Aniracetam restores the excitation-inhibition balance of neurotransmitters in the prefrontal cortex of mice with ADHD

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in childhood and a common chronic condition among school-aged children. However, the pharmacological mechanisms and pathophysiology of ADHD remain incompletely elucidated. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit γ8) functions as an auxiliary subunit of AMPA receptors. Previous studies suggest that mice lacking the TARP γ-8 protein may display hyperactivity, impulsivity, and memory deficits, which are hallmarks of ADHD. The nootropic compound aniracetam effectively mitigates ADHD-like symptoms, including hyperactivity, impulsivity, anxiety, cognitive deficits, and memory impairment, observed in adolescent TARP γ-8 knockout (KO) mice. This investigation explored the therapeutic potential of aniracetam and its underlying molecular mechanisms using TARP γ-8 KO mice as an ADHD model. Through cerebral microdialysis coupled with liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, we identified perturbations in neurotransmitter metabolism in the ADHD model of TARP γ-8 KO mice. Real-time quantitative PCR (RT-qPCR) was employed to detect alterations in the expression of key receptor and transporter genes. The results indicate that aniracetam can alleviate ADHD-related behavioral deficits by modulating the excitatory-inhibitory neurotransmitter systems through the modulation of glutamate receptor, γ-Aminobutyric Acid receptor, and monoamine neurotransmitter transporter expression. These findings in a TARP γ-8-deficient ADHD model support further investigation into aniracetam as a potential therapeutic intervention for ADHD, providing novel molecular targets and a theoretical framework for the pharmacological management of ADHD.