Comparison of single-dose and extended methamphetamine administration on reversal learning in rats

Psychopharmacology (Berl). 2012 Dec;224(3):459-67. doi: 10.1007/s00213-012-2774-1. Epub 2012 Jul 4.


Rationale: Protracted use of methamphetamine (mAMPH) can result in long-term impairments in cognitive function in humans. A previous study reported reversal-specific learning impairments in rats after a binge administration of mAMPH. Several studies show that extended exposure to mAMPH may confer protection against cognitive impairments and the insult to monoamine systems typically observed after larger binge doses.

Objectives: To explore this issue, we compared the effects of escalating and single doses of mAMPH (and saline, SAL) on retention, reversal learning, and post-mortem analysis of dopamine and serotonin transporters, DAT and SERT.

Methods: Rats learned to discriminate equiluminant stimuli and then were treated with either: (1) 4 weeks of mAMPH increasing by 0.3 mg/kg, culminating in 6 mg/kg (mAMPH(escal)); (2) 4 weeks of SAL with a single dose of 6 mg/kg on the last day of treatment (mAMPH(single)); or (3) 4 weeks of SAL. Following treatment, rats were tested on retention and reversal learning, with subsequent analysis of DAT and SERT binding across subregions of the striatum and frontoparietal cortex, respectively.

Results: Retention of the pretreatment discrimination was not significantly impaired in either mAMPH treatment group. A significant decrease in ventrolateral striatal DAT binding was observed only in the mAMPH(single) group and frontoparietal SERT was unaffected by either mAMPH treatment. Both treatment groups demonstrated attenuated reversal learning, particularly on measures of accuracy and effort.

Conclusions: These results show that extended and single-dose pretreatment with mAMPH similarly and selectively affect reversal learning, even in the absence of significant DAT or SERT changes.

Publication types

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

MeSH terms

  • Animals
  • Basal Ganglia / drug effects
  • Basal Ganglia / metabolism
  • Behavior, Animal / drug effects*
  • Body Weight / drug effects
  • Central Nervous System Stimulants / administration & dosage*
  • Central Nervous System Stimulants / metabolism
  • Cognition / drug effects*
  • Discrimination, Psychological / drug effects
  • Dopamine Plasma Membrane Transport Proteins / drug effects
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Frontal Lobe / drug effects
  • Frontal Lobe / metabolism
  • Injections, Subcutaneous
  • Light
  • Male
  • Methamphetamine / administration & dosage*
  • Methamphetamine / metabolism
  • Parietal Lobe / drug effects
  • Parietal Lobe / metabolism
  • Photic Stimulation
  • RNA-Binding Proteins / drug effects
  • RNA-Binding Proteins / metabolism
  • Rats
  • Rats, Long-Evans
  • Reversal Learning / drug effects*
  • Reward
  • Time Factors


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • RNA-Binding Proteins
  • Sert1 protein, rat
  • Methamphetamine