Ingestive Classics
Ed Stricker, Joe Verbalis and Oxytocin

MONICA J. McCANN, JOSEPH G. VERBALIS and EDWARD M. STRICKER. LiCl and CCK inhibit gastric emptying and feeding and stimulate OT secretion in rats. American Journal of Physiology 256: R463-R468, 1989.

Comments by Linda Rinaman (April, 2015)

I can easily trace my career-long interest in brain-gut interactions and the neural controls of physiology and behavior to research presented at the “Ninth International Conference on the Physiology of Food and Fluid Intake”, held in Seattle WA in July 1986.  I had just completed my first year of graduate school at the University of Pennsylvania, and it was my first scientific conference.  Interestingly, that conference provided a venue for discussions and strategizing that led to the formation of SSIB the following year [1].

One of the people I met in Seattle was Monica McCann, a dynamic and talented graduate student working with Ed Stricker and Joe Verbalis at the University of Pittsburgh.  Monica was second author on a recently published and somewhat controversial report in Science suggesting that the hypophagic effect of cholecystokinin (CCK) in rats was likely due to gastrointestinal (GI) malaise and stress rather than “satiety”, as evidenced by the similar increases in plasma levels of oxytocin (OT) after treatment with CCK or “nauseogenic” toxins such as LiCl [2].  Conference attendees spent a good deal of time talking about the “nausea vs. satiety” issue, and I was intrigued by the energetic discourse. However, the most exciting thing I took away was the idea that GI vagal sensory signals were somehow relayed to both magnocellular (i.e., pituitary-projecting, endocrine) and parvocellular (i.e., centrally-projecting, non-endocrine) OT neurons in the hypothalamus, and that the latter might control gastric motor function and feeding behavior.  Although this was a new idea for me, it was supported by the findings of Stricker, Verbalis and their colleagues [2, 3] as well as by others [4, 5].  In view of the current resurgence of interest in the role of OT in food intake and energy balance (e.g., [6-9]), it is relevant and useful to revisit early findings from the Pittsburgh group that helped lay the foundational evidence supporting such a role.  With this in mind, I have selected a 1989 study by McCann, Verbalis and Stricker [10] as an SSIB Ingestive Classic.

The goal of their 1989 study [10] was to better characterize relationships among feeding suppression, plasma OT levels, and gastric emptying in rats treated with various doses of CCK or LiCl.  At that time, it was not clear what doses of CCK might be considered "physiological" doses modeling endogenous CCK released during meals, as opposed to "supraphysiological" doses producing stress and nausea.  Systemically administered CCK was known to slow gastric emptying in rats, but the GI effects of LiCl and other nauseogenic, anorexigenic agents was unknown.  McCann and colleagues first demonstrated that intraperitoneal injections of CCK-8 (1-100 µg/kg BW) or LiCl (0.75 – 1.5 mEq/kg BW) produced strikingly similar inverse linear correlations between plasma OT concentration and inhibition of liquid diet intake over 20 min compared to intake under baseline control conditions (Figure 1) [10].  Interestingly, CCK-8 and LiCl doses with similar hypophagic effects also produced similar peak levels of plasma OT (Figure 2).  However, inhibition of food intake after either agent was considerably more long-lasting than the evoked increase in plasma OT, arguing against a direct hypophagic effect of the circulating hormone.  On the other hand, CCK and LiCl dose-dependently inhibited gastric emptying in a manner that was both proportional and time-locked to the inhibition of food intake (Figure 5), evidence that treatment-induced suppression of gastric emptying might underlie the parallel suppression of food intake.  However, since systemically administered OT did not affect gastric emptying in this study, the authors suggested that “. . . activation of magnocellular oxytocinergic pathways is tightly linked to other pathways affecting both gastric motility and food intake” [10] (italics added).  Their candidate “other pathway” was the projection from parvocellular OT neurons to the dorsal vagal complex, a suggestion supported by physiological evidence published in 1987 by Rick Rogers and Gerlinda Hermann [4].

 After completing her Ph.D. in Pittsburgh, Monica McCann went on to enjoy a productive postdoctoral position with Rick Rogers at Ohio State University.  One of their studies demonstrated that OT excites a subpopulation of neurons within the rat dorsal vagal complex that respond to gastric distension, providing a mechanism by which OT might enhance vagally mediated inhibition of gastric emptying and also increase neural responsiveness to GI satiety signals conveyed to the same neurons [11].  Stricker, Verbalis, and their colleagues continued to probe the functional organization of afferent pathways to OT neurons and the role of central OT signaling, including electrophysiological and cFos-mapping work confirming that CCK treatment and gastric distension activate both magnocellular and hindbrain-projecting parvocellular OT neurons in rats [12, 13], and that central OT receptor antagonism blunts the hypophagic effects of exogenous CCK, LiCl, and hypertonic saline [14].  Surprisingly, however, although these and other anorexigenic treatments uniformly inhibited gastric motility and emptying in rats [10, 15], the vagally-mediated gastric effect was not attenuated by central OT receptor blockade [16], evidence that the inhibition of food intake produced by these agents could be uncoupled from their inhibitory effect on gastric emptying. 

It now is well-accepted that brainstem-hypothalamic circuits are critically involved in regulating physiological and behavioral components of food intake and energy balance under normal physiological conditions, and also in response to natural and experimental conditions of homeostatic threat [17].  There also now is consensus that endogenous CCK promotes satiety in rodents and other mammals, including monkeys and humans [18, 19].  However, it also is clear that exogenously administered CCK and other treatments that suppress food intake, including consumption of unusually large meals [20], can dose-dependently provoke malaise and stress responses, making it incumbent upon investigators to probe the underlying causes of treatment-induced hypophagia. Recent studies continue to implicate OT signaling pathways as a functional constituent of the central neural circuits that suppress food intake [7-9].  However, thirty years after Stricker, Verbalis, and colleagues initially discovered that plasma OT levels are increased in rats after anorexigenic treatments, the sites of action and physiological conditions under which central OT signaling pathways control food intake remain elusive.

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