The emerging neuromodulatory role of Homovanillic acid in the medial prefrontal cortex: Implications for anxiety.

Homovanillic acid (HVA), the principal terminal metabolite of dopamine, has long been considered an inactive byproduct of dopaminergic signaling. However, its potential neuromodulatory role in emotional regulation remains largely unexplored. This study investigated the neuromodulatory capacity of HVA within the medial prefrontal cortex (mPFC) and its implications for anxiety-like behavior. We employed an integrated approach in rodents, combining neurochemical profiling, stereotaxic microinfusion, and whole-cell patch-clamp electrophysiology. Rats were phenotyped for anxiety-like behavior using the elevated plus-maze (EPM), revealing a distinct neurochemical signature in the mPFC of high-anxiety individuals: significantly elevated HVA alongside reduced 3-methoxytyramine (3-MT), without alterations in dopamine, norepinephrine, serotonin, or their major metabolites. Crucially, bilateral microinjection of HVA (0.5 or 1.5 μg/side) into the mPFC of naïve rats induced dose-dependent anxiogenic effects, evidenced by reduced open-arm exploration and entries in the EPM. Electrophysiological recordings from deep-layer pyramidal neurons in mouse mPFC slices demonstrated that HVA (80 μM) suppresses calcium channel-mediated plateau potentials. Our findings reveal HVA as an active neuromodulator in the mPFC that shapes anxiety-like behaviors through inhibition of calcium channels, challenging its traditional status as a metabolic waste product.