Interferon-alpha and transforming growth factor-beta 1 have been detected in the brain, suggesting their possible regulatory functions. In the present study, we evaluated the effects of these cytokines on the in vitro release of arginine vasopressin, previously reported to be sensitive to neurotransmitters such as acetylcholine, norepinephrine, and corticotropin releasing hormone as well as to cytokines interleukin-1 and interleukin-2. Interferon-alpha was found to enhance arginine vasopressin release from both hypothalamus and amygdala, as was dibutyryl cyclic GMP. Blockade of nitric oxide synthase antagonized the interferon-alpha induced arginine vasopressin release from the amygdala but not from the hypothalamus. Transforming growth factor-beta 1 had no effect on basal release of arginine vasopressin, nor on the arginine vasopressin-release induced by interferon-alpha, interleukin-2 or norepinephrine, but selectively blocked the acetylcholine-induced release in both hypothalamus and amygdala. When the release of arginine vasopressin induced by interferon-alpha, interleukin-2, acetylcholine and norepinephrine was probed with inhibitors of guanylate cyclase, the interactions exhibited regional selectivity: neither the interleukin-2-induced arginine vasopressin release from hypothalamus, nor the norepinephrine-induced release of arginine vasopressin from either amygdala or hypothalamus was affected by guanylate cyclase inhibitors, but all other arginine vasopressin releasers were blocked. Taken with previous reports that interferon-alpha will enhance hypothalamic corticotropin releasing hormone release, our results suggest that arginine vasopressin release enhanced by interferon-alpha may also contribute to the activation of the hypothalamic-pituitary axis, while the ability of transforming growth factor-beta 1 to diminish the arginine vasopressin released by acetylcholine could mediate some of this cytokine's central effects. The extension of these neurotransmitter-cytokine interactions to the amygdala may provide an additional basis for interactions between neuronal and immune systems.