Systemic infection produces a highly regulated set of responses such as fever, anorexia, adipsia, inactivity and cachexia, collectively referred to as sickness behavior. Although the expression of sickness behavior requires immune-brain communication, the mechanisms by which peripheral cytokines signal the brain are unclear. Several mechanisms have been proposed for neuroimmune communication, including the interaction of cytokines with peripheral nerves. A critical role has been ascribed to the vagus nerve in mediating sickness behaviour following intraperitoneally-delivered immune activation, and converging evidence suggests that this communication may involve neurochemical intermediaries afferent and/or efferent to this nerve. Mice lacking functional CCK_2/gastrin receptors (CCK₂KO) and wild-type (WT) controls were administered LPS (50, 500, or 2500 µg/kg; serotype 0111:B4; ip). Results indicate a role for CCK₂ receptor activation in the initiation and maintenance of LPS-induced sickness behavior. In comparison to WT controls, CCK₂KO mice were significantly less affected by LPS on measures of Tb, activity, body weight, and food intake, with the magnitude of effects increasing with increasing LPS dose. Although activation of CCK₂ receptors at the level of the vagus nerve cannot be excluded, a possible role for these receptors in non-vagal routes of immune-brain communication is suggested.