Ramelteon Improves Post-traumatic Stress Disorder-Like Behaviors Exhibited by Fatty Acid-Binding Protein 3 Null Mice

We previously reported that fatty acid-binding protein 3 (FABP3) knockout (Fabp3 ^-/-) mice exhibit abnormal dopamine-related behaviors such as enhanced dopamine D2 receptor antagonist-induced catalepsy behaviors. Here, we report that Fabp3 null mice exhibit cognitive deficits, hyperlocomotion and impaired fear extinction, and thus show post-traumatic stress disorder (PTSD)-like behaviors. Notably, chronic administration of ramelteon (1.0 mg/kg, p.o.), a melatonin receptor agonist, improved all PTSD-like behaviors tested in Fabp3 ^-/- mice. Relevant to mechanisms underlying impaired fear extinction, we observed significantly reduced levels of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation without changes in ERK phosphorylation in the anterior cingulate cortex (ACC). Inversely, CaMKII autophosphorylation increased in the basolateral amygdala (BLA) but remained relatively unchanged in hippocampus of Fabp3 ^-/- mice. Likewise, the number of c-Fos-positive neurons in BLA significantly increased after exposure to contextual fear conditions but remained unchanged in the central nucleus of the amygdala (CeA). Importantly, chronic ramelteon administration (1.0 mg/kg, p.o.) restored abnormal c-Fos expression and CaMKII autophosphorylation in the ACC and BLA of Fabp3 ^-/- mice. Finally, the melatonin receptor antagonist luzindole (2.5 mg/kg, i.p.) blocked ramelteon-dependent improvements. Taken together, Fabp3 ^-/- mice show PTSD-like behaviors, and ramelteon is a likely attractive candidate for PTSD therapy.