Abstract
<jats:p>Dopamine has long been regarded as the key neurotransmitter governing motor function through the direct and indirect striatal outflow pathways. However, the tripeptide ophthalmate (ophthalmic acid, OA), a glutathione analog, has recently emerged as another regulator of motor function. While the neural mechanisms by which OA regulates motor function remain unknown, we explored how OA behaves as a striatal neuromodulator. Using radiotracer-based uptake and release assays in mouse striatal tissue, combined with whole-cell electrophysiological recordings, we found that OA is taken up through a saturable, glutathione-competitive transport mechanism and is released in a Calcium-dependent manner upon depolarization, consistent with regulated exocytotic release. OA enhanced depolarization-evoked release of gamma-aminobutyric acid (GABA) but not glutamate, indicating selective modulation of distinct neurotransmitter systems. OA and dopamine reciprocally regulated one another: OA enhanced dopamine release, while D2 dopamine receptor activation suppressed OA release. Whole-cell recordings from medium spiny neurons (MSNs) showed that OA increased the amplitude of evoked AMPA receptor-mediated currents and shifted short-term plasticity from facilitation toward depression at excitatory synapses onto direct-pathway MSNs (dMSNs). These findings are consistent with an increase in presynaptic glutamate release probability, while sparing synapses onto indirect-pathway MSNs (iMSNs). Together, these findings establish OA as a striatal neuromodulator that interacts with other neurotransmitter systems and preferentially potentiates direct-pathway transmission. This novel discovery identifies a candidate mechanism within the basal ganglia circuitry that governs motor control, with major relevance to Parkinson's disease and other movement disorders.</jats:p>