMA (5 mg/kg twice daily for four days) showed large decreases in serotonin transporter binding in all brain regions when scanned with PET and a serotonin-specific tracer 13 to 40 days later. Reductions ranged from 44% in the pons to 89% in the occipital cortex. Tracers for dopamine transporters showed no changes. At 9 and 13 months, some brain regions partly recovered serotonin transporter levels while others, such as the neocortex, remained persistently low. These findings demonstrate that PET can detect MDMA-induced damage to serotonin neurons in living primates and suggest the method could be used to test whether human MDMA users experience similar neurotoxicity.
Synapse
August 1, 1991
George Battaglia, John Sharkey, Michael J. Kuhar et al.
113 citations
MDMA (ecstasy) causes long-lasting damage to serotonin neurons in the brain. Using a rat model, researchers measured serotonin transporter density—a marker of healthy serotonin neurons—after four days of MDMA treatment. Within 24 hours, many brain regions showed marked decreases in serotonin transporters, including the cortex, hippocampus, and caudate nucleus. These reductions persisted for at least two weeks. Some regions, like the dorsal striatum, showed greater damage at two weeks than immediately after treatment, while others, such as the endopiriform nucleus, showed partial recovery. Regions containing serotonin cell bodies (raphe nuclei) and axons of passage were unaffected. Catecholamine neurons were not damaged, indicating MDMA's selectivity for serotonin terminals.
Synapse
July 14, 2004
Xiaoying Wang, Michael H. Baumann, Heng Xu et al.
101 citations
Two weeks after giving rats MDMA (7.5 mg/kg, three doses) or the toxin 5,7-DHT, the study measured serotonin levels and two protein markers in brain regions. MDMA reduced tissue serotonin by about 50% in cortex, hippocampus, and caudate but did not significantly change the amount of serotonin transporter or glial fibrillary acidic protein, a marker of nerve damage. In contrast, 5,7-DHT reduced serotonin by over 90%, lowered serotonin transporter protein by 20–35%, and increased glial fibrillary acidic protein by 30–39%. The authors conclude that this MDMA regimen does not cause degeneration of serotonin nerve terminals and that lasting serotonin depletion can occur without destroying the axons.
Synapse
January 1, 2001
Mahalakshmi Shankaran, Bryan K. Yamamoto, Gary A. Gudelsky
97 citations
MDMA (ecstasy) causes long-term damage to serotonin (5-HT) neurons in the brain, likely through oxidative stress from free radicals. Giving rats the antioxidant ascorbic acid (vitamin C) blocked the formation of hydroxyl radicals and prevented MDMA-induced depletion of serotonin in the striatum. Rats that received a neurotoxic dose of MDMA later showed blunted serotonin release, behavioral responses, and hyperthermia when given another dose of MDMA; these functional deficits were also prevented by ascorbic acid. MDMA also reduced the brain's natural levels of vitamin E and ascorbic acid. The findings suggest that MDMA's neurotoxicity stems from oxidative stress and diminished antioxidant defenses.
Synapse
January 1, 1987
Dean F. Wong, John R. Lever, Paul Hartig et al.
93 citations
A new radioligand, [11C]-MBL, selectively binds to serotonin 5-HT2 receptors in the brain, as shown by in vitro assays (Ki = 0.5 nM) and PET imaging in baboons and seven healthy human volunteers. In humans, highest binding occurred in frontal, temporal, and parietal cortex, with lower levels in caudate and putamen. Blocking with ketanserin confirmed specificity. Frontal cortex-to-cerebellum ratios ranged from 1.7 to 2.7, with older volunteers showing lower ratios, suggesting age-related decline in 5-HT2 receptor density. [11C]-MBL enables in vivo monitoring of these receptors in most human brain regions.
Synapse
October 1, 1995
Jean Lud Cadet, Bruce Ladenheim, Hiroshi Hirata et al.
81 citations
Mice carrying extra copies of the human superoxide dismutase gene are protected against MDMA-induced damage to brain dopamine neurons. Normal mice showed large drops in striatal dopamine and its metabolite DOPAC one day and two weeks after a single MDMA injection. Mice with one copy of the transgene showed dopamine loss only at one day, while mice with two copies showed no loss at either time point. Three repeated injections caused dopamine loss in normal mice, small losses in one-copy mice, and no loss in two-copy mice. Serotonin levels were unaffected in all groups. The findings indicate that superoxide radicals contribute to MDMA's dopamine toxicity.
Synapse
October 25, 2007
Noelia Granado, Isabel Escobedo, Esther O’shea et al.
59 citations
The drug MDMA (Ecstasy) damages dopamine nerve terminals in the mouse striatum, with a greater effect in striosomes—specialized brain compartments linked to different functions—than in the surrounding matrix. Mice given MDMA showed significant reductions in two markers of dopamine neurons, tyrosine hydroxylase and dopamine transporter, compared with controls. The loss was considerably more pronounced in striosomes, indicating that these compartments are more vulnerable to MDMA's long-term neurotoxicity. This provides the first evidence that striosome and matrix compartments differ in their sensitivity to MDMA, with the damage primarily involving striosomal dopamine fibers.
Synapse
April 27, 2000
Mahmoud M. Iravani, Daniel Asari, Jyoti C. Patel et al.
56 citations
MDMA does not directly cause the release of serotonin or dopamine in brain slices from rats, contrary to some earlier assumptions. Instead, it acts as a potent inhibitor of the reuptake of both neurotransmitters, slowing their removal from the synapse. MDMA also potentiated electrically stimulated serotonin release in the substantia nigra pars reticulata and dopamine release in the caudate putamen, but had no effect on stimulated release in the dorsal raphé nucleus or nucleus accumbens. These findings clarify MDMA's mechanism of action as distinct from that of amphetamine.
Synapse
January 1, 2001
Francesco Fornai, Filippo Sean Giorgi, Marco Gesi et al.
54 citations
In mice lacking the enzyme monoamine oxidase B (MAO-B), the neurotoxin DSP-4 caused the same loss of norepinephrine in brain regions as it did in normal mice, indicating MAO-B is not involved in DSP-4 toxicity. For the neurotoxin MDMA (ecstasy), MAO-B deficiency prevented the serotonin depletion normally seen in wild-type mice but led to a more pronounced dopamine loss. These results suggest MAO-B plays opposite roles in MDMA-induced damage to dopamine and serotonin systems.
Synapse
February 1, 2000
Bryan Horan, Eliot L. Gardner, Charles R. Ashby
50 citations
Rats given the recreational drug MDMA (ecstasy) for four days later showed a stronger conditioned place preference for cocaine than rats given a placebo, indicating that prior MDMA exposure may increase sensitivity to cocaine's rewarding effects and potentially raise the risk of cocaine addiction.
Synapse
February 1, 1993
Jennifer C. Garratt, Meenakshi Alreja, George K. Aghajanian
46 citations
LSD and serotonin (5-HT) both increase the electrical excitability of rat facial motoneurons, but through different mechanisms. While serotonin produces a reversible depolarization of about 5 mV by decreasing resting potassium conductance, LSD causes only a slight depolarization of 1-2 mV. Despite this, LSD strongly enhances the hyperpolarization-activated cation current I_h, more so than serotonin. LSD also attenuates the depolarizing effect of serotonin. The effects of LSD are blocked by the antagonists spiperone and ritanserin, indicating involvement of 5-HT2/5-HT1c receptors. These findings suggest LSD has high efficacy for enhancing I_h current but low efficacy for decreasing potassium conductance.
Synapse
July 14, 2004
Pedro Rosa‐neto, Albert Gjedde, Aage Kristian Olsen Alstrup et al.
39 citations
MDMA (Ecstasy) reduces the binding of two different radioligands to dopamine D2-like receptors in the striatum of living pigs, as measured by PET. The binding potential of [11C]raclopride fell by 35% at 45 minutes and 22% at 165 minutes after MDMA infusion, similar to changes caused by d-amphetamine. Unexpectedly, the binding of [11C]NMSP also decreased, by 30% in the first scan and 50% in the second, unlike its typical insensitivity to dopamine release. The simultaneous release of dopamine and serotonin by MDMA may explain the progressive decline in NMSP binding.
Synapse
September 5, 2002
Liesbeth Reneman, Jan Booij, Jan B. A. Habraken et al.
33 citations
SPECT imaging with [123I]β-CIT can detect reductions in serotonin transporter density caused by MDMA neurotoxicity. A rhesus monkey treated with MDMA showed a 39% decrease in SERT binding in the hypothalamic/midbrain region 31 days after treatment, matching autoradiography data (−34%). Rat studies confirmed significant binding reductions in SERT-rich regions one week after neurotoxic MDMA doses. The findings validate [123I]β-CIT SPECT as a method for measuring MDMA-induced serotonergic damage in the brain.
Synapse
April 5, 2007
Paul Cumming, Mette Møller, Kjeld Benda et al.
28 citations
The psychostimulant MDMA (ecstasy) causes degeneration of serotonin nerve endings in the forebrain of rodents, nonhuman primates, and human users. To study this in a large animal without using primates, researchers used PET scans to map serotonin transporters and 5HT1A receptors in the brains of Göttingen minipigs before and after MDMA treatment. Total doses above 20 mg/kg reduced serotonin transporter binding: a mean 42 mg/kg dose caused a 32% decrease in the midbrain and thalamus and a 53% decrease in forebrain structures. This loss did not consistently alter 5HT1A receptor binding. The number of serotonin-producing neurons in the dorsal raphé nucleus (about 95,000 in normal animals) remained unchanged.
Synapse
January 1, 2005
Luciano Minuzzi, George G. Nomikos, Mark Wade et al.
25 citations
LSD reduces the binding potential of a dopamine D2/3 receptor tracer in the striatum of pigs, suggesting a direct interaction with these receptors. In a PET study, the binding potential of [11C]raclopride decreased by 19% four hours after LSD administration, without changes in cerebral blood flow. In vitro experiments showed LSD displaces the tracer from pig brain tissue with an IC50 of 275 nM, and a two-site model indicated a subnanomolar component comprising 20% of binding. Microdialysis in rats found no changes in dopamine or its metabolites. These findings indicate LSD directly occupies a portion of dopamine D2/3 receptors, which may contribute to its psychoactive effects.
Synapse
December 22, 2009
Ainhoa Plaza‐zabala, Fernando Berrendero, Juan Suárez et al.
3 citations
Repeated high doses of MDMA impaired mice's ability to learn and recall an active avoidance task. Pretreatment with a low dose (5 mg/kg) of the endogenous PPAR-α agonist oleoylethanolamide (OEA) partially protected against these deficits, while a higher dose (25 mg/kg) worsened them. MDMA also reduced dopamine transporter (DAT)-binding sites in the brain four days after the last dose, an effect prevented by both OEA doses. Coexpression of tyrosine-hydroxylase and PPAR-α receptors was observed in the striatum and substantia nigra pars compacta, suggesting OEA modulates MDMA-induced cognitive deficits through a DAT-independent mechanism.