Mice with partial deficiency of c-Jun show attenuation of methamphetamine-induced neuronal apoptosis.
The regional distribution of c-Jun expression and of the number of apoptotic cells was compared in various brain areas after methamphetamine administration to mice. Our results showed that there was methamphetamine-induced overexpression of c-Jun in the cortex and striatum but not in the cerebellar cortex. There was an almost totally similar regional appearance of methamphetamine-induced apoptotic cells in the mouse brain; no apoptosis was present in the cerebellum. Additionally, in the neocortical area, more positive signals for c-Jun immunoreactivity were observed in the piriform cortex, an area that also showed more positive terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) signals than the frontal and parietal cortices. These observations suggested that c-Jun might be involved in methamphetamine-induced apoptosis. This idea was confirmed by using heterozygous c-Jun knockout mice that showed much less apoptosis than wild-type controls. In addition, we found that the majority of TUNEL-positive cells were also positive for c-Jun-like immunoreactivity in both genotypes. Moreover, methamphetamine-induced caspase-3 activity and PARP cleavage were also reduced in c-Jun heterozygous knockout mice. In contrast, methamphetamine-induced hyperthermia was essentially identical in the two genotypes. When taken together, our data support the hypothesis that c-Jun is involved in methamphetamine-induced apoptosis.
Deng
Xiaolin
X
Molecular Neuropsychiatry Section, National Institutes of Health/National Institute on Drug Abuse-Intramural Research Program, Baltimore, Maryland 21224, USA.
Jayanthi
Subramaniam
S
Ladenheim
Bruce
B
Krasnova
Irina N
IN
Cadet
Jean Lud
JL
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D000697:Central Nervous System Stimulants; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D048031:JNK Mitogen-Activated Protein Kinases; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013696:Temperature
D000697:Central Nervous System Stimulants; D011506:Proteins; D016755:Proto-Oncogene Proteins c-jun; D008694:Methamphetamine; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases