Interleukin-1-induced long-lasting changes in hypothalamic corticotropin-releasing hormone (CRH)--neurons and hyperresponsiveness of the hypothalamus-pituitary-adrenal axis

Abstract

Hypothalamic CRH neurons that control ACTH secretion from the pituitary gland have secretory terminals in the external zone of the median eminence (ZEME). These neurons can coproduce vasopressin (AVP), a neuropeptide that potentiates the ACTH releasing effects of CRH. Recently, we found increased AVP production in adult rats weeks after single exposure to a stressor, which may play a role in event-induced stress disorders. Here, we describe the long-term changes in the HPA axis of adult male rats following a single exposure to a stressor, the cytokine interleukin-1 beta (IL-1 beta). The effects on storage and release of AVP and CRH were established by quantitative immunocytochemistry, the effects on ACTH and corticosterone responses by radioimmunoassay. Single administration of IL-1 beta (5 micrograms/kg i.p.) induces a delayed (at least 4 d) and a long-lasting (at least 3 weeks) increase of vasopressin (AVP) stores in CRH terminals of the ZEME without affecting the CRH stores, and a marked increase of the fraction of CRH terminals that costore AVP. Eleven days after IL-1 beta administration, a second IL-1 beta challenge causes a marked depletion of the AVP stores in the ZEME within 2 hr, which is not seen in rats treated with vehicle 11 d earlier. This is accompanied by twofold higher ACTH and corticosterone responses, as compared to those in vehicle pretreated rats. IL-1 beta-pretreated rats also showed increased ACTH and corticosterone responses to electric footshocks. We conclude that transient activation of the HPA axis by a single administration of IL-1 beta induces a delayed and long-lasting hyperproduction, hyperstorage, and hypersecretion of AVP from hypothalamic CRH neurons that results in hyperresponsiveness of the HPA axis to subsequent stimuli.

An Initial, Three-Day-Long Treatment with Alcohol Induces a Long-Lasting Phenomenon of Selective Tolerance in the Activity of the Rat Hypothalamic–Pituitary–Adrenal Axis

“…For example, repeated exposure to a particular stressor tends to facilitate the ACTH and corticosterone response to a subsequent novel acute stressor (Hennessy, 1991;Marti et al, 1994), a phenomenon that has been attributed to increased CRF expression in the hypothalamus (Makino et al, 1995) and to changes in the sensitivity of the HPA axis to steroid feedback (Akana et al, 1992). Also, a single intraperitoneal injection of IL -1 is reported to prolong the AC TH response to a second challenge, whether it is immune (IL -1 injection) or nonimmune (exposure to foot shocks) (Schmidt et al, 1995). In this model, increased median eminence levels of V P have been held responsible for the changes in HPA axis activity (Dijken et al, 1993).…”

“…Most studies have focused on animals that were exposed to a particular stressor immediately after a period of repeated or continuous exposure to this same or another signal (Kant et al, 1985;Akana et al, 1992;Ottenweller et al, 1992;vanRaaij et al, 1997), including work showing adaptation of the HPA axis of rats chronically exposed to alcohol and to the drug itself but not to other stresses (Spencer and McEwen, 1990). To our knowledge, the only report of a long-lasting change in the activity of the HPA axis that persisted once the initial stressor had been removed indicated a prolongation, not a blunting, of the AC TH and corticosterone response to a single injection of the proinflammatory cytokine interleukin-1 (IL-1) (Schmidt et al, 1995). We therefore believe that the present study represents the first example of a phenomenon of selective tolerance that not only develops several days after the initial stimulus has been removed but also persists for a long time.…”

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

“…206 Cyto-kine administration increases the response to stressors or further cytokine exposure. 206,[238][239][240][241] It is possible that exposure to stress, including the activation of the inflammatory immune system, may result in greater vulnerability to stressor-related pathology (for review see Connor and Leonard, 125 Hayley et al 236 ).…”

Dysthymia: a review of pharmacological and behavioral factors

“…Tilders and his associates [243][244][245][246] indicated that in response to repeated stressor experiences, or with the passage of time following a stressor or IL-1␤ challenge, 247 phenotypic variations may occur within hypothalamic neurons that are ordinarily responsive to stressors. In particular, increased coexpression of CRH and AVP was observed within CRH containing neurons originating in the paraventricular nucleus (PVN) and having terminals in the external zone of the median eminence.…”

“…However, while processive stressors do so via limbic circuits, the HPA alterations elicited by systemic stressors may result from limbicindependent processes. 245 Yet, it ought to be underscored that systemic stressors, including IL-1␤, IL-2 and TNF␣ have all been shown to influence central monoamine activity at both hypothalamic and extrahypothalamic sites, including hippocampal 5-HT activity, as well as that of NE and DA in hypothalamus, locus coeruleus and mesolimbic regions. 235,[254][255][256] Thus, the possibility exists that cytokine elevations, by virtue of these monoamine effects, may come to promote or exacerbate depressive disorders, quite apart from any actions involving the HPA axis.…”