Abstract
Acute methadone toxicity is a major public health concern which has adverse effects on brain tissue and results in recurrent or delayed respiratory arrest. Our study aimed to investigate the time-dependent changes in several serum biochemical markers of brain damage, spatial working memory, and the brain tissue following acute methadone overdose. Adolescent male rats underwent an intraperitoneal (i.p.) injection of 15 mg/kg methadone. In case of apnea occurrence, resuscitation was performed by a ventilatory pump and administrating naloxone (2 mg/kg; i.p.). The animals were classified into groups of treated rats; methadone and naloxone-Apnea (M/N-Apnea), M/N-Sedate, Methadone, Naloxone, and control (saline) groups. The serum levels of S100B, neuron-specific enolase (NSE), myelin basic protein factors, and (Lactate/Pyruvate) L/P ratio were evaluated at the time-points of 6, 24, and 48 h (h). We found that the alterations of S100B and L/P ratio were considerable in the M/N-Apnea and Methadone groups from the early hours post-methadone overdose, while NSE serum levels elevation was observed only in M/N-Apnea group with a delay at 48 h. Further, we assessed the spatial working memory (Y-maze test), morphological changes, and neuronal loss. The impaired spontaneous alternation behavior was detected in the M/N-Apnea groups on days 5 and 10 post-methadone overdose. The morphological changes of neurons and the neuronal loss were detectable in the CA1, striatum, and cerebellum regions, which were pronounced in both M/N-Apnea and Methadone groups. Together, our findings suggest that alterations in the serum levels of S100B and NSE factors as well as L/P ratio could be induced by methadone overdose with the presence or absence of apnea before the memory impairment and tissue injury in adolescent male rats.
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Acknowledgment
This study was carried out as a part of the Ph.D. thesis and supported by funding from the School of Medicine, Shahid Beheshti University of Medical Sciences (Grant No. 70), Tehran, Iran. This work was also supported by the Vice-Chancellor for Research & Technology of Shahid Beheshti University of Medical Sciences (Grant No. 98-21486-1398-11-29). The authors extend appreciation to the Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran for valuable cooperation.
Funding
This study was supported by funding from the School of Medicine, Shahid Beheshti University of Medical Sciences (Grant No. 98-21486-1398-11-29), Tehran, Iran. This funding source had no role in the design of this study, execution, analysis, and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.
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Abbas Haghparast was responsible for the study concept and design. Leila Ahmad-Molaei and Mahsa Pourhamzeh conducted the working memory test, histological and molecular studies. Abbas Haghparast, Fariba Khodagholi, Reza Ahadi, Hassanian-Moghaddam and Leila Ahmad-Molaei assisted with data analysis and interpretation of findings. Mahsa Pourhamzeh and Leila Ahmad-Molaei drafted the manuscript. All authors critically revised and approved final version for publication.
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Ahmad-Molaei, L., Pourhamzeh, M., Ahadi, R. et al. Time-Dependent Changes in the Serum Levels of Neurobiochemical Factors After Acute Methadone Overdose in Adolescent Male Rat. Cell Mol Neurobiol 41, 1635–1649 (2021). https://doi.org/10.1007/s10571-020-00931-1
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DOI: https://doi.org/10.1007/s10571-020-00931-1