A diurnal rhythm of stimulatory input to the hypothalamo-pituitary-adrenal system as revealed by timed intrahypothalamic administration of the vasopressin V1 antagonist

Abstract

The mammalian suprachiasmatic nuclei (SCN) contain an endogenous pacemaker that generates daily rhythms in behavior and secretion of hormones. We hypothesized that the SCN imposes its circadian rhythm on the rest of the brain via a rhythmic release of its transmitters in its target areas. Previously, we demonstrated a pronounced inhibitory effect of vasopressin (VP), released from SCN terminals in the dorsomedial hypothalamus, on the release of the adrenal hormone corticosterone. In the present study, microdialysis-mediated intracerebral administration of the VP V1-receptor antagonist was used to pursue the study of the mechanisms underlying the circadian control of basal corticosterone release. Using timed administrations of the VP antagonist divided equally over the day/night cycle, we were able to uncover the existence of an additional stimulatory input from the SCN to the hypothalamopituitary-adrenal (HPA) axis. Peak activity of this stimulatory SCN input takes place during the second half of the light period, after the daily peak of VP secretion, with a delay of approximately 4-6 hr. In all likelihood, the inhibitory and stimulatory circadian input via separate mechanisms affects corticosterone release. Together, these two opposing circadian control mechanisms of the HPA axis enable a precise timing of the circadian peak in corticosterone release.

Fig. 1.

Schematic outline of the experimental design used in the present study. Dark period is indicated by the solid horizontal bar. The stippled boxes indicate the 1 hr infusion periods of VP antagonist. Trianglesindicate time points of blood sampling.

Fig. 5.

Plasma corticosterone (A) and ACTH (B) responses at different CT times, 30 min after onset of Ringer’s (dark bars) or VP antagonist (light bars) administration. For absolute corticosterone and ACTH values at t = −1, see Table 2.Circle, Ringer’s versus VP antagonist,p < 0.05. Asterisks,t = 30 versus t = −1; *, **, and *** indicate p < 0.05, p < 0.01, and p < 0.001, respectively.

Fig. 2.

Plasma corticosterone values (mean ± SEM) during Ringer’s dialysis at different CT times (i.e., Plasma ’95, ○) compared with a previously established plasma corticosterone curve (i.e., Plasma ’92, •;n = 10) in control animals without an intracerebral probe. The plasma ’92 data are redrawn from Kalsbeek et al. (1996).

Fig. 3.

Plasma corticosterone values (mean ± SEM) during Ringer’s (○) or VP antagonist (•) administration in the PVN/DMH area. Hatched boxes indicate the timing of the 1 hr period of VP antagonist administration.

Fig. 4.

Plasma ACTH responses (mean ± SEM) during Ringer’s (○) and VP antagonist (•) administration in the PVN/DMH area. ACTH values are expressed as the difference compared witht = −1 (i.e., just before VP antagonist enters the brain). For ACTH values at t = −1, see Table 2.Hatched boxes indicate the timing of the 1 hr period of VP antagonist administration.

Fig. 6.

Plasma corticosterone values (mean ± SEM) as a result of Ringer’s (open symbols) and VP antagonist (solid symbols) administration into either the DMH (circles) or VMH (triangles).a, Significantly different from all three other groups;b, significantly different from Ringer’s-infused groups.

Fig. 7.

Changes in circulating levels of plasma corticosterone (A) and ACTH (B) induced by microdialysis-mediated administration of VP antagonist in the PVN/DMH area at CT6 (Ringer’s, ▪, n = 11; VP antagonist, •, n = 10) or exposure to a new environment (New cage, ▵, n = 7).Letters indicate significant differences compared with Ringer’s (a) and VP antagonist (b) according to Student–Newman–Keuls (p < 0.05).

Fig. 8.

Plasma corticosterone concentration as a function of plasma ACTH during Ringer’s (A) or VP antagonist (B) infusions at different times of the light/dark cycle. For the “novelty” experiment, values fromt = 15, 30, and 60 min samples were used. From the VP antagonist infusions, only the t = 30 values are displayed. Data from the Ringer’s infusions are derived also from thet = 30 samples, except the infusion at CT10, from which data from the t = 60 samples are also displayed. CT2 = ○; CT6 = ▵ (A) or ▴ (B); CT10 = ▪; CT14 = □; CT22 = ▿;novelty = ⋄.

Fig. 9.

Schematic presentation of the diurnal release pattern of SCN transmitters involved in the circadian control of corticosterone release. Vasopressin (i.e., inhibitory SCN signal) and corticosterone data are redrawn from previously published data (Kalsbeek et al., 1995, 1996), whereas the release pattern of the SCN transmitter stimulating the HPA axis is extrapolated from the data presented in Figure 5.