Time-dependent sensitization of corticotropin-releasing hormone, arginine vasopressin and c-fos immunoreactivity within the mouse brain in response to tumor necrosis factor-alpha

Stressor or cytokine treatments, such as interleukin-1 beta, promote time-d ependent alterations of hypothalamic-pituitary-adrenal functioning, includi ng increased arginine vasopressin stores within corticotropin-releasing hor mone (CRH) terminals in the external zone of the median eminence. Likewise, we have previously shown that the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), provoked a time-dependent sensitization of neuro endocrine and brain monoamine activity. To further explore the protracted c onsequences of TNF-alpha, the present investigation determined whether the cytokine sensitized activity of neuroendocrine regulatory brain regions, as assessed by c-fos expression, and had protracted consequences on amygdaloi d CRH, as well as hypothalamic corticotropin secretagogues. Indeed, immunor eactivity for arginine vasopressin and corticotropin-releasing hormone, and their colocalization within cell terminals of the median eminence, varied over time following an initial 4.0-mug tumor necrosis factor-a treatment, p eaking after 7 days and normalizing within 28 days. Within the central amyg dala, a sensitization effect was evident as reflected by increased CRH immu noreactivity, but this effect required re-exposure to the cytokine, unlike the median eminence, changes that simply evolved with the passage of time. As well, tumor necrosis factor-a provoked a marked sensitization of c-fos s taining within the paraventricular nucleus of the hypothalamus, supraoptic nucleus and the central amygdala. From these data we suggest that tumor necrosis factor-alpha influences resp onsivity of stressor-reactive brain regions and has protracted effects on c entral neuropeptide expression within the hypothalamus and central amygdala , although the time course for the effects vary across brain regions. Evide ntly, exposure to tumor necrosis factor-a may promote neuroplasticity of br ain circuits involved in mediating neuroendocrine, sickness or inflammatory responses. It is suggested that such a sensitization may influence the res ponse to immunological and traumatic insults and may thus be relevant to be havioral pathology. (C) 2001 IBRO. Published by Elsevier Science Ltd. All r ights reserved.