Evidence That Methylphenidate Treatment Evokes Anxiety-Like Behavior Through Glucose Hypometabolism and Disruption of
Felipe Schmitz1,2, Josiane S Silveira3,4, Gianina T Venturin5
1Neuroprotection and Neurometabolic Diseases Laboratory (Wyse's Lab), Department of Biochemistry, ICBS, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil. felipe.schmitz@ufrgs.br.
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.
Insights
Methylphenidate (MPH) alters brain glucose metabolism and network connectivity in adolescent rats, affecting behavior and causing anxiety. This study explores the consequences of MPH misuse in developing brains.
Area of Science:
- Neuroscience
- Pharmacology
- Metabolic Research
Background:
- Methylphenidate (MPH) misuse is prevalent in adolescents without ADHD diagnoses, with unclear consequences.
- Understanding MPH's impact on developing brains is crucial for public health.
- Adolescent brain development is sensitive to neurochemical alterations.
Purpose of the Study:
- To investigate the effects of MPH on brain glucose metabolism and metabolic network.
- To assess behavioral changes in rats following MPH administration.
- To explore the neurobiological mechanisms underlying MPH's impact on the developing brain.
Main Methods:
- Wistar male rats received daily MPH injections from postnatal day 15 to 44.
- Micro-positron emission tomography (micro-PET) with fluorodeoxyglucose-18 was used to measure cerebral metabolism.
- Brain metabolic network analysis via cross-correlation matrices and behavioral tests (light-dark transition, sucrose preference) were performed.
Main Results:
- MPH induced glucose hypermetabolism in several cortical regions but hypometabolism in the orbitofrontal cortex.
- MPH-treated rats exhibited a more efficient and connected brain metabolic network.
- MPH disrupted orbitofrontal cortex communication and induced anxiety-like behaviors.
Conclusions:
- MPH significantly alters brain glucose metabolism and network connectivity in a region-specific manner.
- Observed metabolic and network changes correlate with behavioral alterations, including anxiety.
- This research provides insights into the mechanisms and consequences of MPH exposure during adolescence.
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