Short communicationIntranasal oxytocin administration attenuates the ACTH stress response in monkeys
Introduction
It is well established that stressful events contribute to the development of depressive and anxiety disorders (Brown and Harris, 1993, Paykel, 1978). In mammals, the stress response is primarily mediated through the hypothalamic–pituitary–adrenal (HPA) axis. Of all the biological systems examined in the pathogenesis of depressive and anxiety disorders, HPA axis abnormalities have been most consistently implicated (Arborelius et al., 1999, Holsboer, 2001, Parker et al., 2003).
In contrast to stressful events, strong social relationships provide important health benefits. Social support decreases stress responsivity, protects against the onset of psychiatric disorders, and improves treatment outcomes in patient populations (Paykel, 2001). Little, however, is known about the biological mechanisms that regulate this phenomenon. A systematic analysis of this underlying biology is warranted and may have important clinical implications. We investigate herein a role for the neuropeptide, oxytocin (OT), which exhibits promising anti-stress properties (Amico et al., 2004, Heinrichs et al., 2003, Neumann, 2002, Windle et al., 2004).
OT is synthesized in the hypothalamus and released into systemic circulation via the posterior pituitary. OT receptors are found in many peripheral sites, including the pituitary and adrenal glands (Gimpl and Fahrenholz, 2001). OT is also released into the central nervous system via widely distributed pathways, and central OT receptors are found in a variety of socially relevant and stress-sensitive limbic brain regions (Gimpl and Fahrenholz, 2001). Central OT administered to rodents facilitates social contact, maternal–infant attachment, and pair-bond formation (Pedersen et al., 1992, Williams et al., 1992, Witt et al., 1992). In humans, intravenously administered OT attenuates metyrapone-induced ACTH secretion (Chiodera and Coiro, 1987). Studies of rats corroborate this latter finding, as centrally administered OT diminishes stress-induced corticotropin-releasing factor (CRF) mRNA expression in the hypothalamus and attenuates the neuroendocrine stress response (Windle et al., 2004). OT deficient mice, in contrast, exhibit greater stress-induced corticosterone responses (Amico et al., 2004). This collective evidence suggests the intriguing hypothesis that OT released during positive social interactions reduces the HPA axis response to stressful events (Uvnas-Moberg, 1998), and in humans, may account for the extensive evidence that social support protects against the onset of stress-related depressive and anxiety disorders.
Despite these promising findings, OT has little potential as a therapeutic agent if its route of administration is invasive (e.g. central; intravenous). These invasive methods have also curtailed OT research in species other than rodents, and as a result, few studies have directly assessed the anti-stress effects of OT in monkeys and humans. An alternative to these invasive techniques is intranasal administration, which presents a viable, non-invasive delivery method (Liu et al., 2001). Moreover, peptides administered intranasally are delivered directly to cerebrospinal fluid in humans (Born et al., 2002) and a variety of brain regions in rats (Ross et al., 2004) and squirrel monkeys (Balin et al., 1986). In a recent experiment, a single intranasal OT administration, combined with social support, was found to decrease salivary cortisol responses to psychological stress in humans (Heinrichs et al., 2003). In this monkey experiment, we extend this initial research to investigate the effects of chronic intranasal OT administration—without the added buffer of social support—on stress-induced increases in plasma adrenocorticotropin hormone (ACTH) and cortisol.
Section snippets
Subjects
Twelve adult female squirrel monkeys (age range 6–17 years) of Guyanese origin (Samiri sciureus) served as subjects in this experiment. Monkeys were housed in same-sex social groups at the Stanford Research Animal Facility in 1.8×1.2×1.8 m wire-mesh cages that were cleaned daily. Housing and testing occurred in climate-controlled rooms on a 12:12 light/dark cycle with an ambient temperature of 26 °C. Monkeys had ad libitum access to water, food (e.g. commercial New World monkey chow, fresh
Results
Most blood samples (93%) were collected within 180 s from cage entry (median latency to sample collection, 46 s; range 24–242 s), and all but one sample (99%) was collected within 240 s. In keeping with reports that squirrel monkey plasma measures of ACTH and cortisol obtained within these time limits and using these procedures do not reflect disturbance effects from sampling per se (Lyons et al., 1995, Lyons et al., 1999), sample collection latencies accounted for less than 1% of the variance in
Discussion
This experiment demonstrated that chronic intranasal oxytocin administration prior to acute social isolation attenuates the ACTH response to stress in monkeys. No significant effect of OT on stress-induced cortisol levels was observed. Because the adrenal response to stress temporally follows that of the pituitary, it is likely that our assessment period was too short to capture the treatment-related changes in cortisol levels reported by others (Neumann, 2002, Windle et al., 2004). It has been
Acknowledgements
This research was supported, in part, by grant MH47573 from the National Institute of Mental Health, Bethesda, MD. We thank Dr Maurice Manning for generously donating the oxytocin compound; Dr William Frey and Dr Leah Hanson for helpful discussions on intranasal technique; Dr Jamie Zeitzer for assistance in basal blood sampling; and Mr Stuart Anhorn for excellent care of our animals.
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