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Therapeutic doses of methylphenidate following repetitive mild traumatic brain injury transiently disrupts risk/reward decision making in a sex dependent manner.

Year: 2025

Type: article

Abstract: Mild traumatic brain injury (mTBI) can often impair prefrontal cortex (PFC)-mediated higher-order decision making processes that lead to increased risk-taking behaviors, and repetitive mTBIs (rmTBIs) increase susceptibility to more severe and lasting symptoms. The catecholamine transmitters, dopamine and norepinephrine, modulate neural activity within the PFC and catecholamine dysregulation associated with TBI may underly aberrant decision making. The psychostimulant, methylphenidate (MPH), elevates catecholamine levels by blocking their reuptake transporters and is often used off-label to treat post-injury cognitive symptoms. However, to establish a treatment regimen, it is necessary to characterize how chronic therapeutic doses of MPH affect rmTBI-induced disruptions of decision making. Here, male and female rodents were trained on the probabilistic discounting task (PDT) prior to receiving rmTBI induced by the closed head-controlled cortical impact model. Rats then received daily administration of saline or low-dose MPH (0.5 or 2 mg/kg, i.p.) upon return to the PDT to assess their risk/reward decision-making behavior for 4 weeks post-surgery. The combination of rmTBI and MPH treatment significantly increased risky choice preference in males for 2 weeks. In contrast, MPH (2 mg/kg) disrupted choice preference only in uninjured females within the first week post-surgery. Upon completion of chronic MPH treatment and PDT testing, no changes in catecholamine transporter protein levels within subregions of the PFC were observed. These results indicate MPH treatment transiently exacerbates risky behavior in males, but not females, following rmTBI. These sex-specific responses advise caution for males exposed to making decisions that involve uncertain risk/reward outcomes when considering MPH to treat post-rmTBI cognitive symptoms.

Source: Experimental Neurology

DOI: 10.1016/j.expneurol.2025.115478