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Oxytocin (OT) is a neurohypophyseal peptide traditionally associated with female reproductive functioning, and more recently with prosocial behavior. OT and its receptor are also expressed in the heart and vascular tissue and play a role in cardiovascular homeostasis. In vitro, it has been demonstrated that OT decreases NADPH-dependent superoxide production and pro-inflammatory cytokine release from vascular endothelial cells and macrophages, suggesting that OT may attenuate pathophysiological processes involved with atherosclerotic lesion formation. The present study sought to determine the effect of chronic exogenous OT administration on inflammation and atherosclerosis in an animal model of dyslipidemia and atherosclerosis, the Watanabe Heritable Hyperlipidemic (WHHL) rabbit. Twenty-two, 3-month-old WHHLs were surgically implanted with osmotic mini-pumps containing OT (n=11) or vehicle (n=11), and then were individually housed for the entire study. Blood and 24-h urine samples were taken at baseline and after 8 (midpoint) and 16 (endpoint) weeks of treatment. At endpoint, the aortas and visceral fat samples were dissected and stored for analyses. There were no group differences in body weight, serum lipids, plasma/urinary measures of oxidative stress, plasma cortisol or urinary catecholamines over the 16-week treatment. OT-treated animals exhibited significantly lower plasma C-reactive protein levels at midpoint and endpoint and developed significantly less atherosclerosis in the thoracic aorta relative to vehicle control animals at endpoint (p<0.05). Cytokine gene expression from visceral adipose tissue samples suggested that there was a decrease in adipose tissue inflammation in the OT-treated group compared to the vehicle control group, however these differences were not statistically significant. These results suggest that chronic peripheral OT administration can inhibit inflammation and atherosclerotic lesion development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Social experience influences behavior and the progression of atherosclerosis in the Watanabe Heritable Hyperlipidemic (WHHL) rabbit, such that WHHL rabbits exposed to a consistent, stable social experience exhibited more affiliative social behavior and less aortic atherosclerosis compared to other social groups. Oxytocin (OT) has been implicated in the expression of social behavior, stress responses, and may provide a mechanism by which social experience influences atherogenesis in WHHL rabbits. The current study examined acute and chronic changes in central and peripheral OT before and after WHHL rabbits were exposed to one of three social conditions. Cannula implanted adjacent to the hypothalamic paraventricular nucleus (PVN) allowed chronic sampling of extracellular OT concentration via microdialysis. Rabbits were exposed to one of three social conditions: an Unstable group, with initially unfamiliar rabbits paired daily for 4h during the initial week and similarly paired with a different, unfamiliar rabbit each week; a Stable group; with the same 2 littermates paired daily for 4h the entire study; and an Individually Caged group. Dialysates from the PVN and blood from the marginal ear vein were collected twice, 20 days apart, from rabbits before and after 2h of exposure to their respective social condition. Dialysates were assayed for OT and plasma was assayed for OT, catecholamines and glucocorticoids. There were no changes in PVN OT in any group following the initial social experience. In contrast, after 20 consecutive days of exposure to their respective social condition, PVN OT increased significantly in the Unstable group, but was relatively unchanged in the Stable group following the social experience on day 22. Peripheral OT was not altered in any group following the 2h social experience on day 1 or 22. The concentration of peripheral OT was the highest in the Stable group at all times. The Stable group also exhibited significantly less aortic atherosclerosis, consistent with earlier findings from our laboratory. Data from the present study suggest that the type of social experience WHHL rabbits are exposed influences PVN OT, social behavior and the progression of atherosclerosis in the WHHL rabbit model of disease.

Social environment influences the progression of atherosclerosis in an important experimental model of disease, the Watanabe Heritable Hyperlipidemic rabbit (WHHL). Although the hypothalamic-pituitary-adrenocortical (HPA) system is likely to play an important role in the behavioral modulation of disease, relatively little is known about the glucocorticoid responses in these animals, or in other strains of rabbits. The purpose of the present study was to: (1) evaluate the rabbit glucocorticoid circadian rhythm, (2) compare plasma cortisol and corticosterone responses to social stress, and (3) examine strain differences (i.e., WHHL vs. New Zealand White (NZW)) in rabbit glucocorticoid responses to assess whether WHHLs have an aberrant HPA system. It was found that male rabbits secrete both corticosterone and cortisol in a circadian rhythm that peaks in the afternoon and reaches a nadir at 0600 h, i.e., approximately 12 h out-of-phase with the human glucocorticoid rhythm. Both glucocorticoids responded similarly to social stress induced by repeated daily 4 h pairings with another male rabbit; after 10 days of pairings, glucorticoid values were significantly correlated with the amount of defensive agonistic behavior exhibited. Finally, there were no significant strain differences in glucocorticoid circadian rhythms, baselines, or responses to social stress. These data suggest that glucocorticoid responses (i.e., circadian rhythms, responses to social stress) in the WHHL are similar to glucocorticoid responses in standard laboratory white rabbits.