Dorsal neostriatum has been traditionally viewed to mediate movement and habits [] and to respond to learned cues [], whereas ventral striatum is known to generate reward and motivation to consume incentives (in large part mediated by opioid circuitry) []. Dorsal striatum recently has also become implicated in reward-related functions [], and here we report that opioid signaling in an extremely dorsal region of neostriatum contributes to generating intense motivation to overconsume palatable food reward. In dorsal neostriatum, mu opioid receptors are localized mainly in “patch” or “striosome” compartments []. Patches or striosomes in neostriatum receive converging inputs from limbic regions of prefrontal cortex, including from orbitofrontal, prelimbic, and anterior cingulate regions []. We focused here on the medial region of dorsal neostriatum, which has been implicated by previous studies in processing value of reward [].

The role of the dorsomedial striatum in instrumental conditioning.

Corticostriatal innervation of the patch and matrix in the rat neostriatum.

A simple ordering of neocortical areas established by the compartmental organization of their striatal projections.

Fibers from the basolateral nucleus of the amygdala selectively innervate striosomes in the caudate nucleus of the cat.

Axonal arborization of corticostriatal and corticothalamic fibers arising from prelimbic cortex in the rat.

Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey.

Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments.

Basal ganglia disorders associated with imbalances in the striatal striosome and matrix compartments.

Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice.

Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction.

“Nonhedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect.

Relation of reward from food intake and anticipated food intake to obesity: a functional magnetic resonance imaging study.

Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction.

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

Dorsal as well as ventral striatal lesions affect levels of intravenous cocaine and morphine self-administration in rats.

The role of the dorsal striatum in reward and decision-making.

In short, our microinjection results revealed that exogenous mu opioid stimulation by [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) microinjection into the anteromedial dorsal neostriatum potently enhanced consumption of palatable M&M chocolates, more than doubling total M&M intake. This hyperphagic effect was specifically localized within the anteromedial quadrant of the dorsal neostriatum (DAMGO = 251% average increase over vehicle levels). Accordingly, our microdialysis study of that same anteromedial quadrant of dorsal neostriatum found that endogenous enkephalin levels rose to 150% of baseline when rats were suddenly allowed to eat chocolates. These endogenous and exogenous results are described in detail below.

Finally, we found that the magnitude of the enkephalin surge in each rat correlated with that individual’s speed or latency to begin consuming its first M&M (Spearman’s rho = −0.90, p = 0.002, 95% confidence index [CI] [−1, −0.392]; Figure 1 inset): the faster a rat started eating, the higher its relative increase in enkephalin levels. This correlation raised the possibility that anteromedial dorsal neostriatum opioid levels might contribute a motivational “eat now” command. That causal hypothesis was tested further in the microinjection study below.

Enkephalin surges did not seem to be a consequence of mere motor activity. Enkephalin changes were measured during “motor” periods when the rat performed noningestive active movements, such as oromotor gnawing of plastic or wood objects, spontaneous body grooming, or locomotion (walking and/or rearing) in the absence of food ( Figure 2 C). During these noningestive activities, enkephalin levels never increased (Friedman’s test, p = 1, NS), suggesting that the increase described above in the same rats in response to eating chocolates was not due simply to the motoric production of active movements involved in eating. In contrast, enkephalin levels did increase when M&Ms were presented and eaten, compared to the previous periods when rats engaged in locomotor and other movements (Friedman’s test, p = 0.023), again suggesting that enkephalin reflected more than simply the occurrence of ongoing motor activities ( Figure 2 C). Therefore, it appears that enkephalin increased specifically with onset of the reward experience of eating palatable chocolates, remained elevated during eating, and declined soon after.

In contrast to enkephalin levels, dynorphin levels failed to increase during eating and instead remained unchanged throughout the meal (Friedman’s test, p > 0.1; Figure 2 B). Therefore, only enkephalin in the anteromedial quadrant of dorsal neostriatum became dynamically elevated during consumption of palatable food.

Microdialysis probes implanted in anteromedial dorsal neostriatum measured extracellular levels of endogenous striatal opioid peptides: enkephalin (likely released from “indirect path” neurons that also express dopamine D2 receptors) and dynorphin (likely released from “direct path” neurons that express dopamine D1 receptors). Enkephalin and dynorphin were measured first during a normal (“quiet”) behavioral state in mildly hungry rats before any meal to establish a baseline, and next when a large quantity of palatable chocolate candies (M&Ms) were suddenly presented. Opportunity to eat chocolate M&Ms evoked avid consumption, averaging 10 M&Ms in 20 min (≈10 g), and elicited an immediate increase in endogenous levels of met-enkephalin and leu-enkephalin, reaching an elevation of >150% over premeal baseline (baseline ± SEM: met-enkephalin = 2.61 ± 0.56 pM, leu-enkephalin = 2.32 ± 0.30 pM; Friedman’s test, p < 0.01; baseline = 100%; Figures 1 and 2 A ). Enkephalin levels remained elevated throughout the roughly 20–40 min period during which each rat continued to eat and then began to decline as rats slowed and gradually ceased eating, typically returning fully back to baseline within the next 40 min (first baseline versus last sample, Wilcoxon’s test, not significant [NS]).

(C) Enkephalin levels did not increase during noningestive activities involving forelimbs, body, or orofacial movements (walking, rearing, gnawing, grooming), here the “motor” period. Enkephalin levels are presented as percent of “quiet.” Average percent of time the rats engaged in each behavior is shown in the pie charts.

(A and B) Absolute concentrations of met enkephalin and leu enkephalin are displayed in (A). In contrast, dynorphin remained relatively stable throughout resting, eating, and other behaviors (B).

Extracellular enkephalin levels surged when rats began to eat milk chocolate M&Ms. Onset of eating coincided with a robust increase in extracellular enkephalin (met and leu), which remained sustained during eating and gradually tapered off as eating declined. The magnitude of the enkephalin increase in individuals correlated with their latency to eat their first M&M: higher enkephalin increase for the fastest eaters. The correlation between faster speed to start eating and higher enkephalin also remains significant if the highest outlier individual (upper right of inset) is removed (Spearman’s rho = −0.85, p = 0.013, 95% CI [−1, −0.4]). ∗ p < 0.05. Error bars represent SEM.

In contrast to mu stimulation of eating, delta opioid receptor stimulation by [D-Pen2,5]-enkephalin (DPDPE) microinjections failed to increase eating behavior or intake over vehicle control levels at all sites in dorsomedial neostriatum, even in the anteromedial quadrant (F= 0.4, p > 0.1; see Figure S1 available online). Accordingly, M&M intake was much higher after mu agonist DAMGO microinjection than after delta agonist DPDPE microinjection at the same anteromedial dorsal neostriatum sites (DAMGO = 6.31 ± 1.13 g, DPDPE = −0.46 ± 0.68 g; t= 5.10, p < 0.001, 95% CI [9.47, 4.09], Cohen’s d = 1.65). This difference suggests that enkephalin may act primarily at mu receptors in anterior dorsomedial neostriatum to stimulate increases in consumption, rather than at delta receptors. Furthermore, DAMGO microinjections in all areas of neostriatum, including the anterior dorsomedial quadrant, failed to produce any general increases in locomotor or oromotor activity, measured by cage crosses, rearing, grooming, or treading behaviors; chow consumption; or wooden block gnawing (behaviors F= 0.151, NS; chow consumption F= 0.68, NS; gnawing t= 2.1, NS).

In contrast to the anteromedial quadrant, as microinjection sites moved posteriorly in medial dorsal neostriatum, the level of stimulated eating gradually declined. Strong elevation of eating was still produced at intermediate medial sites where the diameter of Fos plumes straddled the border between anteromedial and posteromedial quadrants of dorsal neostriatum (190% increase). No significant elevation was produced by more posterior sites fully contained within the posteromedial quadrant (i.e., where no part of a posterior site’s Fos plume would contact the anteromedial border; average 118%, NS).Thus, for the entire posteromedial quadrant overall, intermediate 150% elevations of eating were found, due mostly to the medial sites that straddled the anterior/posterior border (t= 2.52, p = 0.036, 95% CI [7.28, 0.33], Cohen’s d = 0.939). Comparing anterior versus posterior directly as entire quadrants, DAMGO in the anteromedial quadrant produced a greater increase in intense eating than DAMGO in the posteromedial quadrant (t= 2.21, p = 0.037, 95% CI [201.6, 6.96], Cohen’s d = 0.85). Eating increases abruptly fell off to zero as microinjection sites moved laterally from the anteromedial quadrant. Anterolateral quadrant sites produced no increase at all over vehicle levels (i.e., outside of and lateral to effective sites in dorsomedial neostriatum; only 103%; t= 0.1, p = 0.917; Figure 3 A).

DAMGO microinjection in this anteromedial quadrant also made rats faster to begin to eat (in addition to making them eat more), decreasing the latency to begin eating their first M&M of the day (vehicle = 55.4 ± 10.4 s; DAMGO = 28.7 ± 4.2 s; t (25) = 2.49, p = 0.019, 95% CI [4.69, 48.85], Cohen’s d = 2.781). Faster speed to eat supports the hypothesis that mu opioid receptor stimulation in this neostriatum region provides a command to “eat now” as well as to “eat more.”

For sites in the highly effective anteromedial quadrant of dorsal neostriatum, most rats ate over 17 g of M&Ms, equal to about 5% of their 300 g body weight ( Figure 3 A). That level of elevated consumption (5% of body weight) is roughly proportional to a 68 kg human consuming ∼3.6 kg of M&Ms in a single hour, clearly overriding normal satiety signals [].

A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward.

We found that DAMGO microinjection in dorsal neostriatum stimulated more intense eating of chocolates in nondeprived rats, but depending on precise site or quadrant. Sites within the anteromedial quadrant of dorsal neostriatum produced by far the most intense increases of >250% intake of M&Ms (t= 5.1, p < 0.001, 95% CI [9.96, 4.15], Cohen’s d = 1.217 compared to vehicle control intake levels by the same rats; Figure 3 A). Anteromedial quadrant sites produced higher elevations of eating than all other quadrants of dorsal neostriatum (anteromedial versus other quadrants F= 8.44, p = 0.006, 95% CI [136, 235], Cohen’s d = 1.09). Localization of function was further determined by mapping the causal efficacy of neostriatal microinjection sites to stimulate eating, using symbols sized to the measured radius of Fos plumes surrounding DAMGO microinjections in dorsal neostriatum (Fos radius reflects the anatomical spread of drug impact; Figure 3 ). For sites that elevated eating >250%, at least 90% of the volume of DAMGO-induced local Fos plumes would have been contained entirely within the anteromedial quadrant of dorsal neostriatum. That is, DAMGO Fos plumes were measured to have a 0.18 mm total radius (0.02 mmvolume), containing an inhibited small center (0.15 mm radius, 0.016 mmvolume zone of halved Fos expression compared to vehicle baselines) surrounded by a larger excitatory Fos sphere (0.18 mm radius, 0.02 mmvolume zone of doubled Fos expression over normal baseline; the center/surround Fos opposition possibly reflects reciprocal local inhibitory connections between the two zones; Figure 3 A inset). These plume measurements allow confidence that the intense overconsumption was generated by DAMGO stimulation of anteromedial dorsal neostriatum rather than by diffusion to other regions of neostriatum, ventral striatum, or nucleus accumbens.

(B) Taste reactivity results show that DAMGO injected into the same dorsomedial area did not increase hedonic impact of sucrose (during oral infusions) or M&M chocolates (during voluntary eating).

(A) [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) microinjection into anterior dorsomedial neostriatum potently enhanced intake of M&M chocolate candies (high fat and high sugar). All DAMGO-evoked eating behavior and intake changes are expressed as percent increases over vehicle-evoked control levels measured in the same rat. A two-layer “Fos plume” shows the maximal spread of Fos locally surrounding DAMGO microinjections. This measured radius was used to assign the size of symbol to the microinjection site for each behaviorally tested rat. The color of each symbol depicts the magnitude of eating behavior stimulated by DAMGO microinjection at that site, relative to vehicle control level of the same rat. The largest increases in eating were localized to the anteromedial quadrant of dorsal neostriatum.

Exogenous Mu Stimulation Fails to Alter Hedonic “Liking” for Sweetness

2 Peciña S.

Berridge K.C. Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?. 4 Smith K.S.

Berridge K.C. The ventral pallidum and hedonic reward: neurochemical maps of sucrose “liking” and food intake. 27 Mahler S.V.

Berridge K.C. What and when to “want”? Amygdala-based focusing of incentive salience upon sugar and sex. 2 Peciña S.

Berridge K.C. Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?. 4 Smith K.S.

Berridge K.C. The ventral pallidum and hedonic reward: neurochemical maps of sucrose “liking” and food intake. 28 Grill H.J.

Norgren R. The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. 29 Feurté S.

Nicolaidis S.

Berridge K.C. Conditioned taste aversion in rats for a threonine-deficient diet: demonstration by the taste reactivity test. (3,9) = 1.875, p = 0.204; (3,5) = 0.175, p = 0.91; (5) = 15.58, 95% CI [9.90, 7.09], Cohen’s d = 2.3). Thus, DAMGO in dorsomedial neostriatum appeared to make rats selectively “want” to eat M&Ms more intensely, in the sense of enhanced eating behavior and intake, without making them “like” sweetness any more, in the sense of hedonic reactions to sucrose or chocolate tastes. We note that similar dissociations involving selective increases in “wanting” without “liking” are typical of opioid stimulation at many other brain sites, including ventral striatum (except in the hot spot of nucleus accumbens shell) and striatal-related structures [ 2 Peciña S.

Berridge K.C. Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?. 4 Smith K.S.

Berridge K.C. The ventral pallidum and hedonic reward: neurochemical maps of sucrose “liking” and food intake. 27 Mahler S.V.

Berridge K.C. What and when to “want”? Amygdala-based focusing of incentive salience upon sugar and sex. Finally, we used the affective taste reactivity test of orofacial “liking” reactions to investigate whether mu opioid enhancement of motivation to eat sweet food reflected purely generation of motivation to eat (similar to opioid effects in most of ventral striatum outside a cubic-millimeter hot spot and in central amygdala) or additionally involved any enhancement of hedonic impact or “liking” for the taste of sweet reward (typical only of restricted hot spots in ventral striatum, ventral pallidum, etc.) []. This measure draws on rodent affective orofacial reactions (e.g., positive tongue protrusion and lip licking to sweetness versus aversive gapes to bitterness) that are homologous to human infant affective facial expressions elicited by tastes []. We tested for hedonic enhancement in a standard taste reactivity test using a sucrose solution infused directly in the mouth to control stimulus quality and duration, and tested separately for the taste of sweet/fatty chocolate as rats voluntarily ate 0.2 g fragments of M&Ms, replicating the chocolate stimulus and conditions of enhanced eating behavior []. Taste reactivity results of both tests showed that DAMGO microinjections in anterior dorsomedial neostriatum failed to enhance positive hedonic taste reactions at all, either in response to oral infusions of 1% sucrose solution (F= 1.875, p = 0.204; Figure 3 B) or in response to the chocolate taste of solid M&M fragments (F= 0.175, p = 0.91; Figure 3 B). Although no increase in hedonic impact was observed, the DAMGO microinjections again increased motivation to eat in the voluntary intake test, so that the rats doubled their consumption of chocolate over vehicle control levels (t= 15.58, 95% CI [9.90, 7.09], Cohen’s d = 2.3). Thus, DAMGO in dorsomedial neostriatum appeared to make rats selectively “want” to eat M&Ms more intensely, in the sense of enhanced eating behavior and intake, without making them “like” sweetness any more, in the sense of hedonic reactions to sucrose or chocolate tastes. We note that similar dissociations involving selective increases in “wanting” without “liking” are typical of opioid stimulation at many other brain sites, including ventral striatum (except in the hot spot of nucleus accumbens shell) and striatal-related structures []. This dissociation between “wanting” versus “liking” suggests that mu opioid stimulation in anterior dorsomedial neostriatum may generate increases of motivation as a specific psychological mechanism to drive intense eating and consumption of food reward.

3 Zhang M.

Kelley A.E. Enhanced intake of high-fat food following striatal mu-opioid stimulation: microinjection mapping and fos expression. 30 Bakshi V.P.

Kelley A.E. Striatal regulation of morphine-induced hyperphagia: an anatomical mapping study. 31 Bakshi V.P.

Kelley A.E. Feeding induced by opioid stimulation of the ventral striatum: role of opiate receptor subtypes. We acknowledge that our finding of intense overconsumption produced by mu opioid stimulation in the anteromedial dorsal neostriatum contrasts at first sight with previous reports of relative failure to observe any increase in eating after DAMGO microinjection in dorsal neostriatum []. However, earlier studies did not distinguish anatomically among the four quadrants of dorsal neostriatum as defined here and typically used placements that as a whole were more centrally located in the dorsal half of neostriatum (i.e., more ventral and posterior to our eating hot spot). Our finding of eating localization in the anteromedial quadrant of the dorsal level may explain why studies that mixed together different subregions failed to find eating stimulation in dorsal neostriatum.

19 Wise R.A. Roles for nigrostriatal—not just mesocorticolimbic—dopamine in reward and addiction. 20 Nummenmaa L.

Hirvonen J.

Hannukainen J.C.

Immonen H.

Lindroos M.M.

Salminen P.

Nuutila P. Dorsal striatum and its limbic connectivity mediate abnormal anticipatory reward processing in obesity. 21 Stice E.

Spoor S.

Bohon C.

Veldhuizen M.G.

Small D.M. Relation of reward from food intake and anticipated food intake to obesity: a functional magnetic resonance imaging study. 22 Volkow N.D.

Wang G.J.

Fowler J.S.

Logan J.

Jayne M.

Franceschi D.

Wong C.

Gatley S.J.

Gifford A.N.

Ding Y.S.

Pappas N. “Nonhedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. 23 Volkow N.D.

Wang G.J.

Telang F.

Fowler J.S.

Logan J.

Childress A.R.

Jayne M.

Ma Y.

Wong C. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. 24 Palmiter R.D. Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice. 20 Nummenmaa L.

Hirvonen J.

Hannukainen J.C.

Immonen H.

Lindroos M.M.

Salminen P.

Nuutila P. Dorsal striatum and its limbic connectivity mediate abnormal anticipatory reward processing in obesity. 21 Stice E.

Spoor S.

Bohon C.

Veldhuizen M.G.

Small D.M. Relation of reward from food intake and anticipated food intake to obesity: a functional magnetic resonance imaging study. 22 Volkow N.D.

Wang G.J.

Fowler J.S.

Logan J.

Jayne M.

Franceschi D.

Wong C.

Gatley S.J.

Gifford A.N.

Ding Y.S.

Pappas N. “Nonhedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. 23 Volkow N.D.

Wang G.J.

Telang F.

Fowler J.S.

Logan J.

Childress A.R.

Jayne M.

Ma Y.

Wong C. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. 16 Suto N.

Wise R.A.

Vezina P. Dorsal as well as ventral striatal lesions affect levels of intravenous cocaine and morphine self-administration in rats. 17 Schultz W.

Dickinson A. Neuronal coding of prediction errors. 32 Apicella P.

Ljungberg T.

Scarnati E.

Schultz W. Responses to reward in monkey dorsal and ventral striatum. 33 Haracz J.L.

Tschanz J.T.

Wang Z.

White I.M.

Rebec G.V. Striatal single-unit responses to amphetamine and neuroleptics in freely moving rats. 2 Peciña S.

Berridge K.C. Hedonic hot spot in nucleus accumbens shell: where do mu-opioids cause increased hedonic impact of sweetness?. 34 Berridge K.C.

Robinson T.E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?. 35 Carelli R.M.

Ijames S.G. Selective activation of accumbens neurons by cocaine-associated stimuli during a water/cocaine multiple schedule. 36 Will M.J.

Vanderheyden W.M.

Kelley A.E. Striatal opioid peptide gene expression differentially tracks short-term satiety but does not vary with negative energy balance in a manner opposite to hypothalamic NPY. 24 Palmiter R.D. Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice. Other hints of dorsal neostriatum involvement in motivation to consume reward have emerged in the past decade []. In humans, dorsal striatum activation has been reported to be elicited by palatable food and its cues in obese binge eaters, and by cocaine and its cues in drug addicts []. Such dorsal striatal activations have remained slightly ambiguous: they could be viewed as encoding either reward motivation or hedonic impact, incipient movements, habits, cognitive processing, or learned predictions. Similarly, dorsal neostriatal neuronal activations elicited by reward or cues have been reported in monkeys and rodents and have often been interpreted as reflecting learned predictions or teaching signals (e.g., prediction error model) []. Our results more specifically indicate that dorsal striatal activation can participate in generating intense motivation to overconsume a reward. Thus, the generative role shown here might link some functions of dorsal neostriatum more closely to the reward motivation functions of ventral striatum (nucleus accumbens) []. This also seems consistent with reports that restoring synaptic function to a region of dorsal neostriatum can rescue eating in an aphagic mutant mouse model and supports the interpretation that such neostriatum-mediated rescues may involve a motivational component [].

6 Eblen F.

Graybiel A.M. Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. 8 Gerfen C.R. The neostriatal mosaic: striatal patch-matrix organization is related to cortical lamination. 10 Lévesque M.

Parent A. Axonal arborization of corticostriatal and corticothalamic fibers arising from prelimbic cortex in the rat. 11 Ragsdale Jr., C.W.

Graybiel A.M. Fibers from the basolateral nucleus of the amygdala selectively innervate striosomes in the caudate nucleus of the cat. 12 Ragsdale Jr., C.W.

Graybiel A.M. A simple ordering of neocortical areas established by the compartmental organization of their striatal projections. 13 Kincaid A.E.

Wilson C.J. Corticostriatal innervation of the patch and matrix in the rat neostriatum. 10 Lévesque M.

Parent A. Axonal arborization of corticostriatal and corticothalamic fibers arising from prelimbic cortex in the rat. 6 Eblen F.

Graybiel A.M. Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey. 37 Mena J.D.

Sadeghian K.

Baldo B.A. Induction of hyperphagia and carbohydrate intake by μ-opioid receptor stimulation in circumscribed regions of frontal cortex. Figure 4 Anatomical Circuit for Anteromedial Dorsal Neostriatum Show full caption Neurons in patches/striosomes of the anteromedial dorsal neostriatum are rich in mu opioid receptors and receive cortical inputs from limbic areas of prefrontal cortex. Some patch/striosome neurons that express D1 receptors make direct projections to dopamine neurons within substantia nigra. D2-expressing matrix neurons release enkephalin that could act on mu opioid receptors, especially of patch neurons, to generate motivation to eat. The hypothesis that opioid circuitry in dorsomedial neostriatum participates in generating motivation to overconsume a palatable food reward also seems concordant with its anatomical wiring from limbic prefrontal cortical inputs [] ( Figure 4 ). For example, corticostriatal projections to the anteromedial region of dorsal neostriatum (“rostromedial sector of caudate putamen”), similar to that studied here, originate from the prelimbic region of medial prefrontal cortex in rats []. Corticostriatal projections from “posterior [lateral] orbitofrontal/anterior insular cortex and the mediofrontal prelimbic/anterior cingulate cortex” similarly terminate in striosomes in the medial caudate in macaques, which probably overlaps with our eating site []. It is also noteworthy that direct mu opioid stimulation of prefrontal cortex regions, via DAMGO microinjections in orbitofrontal and prelimbic/infralimbic (ventral anterior cingulate) cortex, can stimulate eating in rats, raising the possibility of a larger opioid-related corticostriatal circuit involved in eating and motivation [].

38 Jiang Z.G.

North R.A. Pre- and postsynaptic inhibition by opioids in rat striatum. 39 Wang H.

Pickel V.M. Dendritic spines containing mu-opioid receptors in rat striatal patches receive asymmetric synapses from prefrontal corticostriatal afferents. 40 Fujiyama F.

Sohn J.

Nakano T.

Furuta T.

Nakamura K.C.

Matsuda W.

Kaneko T. Exclusive and common targets of neostriatofugal projections of rat striosome neurons: a single neuron-tracing study using a viral vector. 1 Kelley A.E.

Baldo B.A.

Pratt W.E. A proposed hypothalamic-thalamic-striatal axis for the integration of energy balance, arousal, and food reward. 31 Bakshi V.P.

Kelley A.E. Feeding induced by opioid stimulation of the ventral striatum: role of opiate receptor subtypes. 37 Mena J.D.

Sadeghian K.

Baldo B.A. Induction of hyperphagia and carbohydrate intake by μ-opioid receptor stimulation in circumscribed regions of frontal cortex. 41 Will M.J.

Franzblau E.B.

Kelley A.E. The amygdala is critical for opioid-mediated binge eating of fat. 42 Gosnell B.A. Involvement of mu opioid receptors in the amygdala in the control of feeding. We speculate that opioid surges particularly within anteromedial patches of dorsal striatum might modulate presynaptic corticostriatal glutamate release or modulate postsynaptic activity of eating-related neurons in striosomes that contain mu opioid receptors []. In addition, some D1 receptor-expressing neurons in striosomes may uniquely project directly to dopamine neurons in substantia nigra [], which might facilitate modulation of dopamine systems to additionally help generate intense motivation. Beyond the neostriatum, the anterior dorsomedial neostriatal region described here likely interacts with other parts of the distributed mesocorticolimbic network involved in eating and intake, including hypothalamus, ventral striatum, limbic cortex, amygdala, and mesolimbic dopamine nuclei [].

In conclusion, our results provide novel evidence that enkephalin surges and mu opioid stimulation in the same anteromedial dorsal neostriatum region contribute to signaling the opportunity to eat a sensory reward and to causally generating increased consumption of that reward. The neostriatum-generated increase in motivation can be powerful enough to more than double the amount of food a rat “wants” to eat yet be functionally specific enough to the motivational component of reward, rather than the hedonic component, to not enhance “liking” for the same sweet chocolate treat. Opioid circuitry in anterior dorsomedial neostriatum could in this way participate in normal motivations and perhaps even in generating intense pathological levels of motivation to overconsume reward in binge eating disorders, drug addiction, and related compulsive pursuits.