Methamphetamine-induced dopaminergic neurotoxicity in mice: Long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine

Yossef Itzhak, Julio L. Martin, Syed F. Ali

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

High doses of methamphetamine (METH) cause the depletion of striatal dopaminergic markers; however, little is known about the behavioral consequences of METH-induced neurotoxicity. In the present study, the authors investigated the effect of a neurotoxic dose of METH (5 mg/kg; every 3 h x 3) on the subsequent response of Swiss Webster mice to (a) the psychomotor-stimulating effect of METH and (b) the acquisition and maintenance of conditioned place preference (CPP) by METH. The latter is a paradigm for the assessment of the rewarding properties of abused substances. The administration of the high dose of METH resulted in significant depletion of dopamine (DA) and its metabolites and dopamine transporter (DAT) binding sites in the striatum. The dopaminergic markers were below control levels until the 95th day after METH administration. METH-pretreated mice were sensitized to the psychomotor-stimulating effect of METH (1 mg/kg) as determined on Days 3 and 74 after the initial exposure to the neurotoxic dose of METH. However, the acquisition of CPP by METH (0.5 mg/kg) was markedly reduced in the mice pretreated with the neurotoxic dose of METH compared with the control group. The CPP was maintained for 8 weeks in the control group but not in the METH group. A priming injection of METH (0.5 mg/kg) caused marked reinstatement of place preference in the control group; this response was maintained for three additional weeks. However, the priming injection of METH resulted in diminished place preference in the METH group and the conditioned response dissipated within 3 weeks. These findings suggest that METH-induced striatal dopaminergic neurotoxicity is associated with two opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse.

Original languageEnglish (US)
Pages (from-to)1177-1183
Number of pages7
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume26
Issue number6
DOIs
StatePublished - Oct 1 2002

Keywords

  • Conditioned place preference (CPP)
  • Dopaminergic neurotoxicity
  • Psychomotor stimulation

ASJC Scopus subject areas

  • Biological Psychiatry
  • Pharmacology

Fingerprint Dive into the research topics of 'Methamphetamine-induced dopaminergic neurotoxicity in mice: Long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine'. Together they form a unique fingerprint.

  • Cite this