Induction of striatal pre- and postsynaptic damage by methamphetamine requires the dopamine receptors.
Methamphetamine (METH) is a psychostimulant that induces excessive release of dopamine (DA) in the striatum. In this study we have assessed the role of DA D1 and D2 receptors (D1R and D2R) on striatal METH-induced apoptosis and depletion of DA-terminal markers. Male mice were given one i.p. injection of METH (30 mg/kg). Apoptosis was assessed at 24 h, and DA-terminal marker depletion 3 days, after METH. A single toxic dose of METH induced apoptosis in approximately 10-13% of striatal neurons. This was completely prevented by pretreatment (30 min before METH) with either the D1R antagonist SCH-23390 (0.1 mg/kg) or the D2R antagonist raclopride (1 mg/kg). The same dose of METH induced depletion of DA transporter sites up to 61, 56, 71, and 69% in dorsal-medial, ventral-medial, dorsal-lateral, and ventral-lateral striatum, respectively, relative to vehicle-injected controls. Similarly, METH induced depletion of TH protein levels up to 80, 72, 87, and 90% in those respective quadrants. METH induced the expression of glial fibrillary acidic protein throughout the striatum. All these neurochemical changes were significantly attenuated by pretreatment with SCH-23390 (0.1 mg/kg) or raclopride (1 mg/kg). However, pretreatment with either raclopride or SCH-23390 did not prevent METH-induced hyperthermia in mice. These data demonstrate that the induction by METH of both striatal apoptosis and DA-terminal damage requires the activity of the postsynaptic DA receptors in the mouse brain. Moreover, since blockade of either receptor subtype protected from METH, the activity of both DA receptor subtypes is required for the induction of toxicity by METH in the striatum.
Xu
Wenjing
W
Department of Biological Sciences, Hunter College of the City University of New York, New York, NY 10021, USA.
Zhu
Judy P Q
JP
Angulo
Jesus A
JA
D000661:Amphetamine / Q000633:toxicity*; D019969:Amphetamine-Related Disorders / Q000150:complications; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000633:toxicity; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000187:drug effects / Q000378:metabolism
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D005904:Glial Fibrillary Acidic Protein; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase