Annals of the New York Academy of Sciences
January 8, 2010
Bryan K. Yamamoto, Anna Moszczyńska, Gary A. Gudelsky
280 citations
Methamphetamine and MDMA cause long-lasting reductions in markers of biogenic amine neurotransmission, traditionally linked to nerve terminal damage, in rodents, nonhuman primates, and humans. Recent evidence shows damage may extend to cell bodies of various neurons and blood–brain barrier endothelial cells. The damage involves oxidative stress, excitotoxicity, neuroinflammation, ubiquitin proteasome dysfunction, and mitochondrial and neurotrophic factor impairment. These mechanisms overlap with those in chronic stress and HIV infection, both of which amplify methamphetamine toxicity. The frequent co-occurrence of substituted amphetamine abuse with HIV or chronic stress suggests increased vulnerability to neurotoxicity in these individuals.
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.
Journal of Neurochemistry
October 27, 2004
Michael G. Bankson, Bryan K. Yamamoto
84 citations
MDMA (ecstasy) increases the release of the neurotransmitter GABA in the ventral tegmental area (VTA) of the rat brain, which in turn dampens the rise of dopamine in the nucleus accumbens (NAC) shell. This GABA increase depends on activation of serotonin 5-HT2B/2C receptors in the VTA, because blocking those receptors reduced the GABA rise and allowed dopamine in the NAC to increase more. By contrast, amphetamine also raised GABA in the VTA and dopamine in the NAC, but its GABA increase was not mediated by those serotonin receptors. The findings suggest a serotonergic braking mechanism that limits MDMA's dopamine-releasing effect.
Journal of Neuroimmune Pharmacology
November 17, 2012
John H. Anneken, Jacobi I. Cunningham, Stuart A. Collins et al.
52 citations
Repeated doses of MDMA (Ecstasy) cause a delayed and sustained increase in glutamate release in the rat hippocampus. Blocking cyclooxygenase (COX) enzymes, particularly COX-2, with drugs like ketoprofen or nimesulide reduces this glutamate rise, while a COX-1 inhibitor does not. Direct application of prostaglandin E2, a COX product, also raises glutamate levels. Repeated MDMA treatment reduces the number of parvalbumin-positive GABA interneurons in the dentate gyrus, an effect lessened by ketoprofen. However, COX inhibition does not prevent long-term serotonin depletion in the hippocampus. These findings suggest COX activity contributes to MDMA-induced glutamate release and GABA neuron loss but not to serotonin depletion.
Behavioral Neuroscience
October 1, 2009
Jacobi I. Cunningham, Jamie Raudensky, John Tonkiss et al.
27 citations
Prior exposure to MDMA makes rats vulnerable to stress-induced learning impairments that do not occur with stress alone. Rats pretreated with MDMA and then exposed to mild chronic unpredictable stress seven days later showed impaired learning in the Morris water maze, whereas stress alone did not cause this deficit. MDMA alone increased anxiety-like behavior on the elevated plus maze, but chronic stress alone or combined with MDMA pretreatment did not increase anxiety. The learning impairment was not accompanied by enhanced depletion of the serotonin transporter in the hippocampus, suggesting the effect involves mechanisms beyond serotonin transporter loss.
Journal of Pharmacology and Experimental Therapeutics
July 16, 2010
Bethann N. Johnson, Bryan K. Yamamoto
22 citations
Prior exposure to chronic unpredictable stress (CUS) in rats amplifies the hyperthermia, corticosterone (CORT) secretion, and long-term depletion of serotonin (5-HT) in striatum, hippocampus, and frontal cortex and dopamine (DA) in striatum caused by the psychostimulant MDMA. Lowering ambient temperature to 21°C prevented these augmented effects in stressed rats, reducing them to levels seen in nonstressed, MDMA-treated animals. Blocking CORT secretion with metyrapone did not alter the monoamine depletions, indicating that the stress-induced enhancement of MDMA neurotoxicity is mediated by hyperthermia rather than by CORT itself.
BioMed Research International
January 1, 2014
Georg F. Weber, Bethann N. Johnson, Bryan K. Yamamoto et al.
19 citations
MDMA, a substituted amphetamine and recreational drug, can produce mood-enhancing short-term effects that may lead to its use under stress. Clinical studies suggest MDMA treatment might alleviate symptoms of stress disorders like PTSD, but repeated use causes lasting deficits in serotonergic nerve terminal markers, indicating possible neurotoxicity. Chronic stress worsens MDMA-induced serotonergic neurotoxicity. In rats, MDMA altered gene expression in the hippocampus related to protein folding and neuropeptide signaling. In stressed rats, MDMA changed genetic responses affecting sensory processing and tissue damage responses, and reversed stress-induced downregulation of circadian rhythm genes. These transcriptional changes accompany the drug's persistent effects on neuronal structure and function.