A short piece of the NCAM protein called FGL‑S can get into the brain after being given outside the head and, in rats, it lifts signs of depression without changing anxiety. The brain levels match blood levels in both rats and monkeys, suggesting it can cross the blood‑brain barrier. The antidepressant effect depends on AMPA‑type glutamate receptors.

Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression. The NCAM peptide mimetic, plannexin, acutely increased and chronically decreased anxiety, but did not have antidepressant effects in rats. Another NCAM peptide mimetic, FGL_L, had acute anxiogenic effects and chronic antidepressant effects in rats. A related NCAM peptide mimetic, FGL_S, had antidepressant effects without modulating anxiety-like behavior, and these antidepressant effects were blocked by an AMPA receptor antagonist. Cisternal cerebrospinal fluid (CSF) levels of FGLs correlated with blood plasma levels in rats and non-human primates, and CSF-to-blood ratios of FGL_S were comparable in both species. Results indicate that NCAM peptide mimetics penetrate the brain and support the suggestion that FGL_S may be a candidate for further development as a novel treatment for major depressive disorder in humans.