Methamphetamine-induced dopaminergic deficits and refractoriness to subsequent treatment

Eur J Pharmacol. 2009 Apr 1;607(1-3):68-73. doi: 10.1016/j.ejphar.2009.01.037.

Abstract

Repeated high-dose methamphetamine administrations can cause persistent dopaminergic deficits. As individuals abusing methamphetamine are often exposed to recurrent high-dose administration, the impact of its repeated exposure merits investigation. Accordingly, rats were pretreated with repeated high-dose injections of methamphetamine, and subsequently "challenged" with the same neurotoxic regimen 7 or 30 days later. Results revealed that the initial methamphetamine treatment caused persistent deficits in striatal dopamine levels, dopamine transporter function, and vesicular monoamine transporter-2 function. The subsequent methamphetamine challenge treatment was without further persistent effects on these parameters, as assessed 7 days after the challenge, regardless of the interval (7 or 30 days) between the initial and challenge drug exposures. Similarly, a methamphetamine challenge treatment administered 7 days after the initial drug treatment was without further acute effect on dopamine transporter or VMAT-2 function, as assessed 1 h later. Thus, this study describes a model of resistance, possibly explained by: 1) the existence of dopaminergic neurons that are a priori refractory to deficits caused by methamphetamine; 2) the existence of dopaminergic neurons made persistently resistant consequent to a neurotoxic methamphetamine exposure; and/or 3) altered activation of post-synaptic basal ganglia systems necessary for the elaboration of methamphetamine-induced dopamine neurotoxicity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / administration & dosage
  • Dopamine Uptake Inhibitors / pharmacology*
  • Drug Resistance
  • Male
  • Methamphetamine / administration & dosage
  • Methamphetamine / toxicity*
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Time Factors
  • Vesicular Monoamine Transport Proteins / drug effects
  • Vesicular Monoamine Transport Proteins / metabolism

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Slc18a2 protein, rat
  • Vesicular Monoamine Transport Proteins
  • Methamphetamine
  • Dopamine

Grants and funding