Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory.
Several studies open up the possibility that chronic exposure to opioid drugs in the CNS would interfere with learning and memory through a neurotoxic effect related to activation of apoptotic pathways. Here, we have analyzed the effects of prolonged heroin administration on sensorimotor and cognitive performance in mice, as well as the associated changes in brain expression of proteins regulating the extrinsic (FasL and Fas) and the mitochondrial (Bcl-2, Bcl-X(L), Bad and Bax) apoptotic pathways. Our findings indicate that chronic heroin did not interfere with mice performance in a battery of sensorimotor tests. On the other hand, cognitive ability in the Morris water maze and cognitive flexibility-related performance were strongly impaired by chronic heroin. These effects were associated with up-regulation of pro-apoptotic proteins such as Fas, FasL and Bad, in the cortex and hippocampus, indicating the activation of both the death receptor and the mitochondrial apoptotic pathways. Another indicator of apoptosis was the presence of TUNEL (TdT-mediated dUTP nick-end labeling) positive cells scattered throughout the brain.
Tramullas
Mónica
M
Departamento de Fisiología y Farmacología, Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
Martínez-Cué
Carmen
C
Hurlé
María A
MA
D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D053222:Fas Ligand Protein / Q000378:metabolism; D003932:Heroin / Q000008:administration & dosage* / Q000097:blood; D020287:In Situ Nick-End Labeling / Q000379:methods; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009294:Narcotics / Q000008:administration & dosage* / Q000097:blood; D011597:Psychomotor Performance / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects*; D051025:bcl-Associated Death Protein / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D009294:Narcotics; D051025:bcl-Associated Death Protein; D003932:Heroin