Lipocalin-2 (LCN2) was first described as an acute-phase molecule involved in the innate immune response against several pathological stimuli. However, recent studies have also associated LCN2 as an important mediator in the central nervous system (CNS) physiology. Noteworthy, it was recently shown that peripheral LCN2 is a new ligand of the melanocortin 4 receptor (MC4R) and that, by binding to this receptor in the hypothalamus, LCN2 can suppress food intake, which is considered a type of compulsive behavior. Of interest, it was shown that both constitutive and induced genetic deletion of the gene encoding MC4R, as well as the pharmacological inhibition of MC4R signaling, normalized compulsive grooming and striatal electrophysiology impairments in synapse associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder (OCD). However, in this report, it was not clear the mechanisms through which MC4R deletion leads to the rescue of the phenotype. One possibility is that the ligands for MC4R are no longer inducing its effects once the receptor is deleted. This is especially relevant after the demonstration that MC4R agonists induced compulsive grooming in wild-type mice and in rats. Thus, we hypothesize that the mechanism through which MC4R deletion leads to phenotypic rescue of SAPAP3-null mice can be by LCN2 signaling. For that reason, herein, we took advantage of a mouse strain with a target deletion of the Lcn2 gene (LCN2-null mice), we analyzed the role of LCN2 in the striatum through electrophysiological, morphological, behavioral and cellular approaches. Overall, our findings showed that LCN2-null mice have altered striatal excitatory transmission, implicating the same brain region that has been reported in SAPAP3-null mice. Concomitantly, behavioral approaches showed that LCN2-null mice displayed an excessive burying response and a habitual behavior in an operant conditioning test that is highly regulated by the dorsolateral striatum (DLS). Regarding molecular analysis, we showed that LCN2 ablation leads to an increase in Psd-95 expression. Altogether, a possible novel role for LCN2 in the striatal modulation, not only at the synaptic level but also in morphological and molecular mechanisms, is suggested.