Abstract
Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light–dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.
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Abbreviations
- ADHD:
-
Attention-deficit/hyperactivity disorder
- CNS:
-
Central nervous system
- DA:
-
Dopamine
- DAT:
-
Dopamine active transporter
- 18F-FDG:
-
Fluorodeoxyglucose-18
- FDR:
-
False discovery rate
- MBN:
-
Metabolic brain network
- MPH:
-
Methylphenidate
- microPET:
-
Micro positron emission tomography
- NE:
-
Norepinephrine
- NET:
-
Norepinephrine transporter
- PD:
-
Postnatal day
- PET:
-
Positron emission tomography
- SUV:
-
Standardized uptake value
- SUVr:
-
Standardized uptake value ratio
- VOI:
-
Volume of interest
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Funding
This study was supported by Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN) (grant number no. 465671/2014–4), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) (grant number no. 16/0465–0), and Fundação Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil.
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F.S. and A.T.S.W. designed the studies. G.T.V., S.G., J.C.C. contributed to the MicroPET data collection. G.S. and E.R.Z. contributed to the metabolic network data collection. F.S. and J.S.S. contributed to the behavioral data collection. F.S., A.T.S.W., and E.R.Z. analyzed and interpreted the work. F.S. and A.T.S.W. wrote the manuscript. All authors have read, revised, and approved the final version of this manuscript.
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All animal experimental procedures developed in the present study were approved by the Institutional Ethics Committee on Animal Use (No. 37027) and were following the National Institutes of Health guide for the care and use of laboratory animals (NIH Publications No. 80–23, revised 1996), the guide of the Federation of Brazilian Societies for Experimental Biology and the Arouca Law (no. 11.794/ 2008).
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Schmitz, F., Silveira, J.S., Venturin, G.T. et al. Evidence That Methylphenidate Treatment Evokes Anxiety-Like Behavior Through Glucose Hypometabolism and Disruption of the Orbitofrontal Cortex Metabolic Networks. Neurotox Res 39, 1830–1845 (2021). https://doi.org/10.1007/s12640-021-00444-9
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DOI: https://doi.org/10.1007/s12640-021-00444-9