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Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria‐dependent pathway
Author(s) -
Krasnova Iri.,
Ladenheim Bruce,
Cadet Jean Lud
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-2881fje
Subject(s) - dopaminergic , terminal deoxynucleotidyl transferase , tunel assay , medium spiny neuron , striatum , amphetamine , programmed cell death , dopamine , parvalbumin , apoptosis , chemistry , microbiology and biotechnology , caspase , biology , pharmacology , neuroscience , biochemistry
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.