Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria-dependent pathway.
Amphetamine (AMPH) is a psychostimulant whose chronic abuse may cause impairments in attention and memory in humans. These cognitive deficits might be related to neurotoxic effects of the drug. One such toxic effect is the well-described destruction of striatal dopaminergic terminals in mammals. In the present study, we investigated the possibility that AMPH might also cause neuronal apoptosis in the rodent striatum. Administration of a dose of the drug (10 mg/kg, 4 times, every 2 h) that is toxic to dopaminergic terminals resulted in the appearance of striatal cells that were positive for cleaved caspase-3 and for terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL), observations that are indicative of an ongoing apoptotic process. Dual immunofluorescence staining revealed that cleaved caspase-3-positive cells express calbindin and DARPP-32, but not somatostatin, parvalbumin, or cholinergic markers. In addition, AMPH also caused increased expression of p53 and Bax at both transcript and protein levels; in contrast, Bcl-2 levels were decreased after the AMPH injections. Moreover, Bax knockout mice showed resistance to AMPH-induced apoptotic cell death but not to AMPH-induced destruction of dopaminergic terminals. When taken together, these observations indicate that injections of doses of AMPH that are known to destroy striatal dopamine terminals can also cause apoptotic death of postsynaptic medium spiny projection neurons via mitochondria-dependent mechanisms.
Krasnova
Irina N
IN
Molecular Neuropsychiatry Branch, NIDA-IRP, DHHS/NIH, Baltimore, Maryland, USA.
Ladenheim
Bruce
B
Cadet
Jean Lud
JL
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D064026:Calbindins; D053148:Caspase 3; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000648:ultrastructure; D004298:Dopamine / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000032:analysis; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000139:chemically induced; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064030:S100 Calcium Binding Protein G / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000172:deficiency / Q000235:genetics
D064026:Calbindins; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D004298:Dopamine