Neuropeptide Y (NPY) has been reported to profoundly influence and regulate brain circuits involved in a number of behaviours, like anxiety, alcohol intake, pain and energy homeostasis. Here we show that NPY increases sedation induced by different types of anaesthetics through interactions with the Y1 receptor. Consistently, in Y1–/– (homozygote knockout) mice NPY does not potentiate the pentobarbital-induced sedation. Similar results were obtained for avertin but not for ketalar- (NMDA antagonist) induced sedation. Local microinjection of NPY exhibited the strongest potentiating effect on pentobarbital-induced sedation in the posterior hypothalamic area and Y1 expression was found in the dorsal-premammillary and medial part of medial mammillary nuclei. These results show that Y1 is essential for NPY-induced enhancement of sedation and place this activity of NPY in the posterior hypothalamic area, a region of the brain previously implicated in the regulation of the wake–sleep cycle.