Impaired Object Recognition Memory Following Methamphetamine, but Not P-Chloroamphetamine- Or D-Amphetamine-Induced Neurotoxicity

Neuropsychopharmacology. 2005 Nov;30(11):2026-34. doi: 10.1038/sj.npp.1300771.

Abstract

Repeated moderate doses of methamphetamine (mAMPH) damage forebrain monoaminergic terminals and nonmonoaminergic cells in somatosensory cortex, and impair performance in a novelty preference task of object recognition (OR). This study aimed to determine whether the memory deficit seen after a neurotoxic mAMPH regimen results from damage to dopamine (DA) and/or serotonin (5-HT) terminals. Animals were given a neurotoxic regimen of mAMPH, p-chloroamphetamine (PCA, preferentially damages 5-HT terminals), d-amphetamine (d-AMPH, preferentially damages DA terminals), or saline. After 1 week, animals were trained and tested for OR memory. Rats treated with mAMPH showed no recognition memory during the short-term memory (STM) test, whereas both PCA- and d-AMPH-treated rats showed OR STM scores comparable to controls. After behavioral testing, the specificity of monoaminergic lesions was determined by postmortem [125I]RTI-55 binding to dopamine (DAT) and serotonin (SERT) transporter proteins. Tissue from a separate group of animals killed 3 days after drug treatment was processed for Fluoro-Jade (F-J) fluorescence histochemistry to detect damaged cortical neurons. mAMPH-treated rats showed reductions in striatal DAT and hippocampal (HC) and perirhinal (pRh) SERT, as well as degeneration of neurons in primary somatosensory cortex. In PCA-treated rats, HC and pRh SERT were substantially depleted, but striatal DAT and cortical neuron survival were unaffected. By contrast, d-AMPH-treated animals showed marked depletions in striatal DAT and cortical neurodegeneration, but HC and pRh SERT were unaffected. This pattern of results indicates that no single feature of mAMPH-induced neurotoxicity is sufficient to produce the OR impairments seen after mAMPH treatment.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal / drug effects
  • Body Temperature / drug effects
  • Cell Count / methods
  • Cocaine / analogs & derivatives
  • Cocaine / pharmacokinetics
  • Dextroamphetamine / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopamine Uptake Inhibitors / pharmacology
  • Fluoresceins
  • Male
  • Memory Disorders / chemically induced*
  • Memory Disorders / physiopathology
  • Methamphetamine*
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuropsychological Tests
  • Organic Chemicals / metabolism
  • Parietal Lobe / cytology
  • Parietal Lobe / drug effects
  • Protein Binding / drug effects
  • Radioligand Assay / methods
  • Radiopharmaceuticals / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Recognition, Psychology / drug effects*
  • Serotonin / metabolism
  • Serotonin Agents / pharmacology
  • p-Chloroamphetamine / pharmacology

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Fluoresceins
  • Organic Chemicals
  • Radiopharmaceuticals
  • Serotonin Agents
  • fluoro jade
  • Serotonin
  • Methamphetamine
  • 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
  • p-Chloroamphetamine
  • Cocaine
  • Dextroamphetamine