Modulation of feeding and locomotion through mu and delta opioid receptor signaling in the nucleus accumbens

Abstract

Opioid signaling has been strongly implicated in driving palatable food consumption. The nucleus accumbens (NAcc) is one important site of this effect; hyperphagia elicited by administration of exogenous mu opioid receptor (MOR) ligands in this brain region has been well documented. However, the role that endogenous opioid ligands in the NAcc play in controlling food intake remains poorly understood. Enkephalins, which signal through both the MOR and delta opioid receptor (DOR), are highly expressed within a subset of NAcc neurons, and have been shown to be sensitive to manipulations of diet and motivation. To investigate a potential role for these signaling molecules in regulating palatability-driven consumption, we measured high fat chow intake in rats following a series of pharmacological manipulations of NAcc opioid signaling. NAcc infusion of the MOR agonist [D-Ala2, N-MePHe4, Gly-ol]-enkephalin (DAMGO) robustly increased palatable food intake, as has previously been demonstrated. In contrast, neither infusion of Met-enkephalin, its synthetic analogue [D-Ala2] Met-enkephalin (DALA) nor the DOR-specific ligand [D-Pen2, Pen5]-enkephalin (DPDPE) had significant effects on food intake. However, when administered in combination with DAMGO, DPDPE significantly suppressed the magnitude of DAMGO-evoked feeding. Further analysis of DPDPE effects revealed that the drug strongly increased locomotor activity. Suppressive effects on feeding, then, may have occurred through competition between feeding and locomotion for behavioral expression.

Figure 1

Met-enkephalin infusion into the ventral striatum does not alter high fat chow consumption. Infusion sites in the NAcc core (A), NAcc shell (B), anterior ventrolateral striatum (C), and posterior ventrolateral striatum (D), are shown. In each site, the effects of control saline, met-enkephalin (3 concentrations), and DAMGO (1 concentration) on food intake were assessed. DAMGO reliably elicited hyperphagia (p<0.001 in all sites), while met-enkephalin increased consumption only after the 0.25 nmoles/NAcc dose in the posterior ventrolateral striatum, at a marginally significant level (p=0.049). In this and other bar graphs, bars represent mean value ± SEM. For figures 1–4, consumption is presented as grams of high fat chow consumed over a one hour session.

Figure 2

Neither the enkephalinase inhibitor thiorphan (A), nor the long-lasting synthetic enkephalin analogue DALA (B) alter food intake when injected into the NAcc core. Food intake did not differ from baseline levels after infusion of any concentration of either drug.

Figure 3

The DOR-specific agonist DPDPE attenuates DAMGO-induced hyperphagia. When infused alone, DPDPE had no effects on consumption (third bar). However, when co-infused with DAMGO (fourth bar), DPDPE significantly decreased DAMGO induced consumption (compare with DAMGO alone, second bar). DAMGO was infused at 0.25 nmoles/NAcc in these experiments; DPDPE was infused at 4 nmoles/NAcc. Brackets indicate significantly different levels of high fat chow intake (p< 0.01).

Figure 4

Locomotor activity following manipulation of NAcc core opioid signaling. (A) Locomotion and (B) rearing were significantly elevated relative to baseline levels only after infusion of the DOR-specific agonist DPDPE. DALA caused a transient trend toward increased behavioral activation over the first 20 minutes only.

Figure 5

Cannula placements. (A) Cannula placements in Group 1 were tightly clustered in the medial shell (dashed lines) and central NAcc core (solid lines) near the anterior commissure. Placements in Group 2 were clustered at the border of the ventrolateral striatum and the dorsal endopiriform nucleus for anterior (solid lines) and posterior (dashed lines). Group 1 rats were used in Experiments 1–5, while Group 2 rats were used only in Experiment 1 (Figures 1C–D).