Accumulation of neurotoxic thioether metabolites of 3,4-(+/-)-methylenedioxymethamphetamine in rat brain

The Journal of Pharmacology and Experimental Therapeutics
Gladys V ErivesTerrence J Monks

Abstract

The serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-alpha-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg s.c.) at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-alpha-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC)(0-300 min) for 5-(glutathion-S-yl)-N-Me-alpha-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC(0-300 min) for both 5-(N-acetylcystein-S-yl)-N-Me...Continue Reading

References

Jan 1, 1991·Advances in Experimental Medicine and Biology·B A HillS S Lau
Aug 2, 1988·European Journal of Pharmacology·B J LoganY B Yee
Jan 23, 1998·Chemical Research in Toxicology·Terrence J Monks, S S Lau
May 23, 1998·Annual Review of Pharmacology and Toxicology·Terrence J Monks, S S Lau
Nov 17, 1998·Chemical Research in Toxicology·H E KleinerS S Lau
Jan 1, 2003·Biochimica Et Biophysica Acta·B Hagenbuch, P J Meier
Jul 2, 2004·Therapeutic Drug Monitoring·Rafael de la TorreJordi Camí
Jan 7, 2005·The Journal of Pharmacology and Experimental Therapeutics·Douglas C JonesTerrence J Monks
Jan 13, 2006·American Journal of Physiology. Renal Physiology·Takashi SekineHitoshi Endou
Jul 6, 2006·Trends in Pharmacological Sciences·Susan P C Cole, Roger G Deeley

Citations

May 12, 2011·Chemical Research in Toxicology·Anne NeudörfferMartine Largeron
Apr 8, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Ximena PerfettiRafael de la Torre
Jul 25, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Melanie MuellerG A Ricaurte
Dec 5, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Joseph M HerndonTerrence J Monks
Apr 1, 2014·Journal of Analytical Toxicology·Corinne RamaleyChengan Du
Mar 5, 2014·Toxicological Sciences : an Official Journal of the Society of Toxicology·Joseph M HerndonTerrence J Monks
Mar 7, 2014·Toxicological Sciences : an Official Journal of the Society of Toxicology·Daniel José BarbosaFélix Carvalho
Apr 18, 2009·Molecular Neurobiology·João Paulo CapelaFélix Carvalho
Mar 6, 2010·Annals of the New York Academy of Sciences·Bryan K YamamotoGary A Gudelsky
Mar 6, 2010·Annals of the New York Academy of Sciences·Kyle C Schmitt, Maarten E A Reith
Mar 7, 2015·Archives of Toxicology·Daniel José BarbosaFélix Carvalho
Nov 2, 2013·Archives of Toxicology·Daniel José BarbosaFélix Carvalho
Apr 22, 2011·British Journal of Pharmacology·Daniel José BarbosaFélix Carvalho

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Hereditary Sensory Autonomic Neuropathy

Hereditary Sensory Autonomic Neuropathies are a group of inherited neurodegenerative disorders characterized clinically by loss of sensation and autonomic dysfunction. Here is the latest research on these neuropathies.

Spatio-Temporal Regulation of DNA Repair

DNA repair is a complex process regulated by several different classes of enzymes, including ligases, endonucleases, and polymerases. This feed focuses on the spatial and temporal regulation that accompanies DNA damage signaling and repair enzymes and processes.

Glut1 Deficiency

Glut1 deficiency, an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier, is characterized by mental and motor developmental delays and infantile seizures. Follow the latest research on Glut1 deficiency with this feed.

Separation Anxiety

Separation anxiety is a type of anxiety disorder that involves excessive distress and anxiety with separation. This may include separation from places or people to which they have a strong emotional connection with. It often affects children more than adults. Here is the latest research on separation anxiety.

KIF1A Associated Neurological Disorder

KIF1A associated neurological disorder (KAND) is a rare neurodegenerative condition caused by mutations in the KIF1A gene. KAND may present with a wide range and severity of symptoms including stiff or weak leg muscles, low muscle tone, a lack of muscle coordination and balance, and intellectual disability. Find the latest research on KAND here.

Regulation of Vocal-Motor Plasticity

Dopaminergic projections to the basal ganglia and nucleus accumbens shape the learning and plasticity of motivated behaviors across species including the regulation of vocal-motor plasticity and performance in songbirds. Discover the latest research on the regulation of vocal-motor plasticity here.