Chronic methadone treatment and repeated withdrawal impair cognition and increase the expression of apoptosis-related proteins in mouse brain.
OBJECTIVE
This study analyzes the effects of prolonged administration of methadone and withdrawal on sensorimotor and cognitive performance in mice and explores the associated changes in brain expression of proteins regulating the extrinsic (FasL, Fas, and caspase-8) and the mitochondrial (Bcl-2, Bcl-x(L), Bad, and Bax) apoptotic pathways.


RESULTS
Our findings indicate that, although acute methadone administration impairs some sensorimotor abilities, tolerance to most of the deleterious effects develops after chronic administration. Cognitive abilities in the Morris water maze were impaired by chronic methadone and, to a greater extent, by exposure to precipitated withdrawal every week in the course of methadone treatment. Both the chronic methadone and repeated withdrawal groups showed up-regulation of several pro-apoptotic proteins (FasL, the active fragment of caspase-8, and Bad) in the cortex and hippocampus, indicating activation of both the death-receptor and mitochondrial apoptotic pathways. In contrast, reduced expression of the apoptosis regulatory proteins FasL and Bad was found after a single administration of methadone.


CONCLUSIONS
Our data suggest that neural apoptotic damage could contribute to impairment of the cognitive abilities of mice observed after chronic methadone administration and withdrawal.
Tramullas
Mónica
M
Departamento de Fisiología y Farmacología, Universidad de Cantabria, Santander, Spain.
Martínez-Cué
Carmen
C
Hurlé
María A
MA
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D008691:Methadone / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D012008:Recurrence; D013037:Spatial Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; D008691:Methadone