Persistent cerebrovascular effects of MDMA and acute responses to the drug

Acutely, 3,4,‐methylenedioxymethamphetamine (MDMA) induces cerebrovascular dysfunction [ Quate et al., (2004)Psychopharmacol., 173, 287–295]. In the longer term the same single dose results in depletion of 5‐hydroxytrptamine (5‐HT) nerve terminals. In this study we examined the cerebrovascular consequences of this persistent neurodegeneration, and the acute effects of subsequent MDMA exposure, upon the relationship that normally exists between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu). Dark agouti (DA) rats were pre‐treated with 15 mg/kg i.p. MDMA or saline. Three weeks later, rats from each pre‐treatment group were treated with an acute dose of MDMA (15 mg/kg i.p.) or saline. Quantitative autoradiographic imaging was used to measure LCBF or LCMRglu with [14C]‐iodoantipyrine and [14C]‐2‐deoxyglucose, respectively. Serotonergic terminal depletion was assessed using radioligand binding with [3H]‐paroxetine and immunohistochemistry. Three weeks after MDMA pre‐treatment there were significant reductions in densities of 5‐HT transporter (SERT)‐positive fibres (−46%) and [3H]‐paroxetine binding (−47%). In animals pre‐treated with MDMA there were widespread significant decreases in LCMRglu, but no change in LCBF indicating a persistent loss of cerebrovascular constrictor tone. In both pre‐treatment groups, acute MDMA produced significant increases in LCMRglu, while LCBF was significantly decreased. In 50% of MDMA‐pre‐treated rats, random areas of focal hyperaemia indicated a loss of autoregulatory capacity in response to MDMA‐induced hypertension. These results suggest that cerebrovascular regulatory dysfunction resulting from acute exposure to MDMA is not diminished by previous exposure, despite a significant depletion in 5‐HT terminals. However, there may be a sub‐population, or individual circumstances, in which this dysfunction develops into a condition that might predispose to stroke.

[1]  L. Descarries,et al.  Altered neuronal responsiveness to biogenic amines in rat cerebral cortex after serotonin denervation or depletion , 1982, Brain Research.

[2]  C. Wichems,et al.  Release of serotonin induced by 3,4-methylenedioxymethamphetamine (MDMA) and other substituted amphetamines in cultured fetal raphe neurons: further evidence for calcium-independent mechanisms of release , 1995, Brain Research.

[3]  M. Yoshida,et al.  Cerebral infarction associated with 3,4-methylenedioxymethamphetamine ('Ecstasy') abuse. , 1995, European neurology.

[4]  E. D. De Souza,et al.  3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. , 1987, The Journal of pharmacology and experimental therapeutics.

[5]  G. Bagdy,et al.  Acute and long-term effects of a single dose of MDMA on aggression in Dark Agouti rats. , 2005, The international journal of neuropsychopharmacology.

[6]  Christer Carlsson,et al.  Influence of Amphetamine Sulphate on Cerebral Blood Flow and Metabolism , 1975 .

[7]  M. Bourin,et al.  3,4-Methylenedioxy analogues of amphetamine: Defining the risks to humans , 1999, Neuroscience & Biobehavioral Reviews.

[8]  A. R. Green,et al.  Chlormethiazole, dizocilpine and haloperidol prevent the degeneration of serotonergic nerve terminals induced by administration of MDMA (‘Ecstasy’) to rats , 1994, Neuropharmacology.

[9]  E. Whalley,et al.  Dopamine receptors in human basilar arteries. , 1983, European journal of pharmacology.

[10]  L. Sokoloff,et al.  Measurement of local cerebral blood flow with iodo [14C] antipyrine. , 1978, The American journal of physiology.

[11]  E. Mackenzie,et al.  The concept of coupling blood flow to brain function: Revision required? , 1987, Annals of neurology.

[12]  J. Kelly,et al.  Prior exposure to methylenedioxyamphetamine (MDA) induces serotonergic loss and changes in spontaneous exploratory and amphetamine-induced behaviors in rats. , 2001, Life sciences.

[13]  G. Hanson,et al.  Immediate and long-term effects of 3,4-methylenedioxymethamphetamine on serotonin pathways in brain of rat , 1987, Neuropharmacology.

[14]  W. Lovenberg,et al.  Methylenedioxymethamphetamine: a potentially neurotoxic amphetamine analogue. , 1986, European journal of pharmacology.

[15]  D. Felten,et al.  Neuronal-vascular relationships in the raphe nuclei, locus coeruleus, and substantia nigra in primates. , 1979, The American journal of anatomy.

[16]  J. Sharkey,et al.  Alterations in hippocampal function following repeated exposure to the amphetamine derivative methylenedioxymethamphetamine (“Ecstasy”) , 2006, Psychopharmacology.

[17]  H. J. Olverman,et al.  Acute methylenedioxymethamphetamine administration: effects on local cerebral blood flow and glucose utilisation in the dark agouti rat , 2004, Psychopharmacology.

[18]  G. Battaglia,et al.  Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[19]  M. Colado,et al.  The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA (`ecstasy') , 1998, Neuropharmacology.

[20]  B. Siesjö,et al.  Physiological role of cerebrovascular sympathetic nerves in the autoregulation of cerebral blood flow , 1976, Brain Research.

[21]  J. Richards,et al.  Methylenedioxymethamphetamine-induced serotonin deficits are followed by partial recovery over a 52-week period. Part II: Radioligand binding and autoradiography studies. , 1996, The Journal of pharmacology and experimental therapeutics.

[22]  L S Seiden,et al.  Biochemical and histological evidence that methylenedioxymethylamphetamine (MDMA) is toxic to neurons in the rat brain. , 1987, The Journal of pharmacology and experimental therapeutics.

[23]  S. Ibayashi,et al.  Cerebral Autoregulation in Young Spontaneously Hypertensive Rats , 2005 .

[24]  G. Goodwin,et al.  Review of the pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA or “Ecstasy”) , 1995, Psychopharmacology.

[25]  D. Duverger,et al.  Neurochemical studies on the existence, origin and characteristics of the serotonergic innervation of small pial vessels , 1985, Brain Research.

[26]  E. Arsura,et al.  Methamphetamine-related stroke: four cases. , 1999, The Journal of emergency medicine.

[27]  J J Grome,et al.  The Effects of Serotonin on Local Cerebral Blood Flow , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[28]  G. Gudelsky,et al.  Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT , 2005, Brain Research.

[29]  Jie Yuan,et al.  Loss of Serotonin Transporter Protein after MDMA and Other Ring-Substituted Amphetamines , 2006, Neuropsychopharmacology.

[30]  M. Wheaton,et al.  THE EFFECTS OF METHYLENEDIOXYMETHAMPHETAMINE (MDMA, “ECSTASY”) ON MONOAMINERGIC NEUROTRANSMISSION IN THE CENTRAL NERVOUS SYSTEM , 1996, Progress in Neurobiology.

[31]  E. Azmitia,et al.  MDMA (Ecstasy) Inhibition of MAO Type A and Type B: Comparisons with Fenfluramine and Fluoxetine (Prozac) , 1994, Neuropsychopharmacology.

[32]  C. J. Schmidt,et al.  Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. , 1987, The Journal of pharmacology and experimental therapeutics.

[33]  N. Toda,et al.  Analysis of the contractile response to serotonin and tryptamine of isolated dog cerebral, femoral and mesenteric arteries. , 1983, Japanese journal of pharmacology.

[34]  J L Katz,et al.  Serotonergic recovery after (+/-)3,4-(methylenedioxy) methamphetamine injury: observations in rats. , 1993, The Journal of pharmacology and experimental therapeutics.

[35]  A. Gjedde,et al.  MDMA‐evoked changes in cerebral blood flow in living porcine brain: Correlation with hyperthermia , 2004, Synapse.

[36]  R. Jakus,et al.  Effects of a single dose of 3,4-methylenedioxymethamphetamine on circadian patterns, motor activity and sleep in drug-naive rats and rats previously exposed to MDMA , 2004, Psychopharmacology.

[37]  S. Ibayashi,et al.  Cerebral autoregulation in young spontaneously hypertensive rats. Effect of sympathetic denervation. , 1985, Hypertension.

[38]  M. Galloway,et al.  MDMA induced dopamine release in vivo: role of endogenous serotonin , 2005, Journal of Neural Transmission.

[39]  H. Steinbusch,et al.  Distribution of serotonin-immunoreactivity in the central nervous system of the rat—Cell bodies and terminals , 1981, Neuroscience.

[40]  J. Richards,et al.  Methylenedioxymethamphetamine-induced serotonin deficits are followed by partial recovery over a 52-week period. Part I: Synaptosomal uptake and tissue concentrations. , 1996, The Journal of pharmacology and experimental therapeutics.

[41]  R. de Silva,et al.  ‘Ecstasy’ and Intracerebral Haemorrhage , 1992, Scottish medical journal.

[42]  G. Battaglia,et al.  MDMA-induced neurotoxicity: Parameters of degeneration and recovery of brain serotonin neurons , 1988, Pharmacology Biochemistry and Behavior.

[43]  D. Graham,et al.  Effects of increasing arterial pressure on cerebral blood flow in the baboon: Influence of the sympathetic nervous system , 1979, Pflügers Archiv.

[44]  C. Piérard,et al.  Effect of modafinil on cerebral blood flow of anaesthetised rats , 2000, Experimental Brain Research.

[45]  S. Dawling,et al.  Toxicity and deaths from 3,4-methylenedioxymethamphetamine ("ecstasy") , 1992, The Lancet.

[46]  M. Paule,et al.  Effects of MDMA on Complex Brain Function in Laboratory Animals , 1997, Neuroscience & Biobehavioral Reviews.

[47]  D. E. Nichols,et al.  Structure‐Activity Relationships of MDMA and Related Compounds: A New Class of Psychoactive Drugs? a , 1990, Annals of the New York Academy of Sciences.

[48]  John Sharkey,et al.  Cerebrovascular and functional consequences of 5-HT1A receptor activation , 1991, Brain Research.

[49]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[50]  M. Colado,et al.  5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine , 1993, British journal of pharmacology.

[51]  J. Mcculloch,et al.  Regional cerebral perfusion during hypertension depends on the hypertensive agent , 1986, Neuroscience Letters.

[52]  Linda Carpenter,et al.  Reduced brain serotonin transporter availability in major depression as measured by [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane and single photon emission computed tomography , 1998, Biological Psychiatry.

[53]  N. Toda,et al.  Serotonin antagonism in isolated canine cerebral arteries. , 1976, Japanese journal of pharmacology.

[54]  W. van den Brink,et al.  Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy"): preliminary findings. , 2001, Archives of general psychiatry.

[55]  B. Yamamoto,et al.  Enhancement of 3,4‐methylenedioxymethamphetamine neurotoxicity by the energy inhibitor malonate , 2001, Journal of neurochemistry.

[56]  O B Paulson,et al.  Cerebral autoregulation. , 1984, Stroke.

[57]  H. Weiss,et al.  Effect of amphetamine on cerebral blood flow and capillary perfusion , 1991, Brain Research.

[58]  D. Lowenstein,et al.  Emergence of recreational drug abuse as a major risk factor for stroke in young adults. , 1990, Annals of internal medicine.

[59]  D. Petitti,et al.  Stroke and Cocaine or Amphetamine Use , 1998, Epidemiology.

[60]  H. J. Olverman,et al.  Enhanced Cerebrovascular Responsiveness to Hypercapnia following Depletion of Central Serotonergic Terminals , 1995, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[61]  M. Morales,et al.  (±)-3,4-Methylenedioxymethamphetamine Administration to Rats Does Not Decrease Levels of the Serotonin Transporter Protein or Alter Its Distribution between Endosomes and the Plasma Membrane , 2005, Journal of Pharmacology and Experimental Therapeutics.

[62]  D. O'neill,et al.  Stroke associated with amphetamine use. , 2002, Irish medical journal.

[63]  J. Auer,et al.  Subarachnoid haemorrhage with "Ecstasy" abuse in a young adult , 2002, Neurological Sciences.

[64]  Diana B. Petitti,et al.  Stroke and cocaine or amphetamine use. , 1998 .

[65]  M. Colado,et al.  The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) , 2003, Pharmacological Reviews.

[66]  B. Yamamoto,et al.  Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3, 4-methylenedioxymethamphetamine , 1992, Brain Research.

[67]  Z. Szabo,et al.  Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings , 1998, The Lancet.

[68]  G. Goodwin,et al.  Differential patterns of local cerebral glucose utilization in response to 5-hydroxytryptamine, agonists , 1988, Neuroscience.

[69]  D. Graham,et al.  Effects of Acutely Induced Hypertension in Cats on Pial Arteriolar Caliber, Local Cerebral Blood Flow, and the Blood‐Brain Barrier , 1976, Circulation research.

[70]  S. Peroutka,et al.  Neurochemistry and Neurotoxicity of 3,4‐Methylenedioxymethamphetamine (MDMA, “Ecstasy”) , 1990, Journal of neurochemistry.

[71]  B. Siesjö,et al.  Circulatory and metabolic effects in the brain induced by amphetamine sulphate. , 1978, Acta physiologica Scandinavica.

[72]  M. Wilson,et al.  Neurotoxicity of MDMA and Related Compounds: Anatomic Studies a , 1990, Annals of the New York Academy of Sciences.

[73]  F. Vollenweider,et al.  Psychological and Cardiovascular Effects and Short-Term Sequelae of MDMA (“Ecstasy”) in MDMA-Naïve Healthy Volunteers , 1998, Neuropsychopharmacology.

[74]  E. London,et al.  Effects of methylenedioxymethamphetamine on local cerebral glucose utilization in the rat , 1989, Neuropharmacology.

[75]  B. Jacobs,et al.  Behavioral evidence for supersensitivity following destruction of central serotonergic nerve terminals by 5,7-dihydroxytryptamine. , 1976, The Journal of pharmacology and experimental therapeutics.

[76]  K. Varner,et al.  Changes in cardiovascular responsiveness and cardiotoxicity elicited during binge administration of Ecstasy. , 2002, The Journal of pharmacology and experimental therapeutics.

[77]  E. Agaba,et al.  Massive intracerebral hematoma and extradural hematoma in amphetamine abuse. , 2002, The American journal of emergency medicine.

[78]  J Linder,et al.  Sympathetic control of cerebral blood flow in acute arterial hypertension. , 1976, Acta physiologica Scandinavica.

[79]  Martin Prince,et al.  Is chronic low-level lead exposure in early life an etiologic factor in Alzheimer's disease? , 1998 .

[80]  G. Marek,et al.  Long-term central 5-HT depletions resulting from repeated administration of MDMA enhances the effects of single administration of MDMA on schedule-controlled behavior of rats , 1989, Pharmacology Biochemistry and Behavior.

[81]  K. Rice,et al.  Amphetamine‐type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin , 2001, Synapse.

[82]  G. Rudnick,et al.  The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[83]  J. Mcculloch,et al.  Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists , 1985, British journal of pharmacology.

[84]  G. Hanson,et al.  The effects of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on monoaminergic systems in the rat brain. , 1986, European journal of pharmacology.

[85]  E. Mackenzie,et al.  Evidence for Differing Origins of the Serotonergic Innervation of Major Cerebral Arteries and Small Pial Vessels in the Rat , 1991, Journal of neurochemistry.

[86]  M. Colado,et al.  The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype , 1995, British journal of pharmacology.

[87]  E. Mackenzie,et al.  Effects of 5‐hydrooxytryptamine on pial arteriolar calibre in anaesthetized cats , 1977, The Journal of physiology.

[88]  M. Colado,et al.  Acute and long-term effects of MDMA on cerebral dopamine biochemistry and function , 2004, Psychopharmacology.

[89]  N. Kitchen,et al.  Intracerebral haemorrhage in young adults: the emerging importance of drug misuse , 2000, BMJ : British Medical Journal.

[90]  N. Toda,et al.  Age-dependence of the chronotropic response to noradrenaline, acetylcholine and transmural stimulation in isolated rabbit atria. , 1976, Japanese journal of pharmacology.

[91]  J. A. Henry,et al.  Subarachnoid haemorrhage associated with MDMA abuse. , 1993, Journal of neurology, neurosurgery, and psychiatry.

[92]  B Jarrott,et al.  Isolated brain microvessels: preparation, morphology, histamine and catecholamine contents. , 1980, Blood vessels.