Research ReportOxytocin action in the ventral tegmental area affects sucrose intake
Introduction
Oxytocin (OT)(⁎), a hypothalamic neuropeptide, is most well known for its endocrine effects on reproductive behaviors, labor, and lactation (Gimpl and Fahrenholz, 2001). Magnocellular neurons of the paraventricular nucleus of the hypothalamus (PVN) release OT into the neurohypophysis; however, parvocellular PVN neurons containing OT project to other sites in the brain, including the nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus nerve, and to the spinal cord (Sofroniew, 1983). Centrally-acting OT has a number of behavioral and physiologic effects, including food intake suppression (Olszewski et al., 2010a). Recent studies suggest that these neurons may be especially involved in the control of carbohydrate intake. In rats, peripheral injection of OT inhibits intake of sucrose, whereas rats injected with an OT receptor antagonist increased sucrose consumption (Olszewski et al., 2009, Olszweski et al., 2010b). Similarly, OT deficient (OT−/−) mice consume significantly more than wild-type (WT) mice when given access to a 10% sucrose solution (Amico et al., 2005). Other studies found that OT−/− mice have elevated daily intake of sweet and non-sweet carbohydrate containing solutions relative to WT controls, but there are no sustained differences between OT−/− and WT mice when they are consuming Intralipid (Miedlar et al., 2007, Sclafani et al., 2007). In rats, a significantly greater percentage of PVN OT neurons are activated by a sucrose meal than an Intralipid meal (Olszweski et al., 2010b), supporting the suggestion that acute consumption of sugar recruits OT neurons to promote satiation. Chronic sugar consumption impairs this OT neuronal response to meals (Mitra et al., 2010), so it is possible that dysregulation in this system contributes to overeating of palatable high-sugar food.
Although OT's role in the control of food intake has been studied for several decades, there has been relatively little investigation of which central OT projection sites mediate its feeding effects. Most studies on the feeding effects of central OT have delivered OT or OT receptor antagonists into the cerebral ventricles, an approach that lacks site-specificity. One region that has been implicated is the NTS in the caudal brainstem. The OT projection to the NTS has been proposed to mediate some of the effects of the adiposity hormone leptin and gastrointestinal satiation signals such as cholecystokinin (CCK). Both leptin and CCK induce c-Fos expression in PVN OT neurons that project to the NTS, and central blockade of OT receptors impairs the anorexic responses to leptin and CCK (Olson et al., 1991a, Blevins et al., 2003, Blevins et al., 2004). However, the NTS is not the only feeding-relevant areas of the brain that contains OT terminals and receptors (Olszewski et al., 2010a). Here, we focus on the OT neuronal projection to the ventral tegmental area (VTA). The VTA is known to play a role in reward and motivated behavior in general, and targeted manipulations of VTA neurons affect palatable food intake (Lutter and Nestler, 2009). For example, peripheral or intra-VTA injection of leptin decreases the firing rate of VTA dopamine (DA) neurons, and also decreases food intake in rats (Hommel et al., 2006). Conversely, leptin receptor knockdown in the VTA of rats causes an increase in the consumption of highly palatable sucrose solution (Hommel et al., 2006, Davis et al., 2011).
The presence of OT fibers and receptors within the VTA is well documented (Sofroniew, 1983, Vaccari et al., 1998), and the effects of OT on several behaviors have been examined. Intra-VTA OT treatment promotes grooming behavior in rats, an effect which appears to be mediated by DA receptors at other sites (Stivers et al., 1988). VTA injection of OT also induces penile erection in male rats (Melis et al., 2007), and influences lordosis as well as maternal behavior in female rats (Pedersen et al., 1994). Recent studies have reported that OT fibers are observed in close apposition to DA neurons within the caudal part of the VTA (Melis et al., 2007), and intra-VTA OT treatment increases DA release in the nucleus accumbens (NAc), a major projection site for VTA DA neurons (Melis et al., 2007, Shakrokh et al., 2010). Here, we investigated the possibility that VTA OT receptors also play a role in food intake control, and specifically hypothesized that VTA OT limits sugar intake. We present data from a series of behavioral studies demonstrating that intra-VTA OT suppresses intake of a sucrose solution whereas blockade of OT receptors in VTA increases sucrose intake.
Section snippets
VTA OT effect on sucrose intake
Naïve rats (n=10) received injections of sterile 0.9% saline vehicle or 0.3, 1, or 3 μg OT into the VTA prior to a 30-min 10% sucrose intake test. OT significantly reduced sucrose intake (F (3, 27)=6.09, p<0.01) at both 1 and 3 μg relative to saline (p's <0.05), whereas the 0.3 μg dose was not effective (Fig. 1A). Experimenters observed increased grooming during the sucrose test sessions after OT injection, but this was not measured quantitatively. OT had no significant effects on overnight chow
Discussion
The results presented here support the hypothesis that OT receptors in the VTA contribute to the control of palatable food intake. We first showed that intra-VTA injection of OT suppresses 10% sucrose intake at doses subthreshold for effect when delivered icv, and that these same doses do not affect intake of water. We also observed that the sucrose intake-suppressive effect of OT was attenuated by pre-treatment with an OT receptor antagonist. These effects on sucrose intake demonstrate that
Animals
Naïve male Wistar rats (Charles River, Wilmington, MA) were maintained individually in temperature-controlled vivariums on a 12-h-light:12-h-dark cycle in Plexiglass cages with food hoppers. Distilled water and Purina 5001 rat chow (St. Louis, MO) were available ad libitum except where otherwise noted. Mean body weight for rats in the single-treatment OT and L-368,899 studies examining sucrose intake was 382 g at the start, and mean body weight of rats at the start of the OVT study was 456 g. The
Acknowledgments
The authors would like to thank Nicole Lilly for technical assistance on these studies.
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2022, AppetiteCitation Excerpt :In mice eating a sugary meal alone in the cage, an OT antagonist L-368,899 generates an increase in consumption (Herisson et al., 2014; Olszewski, Allen, & Levine, 2015; Olszewski, Klockars, et al., 2010). Hyperphagia occurs in mice single-housed and in animals housed socially and separated for a meal (Mullis et al., 2013; Olszewski et al., 2015). Importantly, in socially-housed male mice with established hierarchy, dominant mice show an increase in sucrose intake after the OT antagonist injection regardless of whether the sucrose meal was in the non-social or social setting.