Role of striatal dopamine signaling in compulsive eating associated with obesity

Abstract

As access to inexpensive energy-dense foods increases and lifestyles become ever more sedentary obesity levels have climbed. The mesoaccumbens dopamine system is essential to maintaining appropriate control over feeding and associated behaviors. Emerging evidence suggests that consumption of highly palatable energy-dense food profoundly impacts mesoaccumbens dopamine neurotransmission and downstream signaling cascades in cortical and limbic regions. Furthermore, it is increasingly clear that dysregulation of dopamine receptor function contributes to the emergence of compulsive food intake, which likely contributes to weight gain, development of obesity and difficulties losing weight. Understanding the nature of these perturbations in mesoaccumbens dopamine may reveal novel strategies for medications development to combat obesity and obesity-associated diseases.

Introduction

Obesity, defined as a body mass index (BMI) greater than 30 kg.m⁻², is on the rise in most regions of the world [1]. In the US, current estimates place the proportion of adults fulfilling the criteria for obesity at 30% [2]. This represents a dramatic increase since the early part of the 1960s, when approximately 13% of the population was estimated to be obese [3]. Many overweight and obese individuals struggle to reduce calorie intake, a task made more difficult as energy-dense palatable foods are almost ubiquitously available and improving access to personal transportation reduces the need for energy expenditure [4–6].

Many food items eaten to excess, which likely contribute to weight gain and obesity, are highly processed and calorically dense, due to high sugar and fat content, and are considered “hyper-palatable” [7,8]. Indeed, many individuals who report problematic eating patterns display behaviors similar to those who compulsively consume drugs of abuse [9]. There is considerable overlap in brain substrates that regulate the motivational properties of palatable food and drugs of abuse [4,7], with mesoaccumbens dopamine transmission playing a prominent role in both. As such, disruption to dopamine signaling in these systems may be a key point in the development of compulsive food-seeking behavior. Here we review recent literature focused on the neurobiological mechanisms of compulsive food intake contributing to obesity.

Palatable food influences dopamine signaling in feeding relevant circuits in the brain

When laboratory animals are permitted access to sucrose, or are presented with cues that predict sucrose delivery, increases in striatal dopamine release are reliably detected in nucleus accumbens (NAc) [10–12]. Dopamine responses to cues predicting food rewards operate at the millisecond scale, supporting a highly dynamic role for dopamine in coordinating food-seeking behaviors and responses to food-predictive environmental stimuli [13]. Human imaging studies also show that activation of striatal regions occurs in response to food reward [14]. When animals are hungry and below normal free-feeding weight NAc dopamine responses to sucrose are markedly amplified [15]. This suggests that mesoaccumbens dopamine transmission regulates the increased motivational properties of food during periods of negative energy balance and may coordinate behaviors directed toward obtaining food. These findings also suggests that mesoaccumbens dopamine responses may be sensitive to fluctuations in circulating hormonal regulators of satiety and hunger that influence the enhanced or diminished motivational properties of food during periods of negative or positive energy balance, respectively. Indeed, evidence accumulated over recent years suggests that activity of mesoaccumbens dopamine neurons is modulated by insulin, leptin, ghrelin and other hormonal regulators of food intake whose circulating levels fluctuate depending on energy status [16–19].

When palatable energy-dense food is consumed over protracted periods of time adaptive responses in various components of the mesoaccumbens dopamine system are observed [11]. For example, high levels of sugar intake in rodents increases D₂ receptor and decrease D₃ dopamine receptor levels in striatum [20], and increases D₁ receptor sensitivity [21]. Typically when humans consume calorically dense food as part of an obesogenic diet the food items do not consist simply of high levels of sugar or fat but rather combinations of both. To better recapitulate this aspect of modern human diets in laboratory rodents a “cafeteria style” diet is often used in which rats or mice are permitted access to selections of palatable food items high in fat and/or sugar, such as chocolate, bacon, cheesecake etc. Rats with access to a cafeteria diet rapidly gain weight and can become obese, with this increase in adiposity accompanied by decreased levels of striatal D₂ receptors [22]. Downregulation of mRNA levels for D₁ and D₂ receptors, and reduced dopamine levels in the NAc, are also observed [23,24]. Genetically obese Zuker rats also have reduced striatal levels of D₂ receptors [25] and Sprague Dawley rats bred to prefer a calorically dense palatable diet, as well as obesity prone rats, demonstrate lower levels of accumbal dopamine compared with control animals [26,27]. Interestingly, leptin can activate neurotensin-producing receptors in the lateral hypothalamus (LH) [28] to stimulate dopamine production in ventral tegmental area (VTA) neurons [29], suggesting that leptin exerts long-term trophic effects over the mesoaccumbens dopamine system [17]. By contrast, acute increases in leptin action in VTA decrease mesoaccumbens dopamine transmission [16]. Hence, leptin exert complex actions over mesoaccumbens dopamine homeostasis. More recently, it was shown that STAT3 signaling in VTA dopamine neurons, a major signaling cascade activated by leptin, inhibits reward derived from physical activity [30]. This finding suggests that in addition to food reward, leptin acts in VTA to regulate energy expenditure.

The precise mechanism by which highly palatable food intake and weight gain can disrupt messocaccumbens dopamine signaling is unclear, but recent findings highlight the intriguing possibility that extends beyond the brain and involve alterations in gut-brain homeostasis. Mice fed a high-fat diet developed impaired messoaccumbens dopamine signaling, which coincided with suppressed synthesis of the gut messenger lipid oleoylethanolamine (OEA) [31]. Restoration of OEA in gut attenuated deficits in mesoaccumbens in obese mice as well as obesity-related motivational deficits [31]. Together, these findings suggest that mesoaccumbens dopamine systems undergo marked alterations in response to palatable food intake and weight gain and that gut lipid signaling may play an important role in this process. Human imaging data similarly point to altered dopamine signaling in overweight and obese individuals. For example, overweight individuals show reduced striatal D₂ receptor availability [32,33], and reduced striatal activation in response to food cues [34,35], compared with normal weight controls. Individuals possessing the TaqIA A1 allele, which is associated with reduced D₂ receptor expression [36], are more likely to be obese [34] and also display decreased striatal activation in response to palatable food or related cues [37]. Reduced striatal activation in those carrying the TaqIA A1 allele was found to predict BMI increases over a two year period [38]. However, increased striatal responses to a palatable milkshake TaqIA A2/A2 allele carriers predicts future weight gain.

Similarly, adolescents in high-risk groups for the development of obesity, but who themselves were not currently obese, show increased striatal activation in response to palatable food compared to control subjects [14]. These observations suggest that too much or too little D₂ receptor-mediated dopamine signaling can increases risk of weight gain.

Alterations in dopamine transmission can drive compulsive reward seeking behavior.

D₂ receptor levels in striatum have been shown to correlate with metabolic activity in various cortical regions such as dorsolateral prefrontal (PFC), medial orbitofrontal (OCC), anterior cingulate gyrus (ACC) and somatosensory cortices [32]. Proper functioning of these cortical regions, in particular the OFC and ACC, are key to maintaining control (goal-directedness) over behaviors and regulating impulsive responses [39]. In obesity, reduced levels of striatal D₂ receptors correlate with lower levels of activity in cortical brain sites involved in behavioral control (i.e., hypofrontality) [40]. Interestingly these same sites show increased activation in obese individuals when they are presented with pictures of high-calorie food [35,41]. These finding may suggest that baseline control over behavior is diminished in obese individuals, but that cortical systems are hyper-reactive to environmental stimuli that predict availability of food rewards.

Accumulating evidence links alterations in dopamine signaling that arises from diet-induced obesity to the development of many behaviors reminiscent of those produced by drugs of abuse. Rodents allowed extended access to a high sugar and/or fat diets have increased motivation to obtain food, during operant responding [10]. Furthermore, forced abstinence from palatable sucrose solutions produces physical withdrawal symptoms such as a drop in body temperature [42] and emotional deficits, as measured by increased immobility in the forced-swim test (FST) [43]. Compulsive-like patterns of intake emerge in animals with extended access to drugs of abuse [44–46], a phenomenon not typically seen in animals when restricted access to drugs. Intriguingly, similar compulsive-like food seeking also emerges in animals with extended access to calorically dense palatable food. For example, access to a sucrose solution rapidly precipitates escalation in intake [21]. As discussed earlier, our group has observed decreased striatal D₂ receptor levels in rats given extended access to a cafeteria style diet [22]. In addition, access to a cafeteria diet greatly influences food preference. Despite also having access to regular chow, rats with extended access to the cafeteria-style diet obtained the vast majority of their calories from the energy-dense palatable food (>95%) [22], and as a consequence their total calorie intake was more than double that of animals provided only access to standard chow [22]. It is interesting to note that a third group of rats, provided with only limited (1 hour) access to the cafeteria diet, did not consume a higher total calories each day than animals access to only standard chow [22], showing that they maintained homeostatic control over caloric consumption. This suggests that extended access to palatable energy-dense diets is a critical aspect of the diet that leads to increased calorie intake and weight gain. Perhaps more interestingly, as weight gain emerged in rats with extended access to a cafeteria diet, the rats also developed food-seeking responses that were resistant to punishment, as measured by persistent consummatory behavior even in the presence of conditioned stimuli that predicted the delivery of noxious footshocks [22]. Similar addiction-like food seeking behaviors that are resistant to punishment have also been reported by other groups [47–50]. This inflexible pattern of behaviors directed toward obtaining palatable food was not observed in rats that had limited access to the cafeteria diet and did not demonstrate weight gain compared with chow-only rats [22]. Compulsive-like food seeking behaviors can even override survival-orientated behaviors in rodents. For example, mice that previously had access to palatable energy-dense food will expose themselves to brightly-lit aversive environments to continue to obtain this food to a far greater degree than animals with no experience of the diet [51]. It would appear that these mice become progressively more impervious to threatening environmental stimuli [52], risking predation to obtain palatable energy-dense food even though when less palatable food is available at a much lower risk. Thus, as animals consume highly palatable foods they become less sensitive to negative outcomes that may be paired with their food-seeking behavior, a phenomenon similar to that seen in animals with extended access to addictive drugs.

In what may be considered somewhat paradoxical, given the facilitation of dopamine neurotransmission induced by ingestion of palatable food, long-term exposure to high-fat and/or high-sugar diets is associated with decreased motivation for food (as measured by operant responding) in overweight animals [53,54]. However, this decrease in motivation to earn food by overweight rats also coincides with marked deficits in brain reward function, as measured by elevated brain-stimulation reward thresholds [22]. Interestingly, however, obese rats demonstrate marked deficits in baseline and evoked dopamine levels in striatum [24–27]. This suggests that marked adaptive responses develop in the mesoaccumbens dopamine system in response to excessive consumption of palatable food and development of obesity. To directly explore the functional relevance of deficits in striatal dopamine transmission, including reduced D₂ receptor densities, and the emergence of compulsive food-seeking behaviors, our laboratory has investigated the effects of virus-mediated knock down striatal dopamine D₂ receptors in striatum on punishment-resistant food seeking behaviors in rats with extended access to a cafeteria diet [22]. We found that knocking down striatal D2 receptors accelerated the emergence of the punishment resistant compulsive feeding state discussed earlier [22]. Interestingly, the same manipulation resulted in elevated brain-stimulation reward thresholds in rats, suggesting that deficits in brain reward function and the emergence of compulsivity be functionally connected. A role for drug-induced deficits in brain reward function and the emergence of compulsive drug-seeking has long been hypothesized as a major motivational force in the development of compulsive-drug-seeking behaviors. Specifically, it has been argued that excessive stimulation of brain reward systems in rats with extended access to addictive drugs such as cocaine results in adaptive discriminants in the sensitivity of reward systems in brain reward function. Such discriminants paradoxically increase the motivation to consume addictive drugs in order to obtain their stimulatory effects on otherwise sub-functional reward circuits, thereby establishing an escalating pattern of intake.

Hypothalamo-mesodopamine interactions in food-reward

Considering that reduced dopamine transmission in striatum of obese subjects contributes to compulsive food-seeking behaviors, an interesting question becomes which feeding- and motivation-relevant brain circuits may be impacted by feeding-relevant altered dopamine transmission to explain the patterns of maladaptive food-related behaviors that emerge. The striatum provides a major source of input to LH and the LH plays an important role in integrating information relevant to nutrient and energy statues in animals to coordinate feeding-relevant behaviors [55]. In addition to striatum, LH also receives (and sends) information relevant to energy status from other regions of the brain involved in motivated behaviors, such as the ventral tegmental area (VTA), hippocampus, OFC and insula [4,56]. The LH possess a heterogeneous population of neurons that serve to facilitate the integration of nutritive signaling via a diverse range of effectors including classical neurotransmitters, neuropeptides as well as peripheral signalers of energy status. Reciprocal projections to the VTA regulate the release of dopamine into downstream striatal regions in response to feeding-relevant environmental and internal cues (e.g., hunger, satiety) [4,57]. Indeed, classic experiments demonstrated electrical stimulation of VTA-terminating LH projections is highly reinforcing and can induce feeding behavior in otherwise satiated rodents [58]. Stimulation of LH projections to VTA GABAergic neurons can induce feeding behavior [59], consistent with stimulation of VTA GABAergic cells generating a state of negative valence [60]. Furthermore, D₁ expressing medium spiny neurons in the shell region of the NAc provide tonic inhibition over LH GABAergic neurons which when released permits feeding [8]. Conversely, neurotensin and orexigenic neurons originating from the LH promote reward via modulation of the VTA glutamatergic and DA systems [29,61,62]. In turn, the NAc, OCC and insula directly or indirectly modulate activity in LH circuits to modify value of food and food-predictive environmental stimuli [7,56,63]. The arcuate nucleus of the hypothalamus, particularly agouti-related peptide (AgRP) neurons in this site, regulates mesoaccumbens system during hunger states [64] and encode states of aversion during periods of negative energy balance [65]. Further integrating peripheral signals is the periventricular nucleus of the thalamus which sends glutamatergic output to cholinergic interneurons in striatum, which in turn influence signaling on D1 and D2 expressing medium spiny neurons that project to LH [66]. These observations support a complex reciprocal communication network, with the mesoaccumbens dopamine system, hypothalamic and thalamic regions serving as core components of a broad network that integrate signals related to energy and nutrition status to influence the hedonic impact of food and thereby modulate food-seeking behaviors. Maladaptive responses in this circuit likely play an important role in the development and persistence of obesity.

Conclusions and perspectives

“Nothing in biology makes sense except in the face of evolution” was coined by the Russian evolutionary biologist Theodosius Dobzhansky in his 1973 essay of the same name. In light of this axiom it might be worth considering the dysfunction in mesoaccumbens dopamine systems seen in laboratory animals and humans, and subsequent induction of compulsive feeding patterns, as not pathological per se but rather evolutionary beneficial processes that are rendered pathological by modern circumstance. Indeed, it has been argued that since the advent of agriculture and the accompanying famine and seasonal food shortages, sufficient evolutionary selective pressure has been applied to optimize feeding patterns for these boom and bust cycles [67]. Thus, the changes to mesoaccumbens dopamine signaling preceding compulsive feeding patterns can be seen as beneficial, diminishing satiety signals when the opportunity exists to consume energy-dense food, which would like to have been very scare to our forebears. This would enable the overconsumption of valuable calorie-dense food to take precedence over other activities and even in the present of satiety signals opposing such behavior. To maximize caloric intake during these phases of abundant food availability this behavior would not be directed toward all foods equally but rather would be targeted specifically to the most calorically dense items. It is interesting to speculate than an initial surge in mesoaccumbens dopamine signaling when particularly palatable food is first encountered may facilitate the emergence of such behavior.

The notable decrease in functional expression of D2 dopamine receptors as weight gain increases, which likely represents a compensatory adaption to excessive consumption of palatable energy dense food [22], plays an important role in the emergence of compulsive-like patterns of eating and is a response also seen in those with substance use disorders [7]. The mechanism(s) responsible for altered D2 receptor levels is currently unknown, and it will be interesting to investigate the role for circulating regulators of hunger, such as insulin, leptin, ghrelin, in this process [16–19]. Moreover, it is possible that modulating the activity of these hormones may reverse adaptive responses in D2 receptors and other targets in the brain and thereby reverse compulsive-like patterns of food intake. This is an intriguing possibility considering the well-known difficulties in influencing homeostatic feeding systems to regulate the hedonic and compulsive aspects of feeding [68]. What is certain is that deciphering precisely how the mesoaccumbens-striato-hypothalamus circuit is altered by excessive consumption of energy dense palatable food, and identifying mechanisms to reverse such adaptive responses, will be an important goal if obesity and related behavioral disturbances are to be effectively combated.

Highlights.

• The mesoaccumbens-striato-hypothalamus system integrates signals from central and peripheral regulators of energy status and food reward.

• Palatable energy dense food leads to dysregulation of striatal dopamine neurotransmission

• Disruptions to dopamine neurotransmission is associated with the emergence of compulsive eating patterns