Manganese-Enhanced Magnetic Resonance Imaging Reveals Differential Long-Term Neuroadaptation After Methamphetamine and the Substituted Cathinone 4-Methylmethcathinone ( Mephedrone )

Background: In recent years there has been a large increase in the use of substituted cathinones such as mephedrone (4-methylmethcathinone, 4-MMC), a psychostimulant drug that shows a strong resemblance to methamphetamine (METH). Unlike METH, which can produce clear long-term effects, the effects of 4-MMC have so far remained elusive. We employ manganese-enhanced magnetic resonance imaging (MEMRI), a highly sensitive method for detecting changes in neuronal activation, to investigate the effects of METH and 4-MMC on the brain. Methods: In Wistar rats we performed a MEMRI scan two weeks after binge treatments (twice daily for 4 consecutive days) of METH (5 mg/kg) or 4-MMC (30 mg/kg). Furthermore, locomotor activity measurements and novel object recognition tests were performed. Results: METH produced a widespread pattern of decreased bilateral activity in several regions, including the nucleus accumbens, caudate putamen, globus pallidus, thalamus, and hippocampus, as well as several other cortical and subcortical areas. Conversely, 4-MMC produced increased bilateral activity, anatomically limited to the hypothalamus and hippocampus. Drug treatments did not affect the development of locomotor sensitization or novel object recognition performance. Conclusions: The pattern of decreased brain activity seen after METH corresponds closely to regions known to be affected by this drug and confirms the validity of MEMRI for detecting neuroadaptation two weeks after amphetamine binge treatment. 4-MMC, unlike METH, produced increased activity in a limited number of different brain regions. This highlights an important difference in the long-term effects of these drugs on neural function and shows precisely the anatomical localization of 4-MMC–induced neuroadaptation.

[1]  So Young Sohn,et al.  Identifying Emerging Trends of Financial Business Method Patents , 2017 .

[2]  I. McGregor,et al.  Repeated weekly exposure to MDMA, methamphetamine or their combination: long-term behavioural and neurochemical effects in rats. , 2007, Drug and alcohol dependence.

[3]  Michael Brady,et al.  Improved Optimization for the Robust and Accurate Linear Registration and Motion Correction of Brain Images , 2002, NeuroImage.

[4]  Nicola R. Sibson,et al.  Pharmacological MRI in animal models: A useful tool for 5-HT research? , 2008, Neuropharmacology.

[5]  M. Kane,et al.  Mephedrone does not damage dopamine nerve endings of the striatum, but enhances the neurotoxicity of methamphetamine, amphetamine, and MDMA , 2013, Journal of neurochemistry.

[6]  J. Herman,et al.  Neurocircuitry of stress: central control of the hypothalamo–pituitary–adrenocortical axis , 1997, Trends in Neurosciences.

[7]  J. Gee,et al.  Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress , 2013, Physiology & Behavior.

[8]  J. Kehr,et al.  Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5‐HT levels in nucleus accumbens of awake rats , 2011, British journal of pharmacology.

[9]  I. Vardakou,et al.  Drugs for youth via Internet and the example of mephedrone. , 2011, Toxicology letters.

[10]  J. Ramsey,et al.  High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: Neural consequences and comparison with methamphetamine , 2013, Journal of psychopharmacology.

[11]  A. Grace,et al.  Cortico-Basal Ganglia Reward Network: Microcircuitry , 2010, Neuropsychopharmacology.

[12]  A. Hess,et al.  Manganese-Enhanced Magnetic Resonance Imaging for Mapping of Whole Brain Activity Patterns Associated with the Intake of Snack Food in Ad Libitum Fed Rats , 2013, PloS one.

[13]  Cinzia Pezzolesi,et al.  Identifying emerging trends in recreational drug use; outcomes from the Psychonaut Web Mapping Project , 2012, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[14]  H. Haughey,et al.  The Effects of Methamphetamine on Serotonin Transporter Activity , 2000, Journal of neurochemistry.

[15]  C. Vorhees,et al.  Effect of (+)-methamphetamine on path integration learning, novel object recognition, and neurotoxicity in rats , 2008, Psychopharmacology.

[16]  Bryan Kolb,et al.  Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine , 1999, The European journal of neuroscience.

[17]  Yusuke Murayama,et al.  Mapping of functional brain activity in freely behaving rats during voluntary running using manganese-enhanced MRI: Implication for longitudinal studies , 2010, NeuroImage.

[18]  Walter Ling,et al.  Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers. , 2004, Archives of general psychiatry.

[19]  J S Fowler,et al.  Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. , 2001, The American journal of psychiatry.

[20]  T. Robinson,et al.  Reduced striatal vesicular monoamine transporters after neurotoxic but not after behaviorally-sensitizing doses of methamphetamine. , 1997, European journal of pharmacology.

[21]  M. Kane,et al.  Effects of combined treatment with mephedrone and methamphetamine or 3,4-methylenedioxymethamphetamine on serotonin nerve endings of the hippocampus. , 2014, Life sciences.

[22]  J. Javitch,et al.  N-Terminal Phosphorylation of the Dopamine Transporter Is Required for Amphetamine-Induced Efflux , 2004, PLoS biology.

[23]  T. Aigner,et al.  Effects of a high-dose treatment of methamphetamine on caudate dopamine and anorexia in rats , 1981, Pharmacology Biochemistry and Behavior.

[24]  Edward E. Smith,et al.  Is Cognitive Functioning Impaired in Methamphetamine Users? A Critical Review , 2012, Neuropsychopharmacology.

[25]  Robia G. Pautler,et al.  Manganese enhanced MRI (MEMRI): neurophysiological applications , 2011, Reviews in the neurosciences.

[26]  J. Cadet,et al.  Differential neurochemical consequences of an escalating dose‐binge regimen followed by single‐day multiple‐dose methamphetamine challenges , 2008, Journal of neurochemistry.

[27]  D. Kuhn,et al.  Mephedrone, an abused psychoactive component of ‘bath salts’ and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum , 2012, Journal of neurochemistry.

[28]  S. Rozov,et al.  Long-term cognitive and neurochemical effects of “bath salt” designer drugs methylone and mephedrone , 2013, Pharmacology Biochemistry and Behavior.

[29]  A. Winstock,et al.  Mephedrone, new kid for the chop? , 2011, Addiction.

[30]  N. Volkow,et al.  Partial recovery of brain metabolism in methamphetamine abusers after protracted abstinence. , 2004, The American journal of psychiatry.

[31]  M. W. Manning,et al.  Recovery of Presynaptic Dopaminergic Functioning in Rats Treated with Neurotoxic Doses of Methamphetamine , 1999, The Journal of Neuroscience.

[32]  G. Marek,et al.  Neurotoxicity in Dopamine and 5‐Hydroxytryptamine Terminal Fields: A Regional Analysis in Nigrostriatal and Mesolimbic Projections , 1988, Annals of the New York Academy of Sciences.

[33]  Nicholas A Bock,et al.  Manganese-enhanced MRI: an exceptional tool in translational neuroimaging. , 2007, Schizophrenia bulletin.

[34]  S. Lukas.  New perspectives on using brain imaging to study CNS stimulants , 2014, Neuropharmacology.

[35]  Gary F. Egan,et al.  REX: Response Exploration for Neuroimaging Datasets , 2007, Neuroinformatics.

[36]  Daniel J. Bauer,et al.  Crystal methamphetamine use among young adults in the USA. , 2007, Addiction.

[37]  Angelo Bifone,et al.  A stereotaxic MRI template set for the rat brain with tissue class distribution maps and co-registered anatomical atlas: Application to pharmacological MRI , 2006, NeuroImage.

[38]  Paul J. Laurienti,et al.  An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets , 2003, NeuroImage.

[39]  I. McGregor,et al.  MDMA (“ecstasy”), methamphetamine and their combination: long-term changes in social interaction and neurochemistry in the rat , 2004, Psychopharmacology.

[40]  E. Malecki.  Manganese toxicity is associated with mitochondrial dysfunction and DNA fragmentation in rat primary striatal neurons , 2001, Brain Research Bulletin.

[41]  T. Ohmori,et al.  Effect of low doses of L-NAME on methamphetamine-induced dopaminergic depletion in the rat striatum , 2001, Journal of Neural Transmission.

[42]  P. Crits-Christoph,et al.  Prevalence of nonmedical methamphetamine use in the United States , 2008, Substance abuse treatment, prevention, and policy.

[43]  R. Rothman,et al.  The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue , 2012, Neuropsychopharmacology.

[44]  J. Cadet,et al.  Long-Term Protective Effects of Methamphetamine Preconditioning Against Single-Day Methamphetamine Toxic Challenges , 2011, Current neuropharmacology.

[45]  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.

[46]  L. Reneman,et al.  The Effects of Ecstasy (MDMA) on Brain Serotonin Transporters Are Dependent on Age-of-First Exposure in Recreational Users and Animals , 2012, PloS one.

[47]  R. Spanagel,et al.  Neurocircuitry for modeling drug effects , 2012, Addiction biology.

[48]  S. O'dell,et al.  Neurotoxic methamphetamine regimen severely impairs recognition memory in rats , 2003, Synapse.

[49]  Bung-Nyun Kim,et al.  Gene expression profiling in the striatum of amphetamine-treated spontaneously hypertensive rats which showed amphetamine conditioned place preference and self-administration , 2015, Archives of pharmacal research.

[50]  Liesbeth Reneman,et al.  Validity of [123I]β‐CIT SPECT in detecting MDMA‐induced serotonergic neurotoxicity , 2002, Synapse.

[51]  T. Brewerton,et al.  Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study , 2013, Journal of psychopharmacology.

[52]  Irina Simanova,et al.  Behavioral, electrophysiological and histopathological consequences of systemic manganese administration in MEMRI. , 2010, Magnetic resonance imaging.

[53]  B. Kolb,et al.  Persistent gene expression changes in NAc, mPFC, and OFC associated with previous nicotine or amphetamine exposure , 2013, Behavioural Brain Research.

[54]  Karl J. Friston,et al.  The Relationship between Global and Local Changes in PET Scans , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[55]  David P. Daberkow,et al.  Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals , 2013, The Journal of Neuroscience.

[56]  A. Winstock,et al.  Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion , 2012, PloS one.

[57]  L. Jerome,et al.  The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study , 2011, Journal of psychopharmacology.

[58]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .