Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.
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 beta-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.
Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
David
D
Weinshenker
Michela
M
Ferrucci
Carla L
CL
Busceti
Francesca
F
Biagioni
Gloria
G
Lazzeri
L Cameron
LC
Liles
Paola
P
Lenzi
Livia
L
Pasquali
Luigi
L
Murri
Antonio
A
Paparelli
Francesco
F
Fornai
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001596:Benzylamines / Q000633:toxicity; D015306:Biogenic Monoamines / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000648:ultrastructure; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005669:Fusaric Acid / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D046529:Microscopy, Electron, Transmission / Q000379:methods; D014179:Neurotransmitter Uptake Inhibitors / Q000633:toxicity*; D009638:Norepinephrine / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism
D001596:Benzylamines; D015306:Biogenic Monoamines; D004791:Enzyme Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D017382:Reactive Oxygen Species; D008694:Methamphetamine; D004299:Dopamine beta-Hydroxylase; D005669:Fusaric Acid; C012102:DSP 4; D004298:Dopamine; D009638:Norepinephrine