Problematic caloric intake is not only a core component of some eating disorders but also is linked to several public health concerns. For example, binge eating disorder, characterized by consuming a large amount of food in a short period with a behavioral loss of control over eating, can significantly impact overall health, quality of life, and healthcare costs (Ágh et al., 2016). Hyper-palatable foods (HPF), rich in sugar and fat, are the typically preferred foods consumed during these episodes (Leigh et al., 2018) and data suggest that individuals who engage in such problematic eating behavior are at higher risk for developing substance abuse, overweight/obesity, and worsening depressive symptoms (Ross and Ivis, 1999; Swanson et al., 2011; Skinner et al., 2012; Mehlig et al., 2018). Furthermore, substance use disorder frequently co-occurs with eating disorders (Bulik et al., 2004; Harrop and Marlatt, 2010), and a significant proportion of the college-aged population has been reported to engage in episodes of dysregulated drinking/eating, an experience that could trigger alcohol/drug abuse and numerous health concerns (Callas et al., 2004; Ferriter and Ray, 2011; Kelly-Weeder, 2011).

Converging research evidence suggests common neurochemical, behavioral, and physiological determinants of maladaptive eating and alcohol drinking (Fortuna, 2010; Morganstern et al., 2011; Nogueiras et al., 2012). For instance, feeding peptides, traditionally known for controlling appetite and energy metabolism, also regulate the intake and reinforcing properties of alcohol (Vadnie et al., 2014). It is also becoming apparent that hyper-palatable foods can interact with brain reward circuitry (Volkow et al., 2012), and changes in several of these neurochemical systems have been reported following HPF and alcohol intake (Barson et al., 2011; Volkow et al., 2012, 2017). For example, both food and drug reward stimulate DA release in the nucleus accumbens (NAc; Hernandez and Hoebel, 1988; Yoshimoto et al., 1992; Rada et al., 2005; Liang et al., 2006), and alterations in DA turnover and DA receptors gene expression have been reported following prolonged alcohol and HPF exposure (Hajnal and Norgren, 2002; Vasconcelos et al., 2003; Davis et al., 2008; Villavasso et al., 2019). Similarly, serotonergic (5-HT) neurotransmission is also implicated in mediating behavioral and emotional impairments following chronic exposure to alcohol and high-calorie diets (Kurhe and Mahesh, 2015; Zemdegs et al., 2016; Li et al., 2020; Popova et al., 2020). Together, these studies suggest that both hypercaloric foods and alcohol may affect central monoaminergic systems, and neuroadaptations in the mesocorticolimbic circuitry could mediate the effects of chronic HPF and alcohol exposure.

Impaired emotional status resulting from chronic alcohol exposure has been shown to promote escalated alcohol intake (Kissler et al., 2014). Considering that prolonged dysregulated eating of HPFs is capable of triggering negative emotional states (Cottone et al., 2009; Iemolo et al., 2012), excessive consumption of hyper-palatable food and resultant changes in neuroendocrine signaling along with negative affective states could trigger alcohol use disorder (AUD). Interestingly, some studies have suggested a bidirectional positive link between HPF intake and alcohol drinking (Pekkanen et al., 1978; Mitchell et al., 1985; Krahn and Gosnell, 1991; Avena et al., 2004; Carrillo et al., 2004). However, studies have also demonstrated reduced alcohol drinking following both sugar- and fat-rich palatable diets exposure (Yung et al., 1983; DiBattista and Joachim, 1999; Stickel et al., 2016; Takase et al., 2016; Cook et al., 2017; Gelineau et al., 2017; Sirohi et al., 2017b; Villavasso et al., 2019; Shah et al., 2020). It is important to note that several procedural/experimental differences among these studies could explain the differential impact of palatable diets on alcohol drinking and have been reviewed recently (Brutman et al., 2020). Briefly, some studies reported increased alcohol intake provided palatable diets in the acute or chronic manner and assessed alcohol drinking following palatable diets suspension (Pekkanen et al., 1978; Carrillo et al., 2004). On the other hand, studies from our lab provided intermittent access and evaluated alcohol drinking while rats were still maintained on intermittent palatable diet cycling (Sirohi et al., 2017b; Villavasso et al., 2019). Furthermore, hedonic fat or sugar consumption has been suggested to produce fundamentally different behavioral states (Avena et al., 2009). In this regard, a decrease in anxiety-like behavior has been reported by studies providing intermittent access to the high-fat diet in a non-consecutive manner (Mon, Wed, Fri; Sirohi et al., 2017b), whereas when a high-sugar diet was provided in an intermittent but on two consecutive days in a week, increase in anxiogenic behavior was reported (Cottone et al., 2009). In short, how hyper-palatable food overconsumption impact behavioral processes that regulate alcohol drinking is poorly understood.

While most of these studies provided rodent’s purified diets high in sugar or fat, typical dysregulated feeding episodes in the real-world involve hyper-palatable food rich in both fat and sweet. Therefore, the present study evaluated patterned feeding of real-world hyper-palatable food (Oreo double stuffed cookies) on alcohol drinking and monoamines (DA and 5-HT) levels in rat’s corticolimbic areas. Previously, we have shown that a 2-week of patterned high-fat diet pre-exposure is sufficient to reduce alcohol drinking in rats (Villavasso et al., 2019). Considering that the length and exposure history of a calorie-rich food can produce fundamentally different behavioral outcomes (Tracy et al., 2015; Krishna et al., 2016), alcohol drinking in the present study was evaluated following extended (three times a week for 10-weeks), patterned HPF administration. It was hypothesized that patterned feeding of hyper-palatable food would increase alcohol drinking by associated changes in the monoamines content in the brain reward circuitry.

The present study’s goal was to evaluate the impact of prolonged patterned feeding of hyper-palatable real-world food (Oreo double stuffed cookies) on alcohol drinking and alterations in the central monoamine levels. We found that HPF intermittent access induced patterned feeding and reduced alcohol drinking in rats. In addition, dopamine concentration was significantly elevated in the NAc of rats receiving patterned feeding of HPF compared to the chow controls. These data collectively suggest that patterned feeding of HPF reduces alcohol drinking, potentially by modulating dopaminergic neurotransmission in the brain reward circuitry in rats.

We and others have utilized an intermittent palatable diet access model to induce sustained bouts of caloric overconsumption and underconsumption, a hallmark of dysregulated/binge-like feeding behavior (Davis et al., 2007; Corwin and Babbs, 2012; Sirohi et al., 2017b; Villavasso et al., 2019). It is important to note that our intermittent feeding paradigm is distinct from ad libitum protocols that induce acute bouts of caloric overconsumption, which are not sustained and lead to an increase in body weight. In our paradigm, rats display sustained bouts of hyperphagia but no body weight gain; therefore, our results are not confounded by the presence of an obese phenotype. In the present study also, rats receiving intermittent access to Oreo cookies developed a feeding pattern of overconsumption on HPF access days (Mon, Tue, and Wed) and underconsumption on chow only access days (Thu and Fri; Figures 2A–E). It is possible that restricting access to palatable food could facilitate overconsumption of palatable food intake (Fisher and Birch, 1999); in fact, a previous study utilizing a similar approach reported an escalation in overconsumption following renewed access to a palatable diet over a 5 weeks period (Cottone et al., 2009). While the caloric intake in the present study was significantly higher on the first day of renewed HPF access compared to the second and third days, no escalation in this feeding behavior was seen over a period of 8 weeks (Figures 2A,B). We also evaluated average weekly caloric intake on Oreo access days across 8 weeks and found no evidence of escalated feeding behavior.

Preference for a high-sugar or high-fat diet under acute abstinence conditions (24 h following termination of HPF cycling) was also examined. While HFD was preferred over HSD by both chow and Oreo groups, there was no between-group difference in caloric intake (Figures 3A–D), suggesting that HPF’s patterned feeding did not induce a compulsive feeding phenotype. In the present study, rats in the experimental group had a choice between chow and Oreo cookies, which was not the case in Cottone et al. (2009) where animals in the intermittent access group had access to a palatable diet only during binge episodes and displayed compulsive feeding behavior. It is important to note that free choice palatable diet access mimics real-world situations to model neurobiological and behavioral consequences of overconsumption of palatable diets, which could differ if the palatable diet is provided as the only choice (Slomp et al., 2019).

Both animals and human studies have shown that disordered eating behavior shares many similarities and neurobiological characteristics of alcohol and substance use disorders (Cottone et al., 2009; Gearhardt et al., 2009; Volkow et al., 2012) and individuals who engage in such problematic eating behavior are at higher risk for developing alcohol use disorder, overweight/obesity, and worsening depressive symptoms (Ross and Ivis, 1999; Swanson et al., 2011; Skinner et al., 2012; Mehlig et al., 2018). Considering that hyper-palatable food is typically consumed during dysregulated eating episodes and activate similar brain reward circuitry as of drugs of abuse, including alcohol, several studies have examined the impact of overconsumption of palatable diets on alcohol (Pekkanen et al., 1978; Yung et al., 1983; Mitchell et al., 1985; Krahn and Gosnell, 1991; DiBattista and Joachim, 1999; Avena et al., 2004; Carrillo et al., 2004; Stickel et al., 2016; Takase et al., 2016; Cook et al., 2017; Gelineau et al., 2017; Sirohi et al., 2017b; Villavasso et al., 2019). While still unclear, many studies have observed a reduction in alcohol drinking (Pekkanen et al., 1978; Forsander and Sinclair, 1988; DiBattista and Joachim, 1999; Takase et al., 2016; Cook et al., 2017; Gelineau et al., 2017; Sirohi et al., 2017a,b; Constant et al., 2018; Villavasso et al., 2019; Shah et al., 2020). Paradoxical effects of HPF feeding on alcohol drinking could be attributed to palatable diets with different macronutrient compositions (high-fat or high-sugar), palatable diets exposure duration (acute, intermittent, or chronic), and alcohol testing conditions (Brutman et al., 2020). It is important to note that majority of these studies utilized commercially available purified diets high in sugar or fat. Therefore, the impact of binge-like intake of a real-world hyper-palatable food on alcohol drinking remained to be investigated and was the primary goal of the present manuscript.

In order to examine the impact of withdrawal from an extended intermittent palatable diet exposure on alcohol drinking, alcohol intake was evaluated on chow access days following 10 weeks of patterned HPF feeding. Interestingly, rats in the chow group displayed acute deprivation-induced escalated alcohol drinking (24 h) on renewed access to alcohol (Thursday), which gradually reduced to baseline levels over 3 days (Figures 4A,B). On the other hand, rats in the Oreo group were not only protected from this effect but also their 24 h alcohol intake gradually decreased, with significantly decreased alcohol drinking observed on the 4th and 5th week of alcohol testing (Figures 4A,C). Furthermore, 2 h alcohol intake (Figures 4D) was also significantly reduced in the Oreo group of rats accompanied by gradually reduced alcohol preference (Figure 5F). While we predicted that such prolonged cycling of HPF would increase alcohol drinking, surprisingly, alcohol drinking was significantly gradually reduced in the Oreo group of rats. These data are consistent with previous studies from our lab in which reduced alcohol drinking was observed following patterned feeding of a high-fat diet (Sirohi et al., 2017b; Villavasso et al., 2019). While blood alcohol levels were not assessed in the present study, a previously published study (Sirohi et al., 2017b) from our lab using Long Evans rats reported pharmacologically relevant blood alcohol levels (~25 mg/dl) following similar alcohol intake.

It has been suggested that withdrawal from fat and sugar produce fundamentally different behavioral states (Avena et al., 2009). On macronutrient levels, Oreo cookies are composed of 24% Calories from fat and 72% Calories from carbohydrates, of which 45% Calories were derived from sugar. On the other hand, high-fat diet previously used in our paradigm consisted of 40% Calories from fat and 46% Calories from carbohydrates, of which 7.9% Calories are derived from sugar (Sirohi et al., 2017a,b; Villavasso et al., 2019; Shah et al., 2020). Surprisingly reduced alcohol drinking behavior following patterned feeding to both Oreo cookies and high-fat diet suggests a role of palatability rather than macronutrient composition in reduced alcohol drinking following patterned feeding of HPF as reported by a recent study from our lab (Shah et al., 2020).

While reduced alcohol drinking was observed at least until 72 h following the suspension of the HPF, it was unclear how long this effect would last. To address this question, we suspended patterned HPF cycling and carried out alcohol testing exactly as done earlier on chow only access days (Thu, Fri, and Sat). Interestingly, alcohol drinking in the Oreo group of rats increased compared to the last alcohol drinking session and was not significantly different from chow controls (Figure 6B). These data are similar to what we had reported recently when alcohol drinking gradually increased to the level of chow controls within a week following intermittent high-fat diet suspension, suggesting that acute availability of a palatable diet is critical to observe reduced alcohol drinking behavior (Villavasso et al., 2019). In this context, an alternative explanation of reduced alcohol drinking following patterned feeding of a palatable diet could be the caloric overload before alcohol testing as a contributing factor in reduced alcohol drinking. However, previous studies from our lab have repeatedly shown that reduced alcohol drinking following patterned high-fat diet feeding is seen on days when rats did not restrict calories voluntarily (Sirohi et al., 2017b; Villavasso et al., 2019). On a similar note, alcohol drinking was gradually reduced over 5 weeks on a patterned HPF feeding cycle, whereas this behavior disappeared within a week following HPF suspension. Importantly, when tested under similar conditions, feeding peptides remained unchanged following patterned feeding of a high-fat diet (Villavasso et al., 2019). These data collectively suggest that energy homeostasis mechanisms are less likely to drive reduced alcohol drinking following patterned HPF feeding.

This notion also aligns with the data from a recent study from our lab in which selective alterations in the neurotransmitter receptors gene expression was observed in the brain reward circuity compared to the brain region involved in energy homeostasis following patterned feeding of a palatable diet (Villavasso et al., 2019). Mesocorticolimbic dopamine neuronal connectivity from VTA to NAc is highly implicated in food and drug reward processing (Wise, 2006), and palatable foods rich in fat and sugar increase extracellular dopamine in the NAc similar to drugs of abuse (Hernandez and Hoebel, 1988; Rada et al., 2005; Liang et al., 2006). While studies have reported blunted DA release following repeated/chronic palatable food/solution exposure, limited/intermittent access to sugar and fats repeatedly triggers increased DA release in the NAc (Bassareo and Di Chiara, 1997; Rada et al., 2005; Liang et al., 2006). Similarly, increased DA turnover and enhanced behavioral responses to psychostimulants have been registered following intermittent/restricted access to palatable diet (Hajnal and Norgren, 2002, but see Moore et al., 2020). However, prolonged intermittent or chronic access to palatable diets have been shown to reduce extracellular DA levels in the NAc, referred to as deficits in the mesolimbic dopamine neurotransmission (Geiger et al., 2009; Fordahl et al., 2016). While their extracellular DA levels were low, rats in the intermittent palatable diet group display increased behavioral sensitization and a greater increase in extracellular levels following the psychostimulants challenge (Fordahl et al., 2016). These effects are hallmarks of a hypodopaminergic state at baseline with an overactive dopamine system in response to external stimuli—largely due to greater dopamine availability as a result of enhanced synthesis (Mathews et al., 2009; Karkhanis et al., 2016, 2019).

Although it is unclear if extracellular levels were different, the present study found greater DA and attenuated DOPAC levels selectively in the NAc homogenates of the Oreo group compared to the chow controls rats (Figure 7A). It is possible that increased NAc DA availability in the Oreo group of rats promotes heightened sensitivity to the intoxicating effects of alcohol in the Oreo group of rats, thereby reducing the amount of alcohol needed to achieve a state similar to the chow controls, a hypothesis that needs further investigation. Since rats in the Oreo group were voluntarily restricting calories on alcohol testing days, reduced alcohol intake could reflect enhanced reward sensitivity. It is important to note that brain sections were collected on chow only access days ~24 h following patterned palatable food intake ended and >100 h following termination of alcohol drinking. While animals had no access to alcohol on that day, previous alcohol testing occurred under identical conditions on the chow only access days. Since both alcohol anticipation and ingestion increase extracellular DA levels in the NAc (Weiss et al., 1993), increased DA content in the NAc could reflect anticipation of alcohol reward. Future studies are needed to precisely understand the role of mesolimbic DA neurotransmission in regulating alcohol intake following this paradigm. Future studies are also needed to identify any sex differences in the impact of patterned feeding of HPF on alcohol drinking.

In conclusion, the present study identifies that patterned feeding of hyper-palatable food reduces alcohol drinking in rats, and alterations in the dopaminergic neurotransmission within mesolimbic circuitry could mediate reduced alcohol drinking behavior following patterned feeding. These data are consistent with previous studies from the lab and systematically replicates reduced alcohol drinking following patterned feeding a palatable high-fat diet and extend these observations to real-world food.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The animal study was reviewed and approved by Institutional Animal Care and Use Committee guidelines at the Xavier University of Louisiana.

SS was responsible for conceptualization, funding acquisition, methodology, investigation, and formal analysis. SS, ZL, and KS conducted feeding and alcohol drinking experiments, wrote original draft and final version of the manuscript. LB and AK conducted HPLC analysis and wrote corresponding sections. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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