• Non-drug addictions are defined as excesses in otherwise normal behaviors such as shopping, eating, exercising, sexual behavior, and gambling.[1] Of recent interest is food addiction, which has been closely associated with obesity. Obesity is a growing health epidemic in developed countries, characterized by excessive eating behavior and high BMI. 65% of adults are classified as obese or overweight.[2] Despite high prevalence, explanations pertaining to the underlying causes of excessive eating associated with obesity remain limited. However, there is increasing evidence suggesting an etiological basis of obesity as resultant of food addiction .[3] Food addiction represents a new type of “behavioral addiction,” that mimics the neural functioning associated with substance dependence. [4] Numerous clinicians, including those that are revising the DSM-5, have appreciated this.[5] Therefore, in order to understand the basis of food addiction, it is necessary to examine the neurochemical, hormonal, anatomical and molecular correlates characteristic of drugs-of-abuse as a proxy for food addiction.



This video represents one of countless media segments on food addiction.


Dopamine

  • DSMIVTR
    Despite the clinical attention on drugs-of-abuse, the most salient features of non-drug addictions still qualify as maladaptive as per the DSM-IV-TR: "substance dependence is defined as maladaptive substance use leading to clinically significant impairment or distress".
    Dopamine (DA) is the most pertinent neurotransmitter involved in feelings of reward associated with addictive behavior.[6] It is synthesized in dopaminergic nerve terminals from a precursor tyrosine after entrance via a tyrosine pump. DA has been implicated in attention, arousal, conditioned learning and motivation.[7] High volumes of D2 dopaminergic neurons are found in the reward centers of the brain: the orbitofrontal cortex, amygdala, insula, anterior cingulate cortex, and the dorsolateral prefrontal cortex. It is in these regions of the brain wherein DA is a pivotal component in addictive behavior. [8]

Dopamine and Food Addiction


  • DA has several roles in both the type of food we choose to eat and the motivation for seeking food. It is also responsible for the subjective feelings of reward following consumption.When activated, dopamine receptors give rise to the pleasant feelings associated with food consumption; when not stimulated, it motivates food seeking behavior.[9] Drugs are known to mimic this system, making the user feel pleasant when using and craving when not. Excessive food consumption works in a similar way, resulting in prolonged plastic changes in DA responsiveness.[10]

  • Much like substance dependent individuals, DA plays a large role in the addictive feeding of the obese. Placed under an fMRI, obese individuals exhibit blunted dopaminergic release and report weaker subjective feelings of reward than healthy control.[11] This suggests a fundamental change in neurochemical function, altering overt behavior. Thus, obese individuals may overeat as a means of compensating for lack of subjective reward, much like a cocaine addict consumes larger subsequent doses. The danger of this compensatory feeding behavior is exacerbated by decreased D2 receptor availability with increased BMI.[12] This is likely the result of the same D2 receptor downregulation akin to substance abuse addicts.[13]

  • Craving and relapse behavior can also be seen in obese and substance dependent individuals. Relative to healthy controls, the site of appetizing foods to obese individuals activates the mesocorticolimbic pathway and extended amygdala, key areas implicated in the craving of drugs of abuse.[14] fMRI studies also reveal increased activity of D2 receptors in the left anterior cingulate cortex, left medial orbitofrontal cortex, left amygdala, right dorsolateral prefrontal cortex, and right caudate in anticipation of intake of palatable food in obese individuals.[15] This activity suggests that cues associated with substance use (in this case, food), can trigger DA release and initiate consumption behavior.[16] Moreover, this DA-mediated activity elicits a subsequent feeling of reward and adjusts the saliency of anticipated reward. [17]

  • prp.gifFluctuations in DA levels result in behavioral changes in obese individuals that mimic substance dependence. PET scans of obese individuals have revealed alterations in DA receptor expression.[18] Much like those with substance dependence, obese individuals experience intense withdrawal upon high-fat food restriction. Cessation of high-fat foods is associated with increased emotionality, stress, and corticotrophin releasing factor (CRF) in obese individuals.[19] As a result, there is an increase in subsequent palatable food consumption, which alleviates stress and decreases circulating CRF levels but increases excessive feeding.[20] This greatly contributes to the cross-time stability of obesity. Moreover, it explains the high dietary relapse rate associated with obese individuals.[21]






Insulin

  • Insulin signalling plays a pivotal role in regulating blood glucose levels and reporting information regarding energy stores to the hypothalamus and striatum. In the central nervous system (CNS), insulin enters from the periphery by active transport across the blood brain barrier, wherein it regulates homeostatic feeding, reward based high-fat feeding, and metabolic status. [22] [23] It is here where insulin influences behaviors via its interactions with DA, such as learning, memory, appetite, arousal, and mood. Thus, disorders in insulin function, which are often characteristic of obese individuals, may contribute to "disorders of the brain" where dysregulation of the DA neurotransmitter system is implicated. [24]

Insulin, Dopamine, and DAT
Downsteam connection of Insulin via Tyrosine Receptor Kinase on DA and DAT receptor function through PI3K and AtK http://vrn.vanderbilt.edu/2010/CandidateReviews/siutafull.html
Downsteam connection of Insulin via Tyrosine Receptor Kinase on DA and DAT receptor function through PI3K and AtK http://vrn.vanderbilt.edu/2010/CandidateReviews/siutafull.html

  • Insulin and DA operate in orchestra to modulate the motivation to engage in consummatory behavior and calibrate associated levels of reward.[25] . In a normal brain, insulin is highly instrumental in DA rich regions of the brain for maintaining homeostasis and normal reward for food. Individuals with a food addiction experience disordered insulin function, exacerbating their addictive tendencies. More specifically, it is suggested that the regulatory effects of insulin are disordered in obese individuals because of DA overriding metabolic signals that regulate homeostatic food consumption.[26] This disruption is based on the relationship between insulin and the DA transporter DAT.

  • DAT is a high affinity transporter for the neurotransmitter DA. It controls the strength and duration of DA activity in the synapse.[27] Recent clinical investigations using animal models have uncovered that even modest perturbations in insulin acting on tyrosine receptor kinases (i.e. insulin resistance resultant of a high fat diet) interferes with PI3K and subsequent Akt signalling. Thus, in obese individuals, insulin signalling via insulin receptors and PI3K, and DA receptors via D2 receptors may be perturbed in their regulation of DAT plasma membrane expression, function, and trafficking.[28] As a result, DA remains in the synapse, causing excessive craving and motivation to seek food. Coupled with the overriding effect of DA on metabolic signals (such as satiation), the result is a vicious cycle of over-eating and craving.[29] Moreover, this DA activity also fosters intense feelings of withdrawal in the absence of food[30] , causing stress that can result in additional pathologies. The result is the activation of a molecular pathway that elicits feeding behaviors not unlike those of amphetamine abusers.[31]



Molecular Correlates


  • Food addiction is associated with long-term behavioral changes like those of drug addiction. This suggests a long-term alteration in neuronal function, particularly in the striatum. Thus, in order to garner a more polished understanding of the excessive eating of the obese beyond dopamine and insulin (and to a great extent, food addiction), one must also examine the molecular correlates therein.[32]

ΔFosB
deltfosB.jpg
Stark increase in ΔFosB following consumption of high-fat foods


  • ΔFosB (a truncated form of FosB) is a transcription factor that can be induced in the brain's reward centers by drugs-of-abuse (i.e. cocaine or amphetamines).[33] Interestingly, similar molecular dynamics can be seen in the obese. In obese mice, 4-week exposure to a high-fat diet resulted in a significant increase in ΔFosB, influencing molecules involved in long-term expression and encouraging subsequent feeding behavior.[34] It also resulted in greater subsequent consumption. This suggests that in obese individuals, the same ΔFosB increase may occur after prolonged excessive eating and associated reward. It also suggests that ΔFosB may be involved in the persistent motivation to feed despite negative consequences.[35] This animal model exhibits a potential explanation behind the extreme motivation to eat felt by the obese on a molecular level. Moreover, it also underscores the parallels between food addiction, substance abuse, and reward attenuation.


pCREB


  • pCREB (phosphorylated cAMP response element binding protein) is also a factor commonly found in neural cell nuclei. However, unlike ΔFosB, increased pCREB activity follows withdrawal from drugs-of-abuse.[36] Interestingly, dopamine receptor activation leads to the phosphorylation of CREB. More specifically, downstream signalling through this pathway leads to changes in gene expression associated with reward and addiction. [37]

  • In the same animal study investigating ΔFosB, mice that were withdrawn from a high-fat diet exhibited increased levels of pCREB 24-hours and 1-week after withdrawal. This reduction of pCREB specific to the striatum was accompanied by increased CRF, a state of hyperarousal, and greater fecal boli in the open field test.[38] Contrarily, pCREB was restored after mice were returned to their high-fat diet. This change in pCREB volume, coupled with increased anxiety-responses in behavioral assays and pCREB levels illustrates the highly salient reward associated with continued food consumption.[39] Moreover, it exhibits a fundamental molecular correlate behind the stress of withdrawal in the striatum and extreme motivation to eat. Understanding the dynamics of pCREB can greatly assist in understanding the molecular underpinnings of withdrawal in the obese.


PCREBABC.jpg
Levels of pCREB at 4-weeks on high-fat diet (A), 24-hours after diet restriction (B) and 1-week after restriction(C) as revealed by Western Blot analysis


The Amygdala


  • One of the more obvious plastic responses in food addiction is the structural and functional changes in the lateral amygdala. In obese individuals, there is a marked difference in the activity of the lateral amygdala in anticipation of food relative to normal controls. More specifically, obese individuals exhibit hyperactivity in the lateral amygdala relative to healthy controls; this behavior is similar to the anticipatory activity of smokers.[40] Increased amygdala activity also correlated with the results of the Yale Food Addiction Scale (YFAS)[41] ; obese individuals with increased activity in the lateral amygdala also exhibited intense palatable food dependence.[42] Coupled with the role of DA in the motivation to continuously eat despite negative consequences, the amygdala may also form emotional memories associated to excessive eating, contributing to maladaptive cross-time stability.[43]




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