Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine

David Weinshenker, Michela Ferrucci, Carla L. Busceti, Francesca Biagioni, Gloria Lazzeri, L. Cameron Liles, Paola Lenzi, Livia Pasquali, Luigi Murri, Antonio Paparelli, Francesco Fornai

Research output: Contribution to journalArticle

Abstract

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) lesions of the locus coeruleus, the major brain noradrenergic nucleus, exacerbate the damage to nigrostriatal dopamine (DA) terminals caused by the psychostimulant methamphetamine (METH). However, because noradrenergic terminals contain other neuromodulators and the noradrenaline (NA) transporter, which may act as a neuroprotective buffer, it was unclear whether this enhancement of METH neurotoxicity was caused by the loss of noradrenergic innervation or the loss of NA itself. We addressed the specific role of NA by comparing the effects of METH in mice with noradrenergic lesions (DSP-4) and those with intact noradrenergic terminals but specifically lacking NA (genetic or acute pharmacological blockade of the NA biosynthetic enzyme dopamine β-hydroxylase; DBH). We found that genetic deletion of DBH (DBH-/- mice) and acute treatment of wild-type mice with a DBH inhibitor (fusaric acid) recapitulated the effects of DSP-4 lesions on METH responses. All three methods of NA depletion enhanced striatal DA release, extracellular oxidative stress (as measured by in vivo microdialysis of DA and 2,3-dihydroxybenzoic acid), and behavioral stereotypies following repeated METH administration. These effects accompanied a worsening of the striatal DA neuron terminal damage and ultrastructural changes to medium spiny neurons. We conclude that NA itself is neuroprotective and plays a fundamental role in the sensitivity of striatal DA terminals to the neurochemical, behavioral, and neurotoxic effects of METH.

Original languageEnglish
Pages (from-to)471-483
Number of pages13
JournalJournal of Neurochemistry
Volume105
Issue number2
DOIs
Publication statusPublished - Apr 2008

    Fingerprint

Keywords

  • Dopamine
  • Drugs of abuse
  • Locus coeruleus
  • Methamphetamine
  • Noradrenaline
  • Parkinsonism

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this