title: Delayed emergence of methamphetamine's enhanced cardiovascular effects in nonhuman primates during protracted methamphetamine abstinence.
abstract: BACKGROUND
  Methamphetamine abuse is linked with brain abnormalities, but its peripheral effects constitute an integral aspect of long-term methamphetamine use.
  
  
  METHODS
  Eight male rhesus monkeys with long histories of intravenous methamphetamine self-administration were evaluated 1 day, and 1, 4, 12, 26, and 52 weeks after their last methamphetamine self-administration session. On test days, isoflurane-anesthetized animals received a 0.35 mg/kg IV methamphetamine challenge. A control group consisted of 10 age and gender matched drug naïve monkeys. Cardiovascular responses to methamphetamine were followed for 2.5h. Echocardiograms were acquired at 3 and 12 months of abstinence and in the control animals.
  
  
  RESULTS
  No pre-methamphetamine baseline differences existed among 7 physiological measures across all conditions and controls. As expected, methamphetamine increased heart rate and blood pressure in controls. However, immediately following the self-administration period, the blood pressure response to methamphetamine challenge was reduced when compared to control monkeys. The peak and 150-min average heart rate increases, as well as peak blood pressure increases following methamphetamine were significantly elevated between weeks 12 to 26 of abstinence. These data indicate the development of tolerance followed by sensitization to methamphetamine cardiovascular effects. Echocardiography demonstrated decreased left ventricular ejection fraction and cardiac output at 3 months of abstinence. Importantly, both cardiovascular sensitization and cardiotoxicity appeared to be reversible as they returned toward control group levels after 1 year of abstinence.
  
  
  CONCLUSIONS
  Enhanced cardiovascular effects may occur after prolonged abstinence in addicts relapsing to methamphetamine and may underlie clinically reported acute cardiotoxic events.
authors.affiliation: Neuroimaging Research Branch, National Institute on Drug Abuse, Baltimore, MD, United States.
authors.forename: D B
authors.initials: DB
authors.lastname: Vaupel
authors.affiliation: Preclinical Pharmacology Section, National Institute on Drug Abuse, Baltimore, MD, United States. Electronic address: cschind@helix.nih.gov.
authors.forename: C W
authors.initials: CW
authors.lastname: Schindler
authors.affiliation: Neuroimaging Research Branch, National Institute on Drug Abuse, Baltimore, MD, United States.
authors.forename: S
authors.initials: S
authors.lastname: Chefer
authors.affiliation: Neuroimaging Research Branch, National Institute on Drug Abuse, Baltimore, MD, United States.
authors.forename: A M
authors.initials: AM
authors.lastname: Belcher
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, MD, United States.
authors.forename: I
authors.initials: I
authors.lastname: Ahmet
authors.affiliation: Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, Baltimore, MD, United States.
authors.forename: K B
authors.initials: KB
authors.lastname: Scheidweiler
authors.affiliation: Chemistry and Drug Metabolism Section, National Institute on Drug Abuse, Baltimore, MD, United States.
authors.forename: M A
authors.initials: MA
authors.lastname: Huestis
authors.affiliation: Neuroimaging Research Branch, National Institute on Drug Abuse, Baltimore, MD, United States.
authors.forename: E A
authors.initials: EA
authors.lastname: Stein
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002302:Cardiac Output / Q000187:drug effects*; D016022:Case-Control Studies; D004361:Drug Tolerance; D004452:Echocardiography; D006339:Heart Rate / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D012646:Self Administration; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D008694:Methamphetamine
keywords: Abstinence; Blood pressure; Heart rate; Methamphetamine; Rhesus monkey