Antagonists of the neurokinin-1 or dopamine D1 receptors confer protection from methamphetamine on dopamine terminals of the mouse striatum.
Methamphetamine (METH) is a highly addictive compound that induces toxicity of the dopamine (DA) terminals of the neostriatum. Exposure to METH induces long-term deficits in dopamine transporter (DAT) and tyrosine hydroxylase (TH) levels as well as induction of glial fibrillary acidic protein (GFAP) in the caudate putamen (CPu) and the nucleus accumbens (NAc). The primary effect of exposure to METH is elevation of the level of extracellular DA; therefore, we assessed the role of the DA D1 receptor (D1R) and neurokinin-1 receptor (NK-1R) on the expression of toxicity. METH was injected intraperitoneally (10 mg/kg) four times at 2-h intervals (an acute toxic dose), and the mice were sacrificed three days after the treatment. Exposure to METH resulted in marked reduction of DAT sites (reduced to 30 and 21% relative to control in medial and lateral aspects of the CPu) assessed by binding of [125I]RTI-121 by autoradiography or Western blot analysis. Pretreatment with the nonpeptide NK-1R antagonist WIN-51,708 (10 mg/kg) 30 min prior to the first and fourth injections of METH prevented the loss of DAT sites of the CPu. Moreover, pretreatment with WIN-51,708 also prevented the reduction of TH levels induced by METH as well as the induction of GFAP in astrocytes. Pretreatment with the D1R antagonist SCH-23390 (0.25 mg/kg) 30 min before the first and fourth injections of METH conferred partial protection on DAT sites of the CPu. These results demonstrate that receptors postsynaptic to the DA terminals of the CPu are needed in order to express the neurotoxic effects of METH on integral components of the DA terminals of the nigrostriatal projection.
Angulo
Jesus A
JA
Department of Biological Sciences, Hunter College of City University of New York, New York, New York 10021, USA. angulo@genectr.hunter.cuny.edu
Angulo
Nieves
N
Yu
Jing
J
D000731:Androstanes / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D008694:Methamphetamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064729:Neurokinin-1 Receptor Antagonists; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism
D000731:Androstanes; D001552:Benzazepines; D001562:Benzimidazoles; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D064729:Neurokinin-1 Receptor Antagonists; D017447:Receptors, Dopamine D1; D018040:Receptors, Neurokinin-1; C493215:Slc6a3 protein, mouse; C086111:WIN 51708; D008694:Methamphetamine