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Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na + channel 1.6 (Na v 1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14 R117 , a critical residue located within a druggable pocket at the FGF14/Na v 1.6 PPI interface. We found that 1028 modulates FGF14/Na v 1.6 complex assembly and depolarizes the voltage-dependence of Na v 1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Na v 1.6 channel. Consistent with the compound's effects on Na v 1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons., Competing Interests: Competing interests: The corresponding author, F.L., is the founder and president of IonTx Inc., a start-up company focusing on developing regulators of voltage-gated Na+ channels. The following patent is related to the present study: LAEZ-F-22A: TMB-0170000. Additional information related to the patent is as follows: Patent Int’l Application No: PCT/US24/32688; Title: Non-Peptide Small Molecule FGF14:Nav1.6 Channel Complex Protein-Protein Interaction Modulators; Tech ID: LAEZ-F-22A; Patent Applicant: The Board of Regents of the University of Texas System; Name of the Inventors: Drs. Jia Zhou, Fernanda Laezza, Pingyuan Wang, Nolan M. Dvorak, Paul A. Wadsworth; Status of the Application: Pending; Specific Aspect of the manuscript covered in the patent application: the synthetic route and chemical structure of 1028 is covered in the patent application. All other authors declare that they have no competing interests., (© 2024. The Author(s).)