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Bryan Yamamoto Addiction Therapy-2014 Chicago, USA August 4 - 6, 2014.

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Presentation on theme: "Bryan Yamamoto Addiction Therapy-2014 Chicago, USA August 4 - 6, 2014."— Presentation transcript:

1 Bryan Yamamoto Addiction Therapy-2014 Chicago, USA August 4 - 6, 2014

2 Bryan Yamamoto, Ph.D. Department of Neurosciences University of Toledo College of Medicine and Life Sciences August 4, 2014

3 Volkow et al, Am. J. Psychiatry, 2001 Callaghan et al., Drug and Alcohol Dependence, 2011 Meth abuse increases risk of Parkinson’s Disease by 76% compared to age- matched controls and cocaine-abusers Methamphetamine Neurotoxicity in Humans

4 Overarching Hypothesis Excitotoxicity and oxidation of proteins and lipids are mechanisms underlying the neurotoxicity of Methamphetamine

5 Glutamate Release Calcium NOS NO ONOO - (peroxynitrite) O 2 - Protein oxidation, Mitochondrial Dysfunction Lipid Peroxidation H2O2H2O2 Calpain Proteolysis Identified Events Leading to a Loss of Dopamine and 5HT Glu Receptor Activation Dopamine Release Fe ++ X X X X XX MAO OH*

6 But, there are caveats to the proposition that the neurotoxicity/excitotoxicity of METH is a result of its direct action on the brain……..

7 Local administration of METH does not increase glutamate Systemic and Local Administration of METH: Burrows Glutamate (pg/20  l) -1 0 1 2 3 4 5 6 7 8 Perfusion Glutamate (pg/20  l

8 Dopamine (pg/  g protein) Without GlutamateWith Glutamate Glutamate Synergizes with Local METH To Deplete Dopamine Content No Meth Meth Meth/Heat No MethMeth Meth/Heat * # Burrows

9  If it is not the direct effect of METH alone on the brain (striatum), what other systems could be responsible for the neurotoxicity?  Another target of METH is the liver  Liver damage can produce encephalopathy (i.e. hepatic encephalopathy)  Tremor, movement disorders  Delirium, stupor, confusion, and coma Thinking Outside the Brain……

10 METH and Evidence of Hepatotoxicity Halpin

11 ALT (IU/L) SalineMETH * AST (IU/L) SalineMETH * Alanine AminotransferaseAspartate Aminotransferase Methamphetamine Increases Liver Enzymes in Plasma Halpin

12 Liver Damage and Ammonia  The liver normally removes excess ammonia from the blood via the urea cycle.  This is important because ammonia is a neurotoxic byproduct of protein metabolism and other metabolic reactions.  If the liver damaged, there is an accumulation of ammonia that is thought to cause hepatic encephalopathy

13 Ammonia Toxicity  Excitotoxicity (Fan and Szerb, 1993, Hermenegildo et al., 1996)  Oxidative stress ( Kosenko et al., 1997 and Kosenko et al., 1995)  Metabolic compromise (Hawkins et al., 1973, McCandless and Schenker, 1981)  Si milar mechanisms that mediate the toxicity to ammonia and the neurotoxicity to METH  Unknown whether peripheral organ (e.g. liver) damage is produced by METH and if it contributes to METH neurotoxicity

14 Overarching Hypothesis Liver Damage Hyperammonemia Methamphetamine Neurotoxicity Lactulose X

15 Saline Lactulose METH METH + Lactulose Plasma Ammonia (  M) * # Methamphetamine Increases Ammonia in Plasma Halpin

16 400 300 200 500 100 Methamphetamine Increases Ammonia in Striatum: Blocked by Lactulose Halpin

17 2 3 1 METHMETH + Lactulose 0 Lactulose Does Not Affect METH Concentrations in the Brain Halpin

18 (pg/  g protein) Vehicle Lactulose Saline METH (pg/  g protein) * * * # # Lactulose Attenuates METH-induced Long-term Depletions of Dopamine and 5HT Content DopamineSerotonin Halpin

19 1.2 1.0 0.8 0.6 0.4 0.2 Vehicle Lactulose Saline METH Dopamine Transporter Immunoreactivity * % Control Lactulose Blocks METH-induced Decreases in Dopamine Transporter Immmunoreactivity Halpin

20 Glutamate (% Baseline) 200 400 500 600 100 300 B Time (hrs) Vehicle-METH Vehicle-Saline Lac-METH Lac-Saline METH-Induced Increases in Striatal Extracellular Glutamate: Blocked by Lactulose Halpin, Northrop

21 Lactulose Blocks METH-Induced Increases in Striatal Spectrin Proteolysis Vehicle Lactulose Saline Saline METH METH 100 40 20 160 140 120 60 80 180 * Percent Control Halpin, Northrop

22 METH-Induced Astroglyosis (GFAP) is Blocked by Lactulose Vehicle Lactulose Saline Saline METH METH Percent Control * Halpin, Northrop

23 Glutamate (% Baseline) Time (hrs) TBOA or aCSF NH3 or aCSF Local Perfusion of Ammonia on Glutamate: Efflux Through Reversal of the Glutamate Transporter * 100 300 250 200 150 50 Halpin, Northrop

24 * * Vehicle NH 3 Saline METH Vehicle Saline METH (pg/  g protein) NH 3 Combined Local Perfusions of Ammonia and METH Dopamine and 5HT Content in the Striatum Dopamine 5HT Halpin, Northrop METH GYKI NH 3 METH GYKI NH 3

25 Are there other targets of ammonia?

26 Amphetamines The Blood-Brain Barrier: A Protective Barrier of the Brain

27 BBB Function in Cortex After Meth Vehicle Saline Lactulose Saline Lactulose Meth Vehicle Meth * # Quantification of FITC-Dextran Extravasation Vehicle+SalineLactulose+SalineVehicle+MethLactulose+Meth Northrop

28 Blood-Brain Barrier Tight Junctions Occludin Claudin 3, 5, 12 JAM

29 * # Occludin Vehicle Saline Lactulose Saline Vehicle Meth Lactulose Meth Claudin-5 * # Vehicle Saline Lactulose Saline Vehicle Meth Lactulose Meth Meth-Induced Disruption of BBB Structure in Cortex * * Northrop Isolated Brain Capillaries

30 Representative Blot for Nitrotyrosine Ammonia as a Pro-Oxidant? Representative Blot for Tight Junction Proteins Northrop Isolated Brain Capillaries from Cortex

31 Cyclooxygenase-2 Ammonia as a Pro-Inflammatory Agent? Northrop Vehicle Saline Vehicle Meth Lactulose Meth Lactulose Saline * & COX-2 Immunoreactivity (% Vehicle + Saline)

32 Summary and Conclusions  Increases in extracellular glutamate and evidence of excitotoxicity and oxidative degradation of proteins  Causes hepatotoxicity and increases ammonia concentrations in peripheral plasma and brain to mediate excitotoxicity  Damages the BBB via ammonia, oxidative stress, and inflammation (COX2-dependent prostaglandin synthesis?)  Opening of the BBB can render the brain vulnerable to toxins by that would otherwise by restricted to the periphery.  Peripheral organ effects should be considered as possible causes of the neurotoxicity associated with psychostimulant drug use Effects of METH:

33  Jeffrey Brown, Ph.D.  Kristan Burrows Cline, Ph.D.  David Eyerman, Ph.D.  Amy Ferng, M.S.  Laura Halpin, Ph.D.  John Irlam, D.O.  J. F. Nash, Ph.D.  Arunan Nadarajah, Ph.D.  Nicole Northrop, Ph.D.  Robert Staszewski, M.S.  Despina Tata, Ph.D  Amanda Blaker  Veronica Chiu, Ph.D.  Stuart Collins  Nicole Harless  Katelyn Marchal  Carmen Mitchell  Reka Natarajan, Ph.D.  Allen Schroering, M.S.  Erin Semple  Branden Stansley Collaborators Methamphetamine Project Past and Current Other Current Lab Members NIH grants DA007606, DA016866, DA035499

34 Addiction Therapy – 2015 Website: Meet the eminent gathering once again at Addiction Therapy-2015 Florida, USA August 3 - 5, 2015

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