title: Dopamine D(1) receptor deletion strongly reduces neurotoxic effects of methamphetamine.
abstract: Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool.
authors: Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002, Madrid, Spain.
authors: S
authors: S
authors: Ares-Santos
authors: N
authors: N
authors: Granado
authors: I
authors: I
authors: Oliva
authors: E
authors: E
authors: O'Shea
authors: E D
authors: ED
authors: Martin
authors: M I
authors: MI
authors: Colado
authors: R
authors: R
authors: Moratalla
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005334:Fever / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; D017447:Receptors, Dopamine D1; D008694:Methamphetamine; D004298:Dopamine