Behav Brain Res. 2026 Mar 5:116143. doi: 10.1016/j.bbr.2026.116143. Online ahead of print.

ABSTRACT

BACKGROUND: The ketogenic process has been reported to play an important role in human pathophysiology and may contribute to the treatment of psychotic disorders. Increased plasma ketone body β-hydroxybutyrate (BHB) levels were observed under the intervention of risperidone with voluntary exercise. Since BHB in the brain originates from both plasma and astrocytic production and plays a neuroprotective role, this study investigated the effects of risperidone and/or voluntary exercise on the expression of genes related to ketone body synthesis, degradation, and transport in the hippocampus and prefrontal cortex (PFC), specifically focusing on mechanisms underlying cerebral BHB production.

METHOD: Thirty-two juvenile female rats were randomly assigned to one of four groups: Vehicle+Sedentary, Risperidone (0.9mg/kg, b.i.d)+Sedentary, Vehicle+Exercise (three hours of daily running wheel access), and Risperidone+Exercise for 4-week treatment.

RESULTS: Enzymes involved in ketone body metabolism: Risperidone reduced Bdh expression in both brain regions. Risperidone/Exercise co-treatment suppressed Hmgcs2 expression in the PFC, but increased Hmgcl and Bdh expression in the hippocampus and Acat1 in both regions. 2) Transporters of ketone bodies and glucose: Exercise increased Slc16a3 expression in the PFC but decreased it in the hippocampus. Risperidone/exercise co-treatment upregulated Slc16a3 and Slc16a7 in the hippocampus and Slc2a1 in the PFC, but downregulated Slc16a3 and Slc2a3 in the PFC.

CONCLUSION: Risperidone may suppress the expression of key ketogenic enzymes, while exercise appears to exert a compensatory, stimulatory effect. Exercise may partially restore ketogenic gene expression in risperidone-treated animals. The results suggest a region-specific modulation of brain energy metabolism by both interventions.

PMID:41794140 | DOI:10.1016/j.bbr.2026.116143

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