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Abstract: The lateral septum has been extensively implicated in regulating anxiety-related defensive behaviors in the rat. Neuropeptide Y (NPY) contributes to anxiety, likely through activity at the NPY Y1 and/or Y2 receptor binding sites. Although the lateral septum contains the highest density of Y2 receptors in brain, the involvement of this receptor in anxiety-related defensive behaviors is not clear. Thus, the purpose of the current study was to characterize lateral septal Y2 receptor contributions to rats'' defensive responses to threat and/or potentially threatening environments. We investigated this by infusing the NPY Y2 agonist NPY13–36 into the lateral septum and testing rats across a battery of animal models of anxiety (Experiment 1). To verify the role of Y2 in mediating the observed effects, rats were pre-infused with the potent and highly selective Y2 antagonist BIIE 0246 prior to infusion with NPY13–36 (Experiment 2). Infusions of NPY13–36 into the lateral septum increased rats'' open-arm exploration in the elevated plus-maze test (p<0.01) and decreased the proportion of rats'' that buried (p<0.05) as well as their latency to initiate burying in the shock-probe burying test (p<0.01). By contrast, NPY13–36 did not affect either anxiety- or appetite-related responses in the novelty-induced suppression of feeding test (all ps>0.3; Experiment 1). Pre-treatment with the Y2 antagonist BIIE 0246 prevented the anxiolytic-like actions of NPY13–36 in the plus-maze but not in the shock-probe test (Experiment 2). Thus, it appears that the anxiolytic-like actions of lateral septal NPY13–36 are mediated by the Y2 receptor in a test-specific manner. [Copyright &y& Elsevier]