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Self-vaccination by methamphetamine glycation products chemically links chronic drug abuse and cardiovascular disease

Academic Article
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Overview

related to degree

  • Treweek, Jennifer, Ph.D. in Chemical Biology, Scripps Research 2005 - 2011

authors

  • Treweek, Jennifer
  • Wee, Sunmee
  • Koob, George
  • Dickerson, Tobin
  • Janda, Kim

publication date

  • July 2007

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

abstract

  • Methamphetamine abuse is spreading rapidly throughout the United States and is characterized by significant health consequences. The powerfully rewarding effects of methamphetamine are attributed to multiple neuropharmacological actions such as its ability to block plasma membrane transporters of all monoamines, reduce dopamine transporter expression, and inhibit monoamine oxidase activity while increasing tyrosine hydroxylase activity. However, subsequent neuroreceptor changes including monoamine deficits complement this striking increase in monoamine release. Chronic methamphetamine abuse, as studied via self-administration paradigms in rodents, causes progressive dopaminergic neurotoxicity, a neuroanatomical change accompanied by increasing drug tolerance and escalating intake, two behavioral parameters of addiction. We have recently proposed that methamphetamine covalently glycates endogenous proteins. Such an event spurs antibody production against these immunoconjugates, possibly leading to drug sequestration by antibody binding of drug. Here we demonstrate that this drug-dependent glycation mechanism is operative in vivo through the dose-dependent detection of antibodies against methamphetamine-derived advanced glycation end products in rats chronically self-administering methamphetamine. Furthermore, increased levels of proinflammatory cytokines, evidence of potent immunoactivation, were also detected. Given the known role of advanced glycation end products in the alteration of protein function in vivo and the participation of these molecules in various diseases, methamphetamine-derived advanced glycation end products provide an unrecognized molecular mechanism for the development of vasculitis and other cardiovascular maladies reported with high incidence in chronic methamphetamine users.

subject areas

  • Animals
  • Autoantibodies
  • Blood-Brain Barrier
  • Cardiovascular Diseases
  • Chronic Disease
  • Glycosylation End Products, Advanced
  • Immunologic Factors
  • Male
  • Methamphetamine
  • Rats
  • Rats, Wistar
  • Self Administration
  • Substance-Related Disorders
  • Time Factors
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Research

keywords

  • addiction
  • advanced glycation end product
  • vasculitis
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Identity

PubMed Central ID

  • PMC1913859

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0701328104

PubMed ID

  • 17592122
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Additional Document Info

start page

  • 11580

end page

  • 11584

volume

  • 104

issue

  • 28

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