title: Methamphetamine-induced cell death: selective vulnerability in neuronal subpopulations of the striatum in mice.
abstract: Methamphetamine (METH) is an illicit and potent psychostimulant, which acts as an indirect dopamine agonist. In the striatum, METH has been shown to cause long lasting neurotoxic damage to dopaminergic nerve terminals and recently, the degeneration and death of striatal cells. The present study was undertaken to identify the type of striatal neurons that undergo apoptosis after METH. Male mice received a single high dose of METH (30 mg/kg, i.p.) and were killed 24 h later. To demonstrate that METH induces apoptosis in neurons, we combined terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining with immunohistofluorescence for the neuronal marker neuron-specific nuclear protein (NeuN). Staining for TUNEL and NeuN was colocalized throughout the striatum. METH induces apoptosis in approximately 25% of striatal neurons. Cell counts of TUNEL-positive neurons in the dorsomedial, ventromedial, dorsolateral and ventrolateral quadrants of the striatum did not reveal anatomical preference. The type of striatal neuron undergoing cell death was determined by combining TUNEL with immunohistofluorescence for selective markers of striatal neurons: dopamine- and cAMP-regulated phosphoprotein, of apparent Mr 32,000, parvalbumin, choline acetyltransferase and somatostatin (SST). METH induces apoptosis in approximately 21% of dopamine- and cAMP-regulated phosphoprotein, of apparent Mr 32,000-positive neurons (projection neurons), 45% of GABA-parvalbumin-positive neurons in the dorsal striatum, and 29% of cholinergic neurons in the dorsal-medial striatum. In contrast, the SST-positive interneurons were refractory to METH-induced apoptosis. Finally, the amount of cell loss determined with Nissl staining correlated with the amount of TUNEL staining in the striatum of METH-treated animals. In conclusion, some of the striatal projection neurons and the GABA-parvalbumin and cholinergic interneurons were removed by apoptosis in the aftermath of METH. This imbalance in the populations of striatal neurons may lead to functional abnormalities in the output and processing of neural information in this part of the brain.
authors.affiliation: Department of Biological Sciences, Hunter College of the City University of New York, 695 Park Avenue, New York, NY 10021, USA.
authors.forename: J P Q
authors.initials: JP
authors.lastname: Zhu
authors.forename: W
authors.initials: W
authors.lastname: Xu
authors.forename: J A
authors.initials: JA
authors.lastname: Angulo
mesh_terms: D019969:Amphetamine-Related Disorders / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D000697:Central Nervous System Stimulants; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009498:Neurotoxins; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; D008694:Methamphetamine