Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?

Abstract

Mu-opioid systems in the medial shell of the nucleus accumbens contribute to hedonic impact ("liking") for sweetness, food, and drug rewards. But does the entire medial shell generate reward hedonic impact? Or is there a specific localized site for opioid enhancement of hedonic "liking" in the medial shell? And how does enhanced taste hedonic impact relate to opioid-stimulated increases in food intake? Here, we used a functional mapping procedure based on microinjection Fos plumes to localize opioid substrates in the medial shell of the nucleus accumbens that cause enhanced "liking" reactions to sweet pleasure and that stimulate food intake. We mapped changes in affective orofacial reactions of "liking"/"disliking" elicited by sucrose or quinine tastes after D-Ala2-N-Me-Phe4-Glycol5-enkephalin (DAMGO) microinjections in rats and compared hedonic increases to food intake stimulated at the same sites. Our maps indicate that opioid-induced increases in sucrose hedonic impact are generated by a localized cubic millimeter site in a rostrodorsal region of the medial shell. In contrast, all regions of the medial shell generated DAMGO-induced robust increases in eating behavior and food intake. Thus, our results identify a locus for opioid amplification of hedonic impact and reveal a distinction between opioid mechanisms of food intake and hedonic impact. Opioid circuits for stimulating food intake are widely distributed, whereas hedonic "liking" circuits are more tightly localized in the rostromedial shell of the nucleus accumbens.

Figure 1.

Fos plumes. A, Coronal section showing point sample positions used to identify local Fos plumes around microinjection site (125 × 125 μm blocks on radial arms extending from center; 5× magnification) after vehicle microinjection. B, Coronal section showing Fos expression after vehicle microinjection. C, Photograph map shows a representative Fos plume after a microinjection of low-dose (0.01 μg) DAMGO (in 0.2 μl volume). D, Fos plume produced by higher-dose (0.1 μg/0.2 μl) DAMGO. Intense elevation in Fos expression compared with normal levels was compared with normal accumbens shell tissue (absolute increases; 10× denoted by red color; 5×, green; 2×, blue) and over vehicle microinjection levels at equivalent points surrounding a cannula site (relative increases; 2×, by thick dotted line; 5×, thin dotted line; top right). Microinject., Microinjection.

Figure 2.

Changes in hedonic “liking” (A, B), aversive “disliking” (C, D), and food intake (E, F) caused by DAMGO microinjections. Doses are shown separately: A, C, E, Low dose (0.01 μg/0.2 μl); B, D, F, high dose (0.01 μg/0.2 μl). Behavioral changes are expressed as within-subject percentage changes from vehicle microinjections at the same sites (vehicle, 100%). Bilateral accumbens sites from left and right brains of each rat are collapsed together here into a unilateral single map of accumbens for simplicity. A, B, Enhancement of positive hedonic impact for sucrose taste. The colors denote intensity of “liking” change from vehicle levels, and symbol size shows the diameter of intense Fos plumes (10× elevation above normal, surrounded by semitransparent halos that show diameter of moderate Fos plumes). The bar graphs show absolute magnitudes of behavioral change caused by microinjections in each AP column or DV row (DAMGO minus vehicle). The colors in bars denote percentage behavioral change, dividing DAMGO by vehicle baseline as in maps. The highest increase in positive hedonic reactions was evoked by DAMGO microinjection in the rostrodorsal quarter of medial shell, represented in orange and red in the diagram. Decreases in positive affective reactions are coded in blue (with diagonal black lines). C, D, Suppression of negative aversive impact of quinine taste. Intensity of suppression of “disliking” reactions are shown by shades of purple; otherwise, as above. E, F, Stimulation of food intake. Increases of eating (cumulative duration of eating behavior) are shown by shades of green; otherwise, as above. All sagittal atlas maps at ML ± 0.9 are from Paxinos and Watson (1996). See also supplemental material (available at www.jneurosci.org; see supplemental Fig. S1 for 3-D horizontal maps of hedonic hot spot; insets show examples of hedonic “liking” reactions to sucrose by rat and homologous equivalent expressions by human infant and disliking reactions to quinine; see supplemental Movie 1 for examples of positive hedonic reactions to sucrose taste and negative aversive reactions to quinine taste). Error bars represent SEM. LSI, Lateral septum intermediate; LSV, lateral septum ventral; VP, ventral pallidum.

Figure 3.

Pinpoint map of microinjection centers and their effects. Increases in sucrose “liking” reactions, suppression of quinine “disliking” reactions, and stimulation of food intake are color-coded as in Figure 2. The pinpoint maps do not show the degree of diffusion from site centers but are still helpful to show functional differences among individual sites (such as the relative lack of effect of site centers in the most extreme far rostral 10–20% column of medial shell, as well as some localization effects shown in Fig. 2).

Figure 4.

Contrast maps for opioid hedonic hot spot versus distributed food intake (A) and affective cold spot (B). A, Combined summary map of DAMGO (0.01 and 0.1 μg doses) hedonic enhancement effects on positive hedonic “liking” reactions to sucrose (shown in red/orange/yellow) versus stimulation of food intake (green). Each rat's dose effects were combined to produce a single hedonic impact increase score for its site and a single food intake increase score. A mapping threshold was set at >200% increase over vehicle (veh) control levels for both hedonic and intake effects. Thus, color reflects only sites where DAMGO caused average doubling or more of hedonic reactions or of food intake. Hedonic effects are mapped on top of intake effects. Red/yellow hedonic hot spot shows where DAMGO caused both increased hedonic “liking” reactions and increased food intake. Blue/green shows areas where DAMGO increased food intake without increasing hedonic “liking” reactions to taste. B, Combined summary map for hedonic hot spot (red/yellow) versus affective cold spot where DAMGO suppressed aversion (purple). Mapping threshold for hedonic hot spot again required DAMGO at a site to double the number of positive reactions elicited by sucrose taste. Threshold for mapping cold spot suppression required DAMGO at that site to cut in half the number of aversive reactions elicited by quinine taste (both 0.01 and 0.1 μg dose effects combined for each rat). Hedonic enhancement was mapped on top of aversive suppression (i.e., aversive suppression extends under red/yellow zone).