Amylin Receptor Signaling in the Nucleus Accumbens Negatively Modulates μ-opioid-Driven Feeding

Abstract

Amylin is a peptide co-secreted with insulin that penetrates into the brain, and produces satiation-like effects via actions in the brainstem, hypothalamus, and mesencephalon. Little is known, however, about the effects of amylin in the nucleus accumbens shell (AcbSh), where a circumscribed zone of intense amylin receptor (AMY-R) binding overlaps reported mappings of a 'hotspot' for m-opioid receptor (m-OR) amplification of food reward. Here, the ability of intra-AcbSh AMY-R signaling to modulate m-OR-driven feeding was explored. Amylin (1-30 ng) was administered with the m-OR agonist, D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) (0.25 mg), directly into the AcbSh of ad libitum-maintained rats. Amylin dose-dependently reversed DAMGO-induced hyperphagia; 3 ng of amylin reduced DAMGO-mediated feeding by nearly 50%. This dose was, however, completely ineffective at altering DAMGO-induced feeding in the anterior dorsal striatum. Intra-AcbSh amylin alone (3-30 ng) modestly suppressed 10% sucrose intake in ad libitum-maintained rats, and chow in food-deprived rats, but only at the 30-ng dose. This result indicates that reversal of AcbSh DAMGO-induced feeding at a 10-fold lower dose was neither due to malaise nor motoric impairment. Finally, intra-AcbSh infusion of the AMY-R antagonist, AC187 (20 mg), significantly attenuated the ability of prefeeding to suppress DAMGO-induced food intake, with no effects in non-prefed rats. Hence, AMY-R signaling negatively modulates m-OR-mediated appetitive responses at the level of the AcbSh. The results with AC187 indicate that endogenous AMY-R transmission in the AcbSh curtails opioid function in the postprandial period, suggesting a novel pathway for peripheral-central integration in the control of appetitive motivation and opioid reward.

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

“…Studies have presented that amylin receptor signalling in VTA, NAc and LDTg (Baisley & Baldo 2014;MietlickiBaase et al 2015b;Reiner et al 2017) is involved in the control of food intake. Albeit these areas are part of the cholinergic-dopaminergic pathway, which is well established as an important pathway involved in reward-related behaviours (Soderpalm & Ericson 2013), very little is known about the role of amylin receptor signalling within these areas in regard to artificial reinforcers, such as alcohol.…”

“…In fact, amylin and sCT express their anorexigenic effects through central mechanisms involving the area postrema and the nucleus of the solitary tract (Lutz et al 2001a;Potes & Lutz 2010;Braegger et al 2014). Recent studies show that amylin receptors in the NAc, VTA and LDTg (Baisley & Baldo 2014;Mietlicki-Baase et al 2015a;Reiner et al 2017) and more specifically amylin receptors on ventral tegmental dopaminergic neurons mediate the effect of sCT on the control of energy balance (Mietlicki-Baase et al 2013;Mietlicki-Baase et al 2015b). Thus, amylin's action on the mesolimbic dopamine system suggests a potential role that extends beyond regulation of natural rewards, and tenuous evidence supports a possible amylinergic mediation of artificial rewards, such as alcohol.…”

Amylin Acts in the Lateral Dorsal Tegmental Nucleus to Regulate Energy Balance Through Gamma-Aminobutyric Acid Signaling

“…Historically, the contribution of central amylin signaling to food intake control has centered on its action in homeostatic feeding centers, primarily the area postrema (AP) of the caudal brainstem (23–30), and secondarily in hypothalamic subnuclei including the arcuate nucleus (ARH) and ventromedial hypothalamus (VMH) (31–33). However, recent work has also established the VTA and nucleus accumbens (NAc) as relevant nuclei for amylin’s energy balance effects, particularly for reward-based feeding (34–36). While this growing body of literature highlights a more distributed CNS system mediating amylin’s energy balance effects than originally thought, the action of amylin in these aforementioned nuclei cannot wholly explain the energy balance and food reward effects of amylin signaling (23, 37, 38).…”

Amylin-mediated control of glycemia, energy balance, and cognition

“…However, when an alternate, angled cannula placement was used to target the shell, thus avoiding potential ventricular diffusion of the injection, food intake was unchanged [146]. A more recent microinjection study in the NAcSh, in which the ventricles were avoided, suggests that amylin may act in the NAcSh to suppress mu-opioid-induced hyperphagia [147]. This paper also demonstrates that direct intra-NAcSh infusion of amylin reduces sucrose intake, as well as food deprivation-induced chow intake, albeit at higher doses of amylin than those required to modify opioidergic feeding [147].…”

“…A more recent microinjection study in the NAcSh, in which the ventricles were avoided, suggests that amylin may act in the NAcSh to suppress mu-opioid-induced hyperphagia [147]. This paper also demonstrates that direct intra-NAcSh infusion of amylin reduces sucrose intake, as well as food deprivation-induced chow intake, albeit at higher doses of amylin than those required to modify opioidergic feeding [147]. These collective findings suggest that amylin in the NAcSh may impact food intake primarily by interacting with and modulating other feeding-relevant signals, in contrast to its ability to independently influence feeding via actions at other nuclei like the AP and the VTA.…”