Hypothalamic oxytocin mediates adaptation mechanism against chronic stress in rats

Abstract

Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Although central oxytocin has antistress effects, the role of central oxytocin in stress-induced gastric dysmotility remains unknown. Solid gastric emptying was measured in rats receiving acute restraint stress, 5 consecutive days of repeated restraint stress (chronic homotypic stress), and 7 consecutive days of varying types of stress (chronic heterotypic stress). Oxytocin and oxytocin receptor antagonist were administered intracerebroventricularly (icv). Expression of corticotropin-releasing factor (CRF) mRNA and oxytocin mRNA in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real-time RT-PCR. The changes of oxytocinergic neurons in the PVN were evaluated by immunohistochemistry. Acute stress delayed gastric emptying, and the delayed gastric emptying was completely restored after 5 consecutive days of chronic homotypic stress. In contrast, delayed gastric emptying persisted following chronic heterotypic stress. The restored gastric emptying following chronic homotypic stress was antagonized by icv injection of an oxytocin antagonist. Icv injection of oxytocin restored delayed gastric emptying induced by chronic heterotypic stress. CRF mRNA expression, which was significantly increased in response to acute stress and chronic heterotypic stress, returned to the basal levels following chronic homotypic stress. In contrast, oxytocin mRNA expression was significantly increased following chronic homotypic stress. The number of oxytocin-immunoreactive cells was increased following chronic homotypic stress at the magnocellular part of the PVN. Icv injection of oxytocin reduced CRF mRNA expression induced by acute stress and chronic heterotypic stress. It is suggested that the adaptation mechanism to chronic stress may involve the upregulation of oxytocin expression in the hypothalamus, which in turn attenuates CRF expression.

Fig. 1.

Effect of intracerebroventricular (icv) injection of oxytocin and oxytocin antagonist on solid gastric emptying in response to acute, chronic homotypic, and heterotypic stress in rats. Acute restraint stress significantly delayed gastric emptying. Delayed gastric emptying observed in acute stress was restored by icv administration of oxytocin. Delayed gastric emptying was restored following chronic homotypic stress. Icv injection of tocinoic acid, which had no effects on gastric emptying in nonrestraint rats, significantly antagonized the restored gastric emptying following chronic homotypic stress. In contrast to chronic homotypic stress, gastric emptying was delayed following chronic heterotypic stress. Delayed gastric emptying was restored by icv administration of oxytocin following chronic heterotypic stress (n = 6, *P < 0.05, **P < 0.01 compared with saline).

Fig. 2.

Effect of acute stress, chronic homotypic stress, and chronic heterotypic stress on corticotropin-releasing factor (CRF; A) and oxytocin (OXT; B) mRNA expression in the paraventricular nucleus (PVN). CRF mRNA expression showed a significant increase in response to acute stress. The increment of CRF mRNA was no longer observed following chronic homotypic stress. In contrast, chronic heterotypic stress significantly increased CRF mRNA expression. Oxytocin mRNA expression showed a significant increase in response to acute stress. Oxytocin mRNA expression at the PVN showed a more pronounced increase following chronic homotypic stress, compared with that of acute stress. The increase of oxytocin mRNA expression was much less following chronic complicated stress, compared with that of chronic homotypic stress. The mRNA expression was standardized with the ratio of internal control of β-actin (n = 6, *P < 0.05, **P < 0.01 compared with controls).

Fig. 3.

Correlation between CRF mRNA and oxytocin mRNA expression in the PVN in response to acute stress (A), chronic homotypic stress (B), chronic heterotypic stress (C). There was a significant negative correlation observed between CRF mRNA and oxytocin mRNA expression in every stress loading (n = 6).

Fig. 4.

Effects of icv injection of oxytocin on CRF mRNA expression in the PVN in response to acute stress and chronic heterotypic stress. Icv injection of oxytocin significantly attenuated the increase of CRF mRNA expression in response to acute stress and chronic heterotypic stress (n = 6, *P < 0.05, **P < 0.01 compared with saline).

Fig. 5.

Immunohistochemistry of oxytocin in control (A), acute stress (B), chronic homotypic stress (C), and chronic heterotypic stress (D) at the PVN [3rd ventricle (3V); scale bar 250 μm].

Fig. 6.

Number of oxytocin-immunoreactive (OXY-IR) cells in control, acute stress, chronic homotypic, and chronic heterotypic stress at the parvocellular subdivision (A) and magnocellular subdivision (B) of the PVN. AP, anterior parvocellular; MP, medial parvocellular; DP, dorsal parvocellular; LP, lateral parvocellular; PV, periventricular parvocellular; AM, anterior magnocellular; PM, posterior magnocellular; n = 4, *P < 0.05, **P < 0.01 compared with control, #P < 0.01 compared with acute stress and chronic heterotypic stress.