This paper reviews recent research on the contribution of the proinflammatory cytokine interleukin-1beta (IL-1beta) and the purine nucleoside adenosine in mediating behavioral depression and related symptoms of conservation-withdrawal in animal models of traumatic stress, major depression, and illness. Activation of brain IL-1beta receptors appears to contribute to conservation-withdrawal by exacerbating the immediate impact of a stressor or by enhancing and prolonging the overall reaction. Moreover, brain cytokine signaling is capable of recruiting adenosine signaling at A(2A), which directly mediates symptoms of behavioral depression. The adenosine receptors densely populate spiny GABAergic neurons in the striopallidal tract in the striatum and form part of an A(2A)/D(2)/mGLU receptor complex. Activation of these A(2A) receptors functionally uncouples dopamine's excitatory motivation influence on ongoing behavior, leading to a state of conservation-withdrawal.