Sugar influences brain reward circuitry in ways similar to those observed when addictive drugs are consumed

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The idea of food addiction is a very controversial topic among scientists. Researchers from Aarhus University have delved into this topic and examined what happens in the brains of pigs when they drink sugar water.

The conclusion is clear: sugar influences brain reward circuitry in ways similar to those observed when addictive drugs are consumed. The results have just been published in the journal Scientific Reports.

Anyone who has desperately searched their kitchen cabinets for a piece of forgotten chocolate knows that the desire for palatable food can be hard to control. But is it really addiction?

“There is no doubt that sugar has several physiological effects, and there are many reasons why it is not healthy. But I have been in doubt of the effects sugar has on our brain and behaviour, I had hoped to be able to kill a myth. ” says Michael Winterdahl, Associate Professor at the Department of Clinical Medicine at Aarhus University and one of the main authors of the work.

The publication is based on experiments done using seven pigs receiving two liters of sugar water daily over a 12-day period. To map the consequences of the sugar intake, the researchers imaged the brains of the pigs at the beginning of the experiment, after the first day, and after the 12th day of sugar.

“After just 12 days of sugar intake, we could see major changes in the brain’s dopamine and opioid systems. In fact, the opioid system, which is that part of the brain’s chemistry that is associated with well-being and pleasure, was already activated after the very first intake,” says Winterdahl.

When we experience something meaningful, the brain rewards us with a sense of enjoyment, happiness and well-being. It can happen as a result of natural stimuli, such as sex or socializing, or from learning something new. Both “natural” and “artificial” stimuli, like drugs, activate the brain’s reward system, where neurotransmitters like dopamine and opioids are released, Winterdahl explains.

We chase the rush

“If sugar can change the brain’s reward system after only twelve days, as we saw in the case of the pigs, you can imagine that natural stimuli such as learning or social interaction are pushed into the background and replaced by sugar and/or other ‘artificial’ stimuli. We’re all looking for the rush from dopamine, and if something gives us a better or bigger kick, then that’s what we choose” explains the researcher.

Both “natural” and “artificial” stimuli, like drugs, activate the brain’s reward system, where neurotransmitters like dopamine and opioids are released, Winterdahl explains.

When examining whether a substance like sugar is addictive, one typically studies the effects on the rodent brain. ¨It would, of course, be ideal if the studies could be done in humans themselves, but humans are hard to control and dopamine levels can be modulated by a number of different factors.

They are influenced by what we eat, whether we play games on our phones or if we enter a new romantic relationship in the middle of the trial, with potential for great variation in the data.

The pig is a good alternative because its brain is more complex than a rodent and gyrated like human and large enough for imaging deep brain structures using human brain scanners. The current study in minipigs introduced a well-controlled set-up with the only variable being the absence or presence of sugar in the diet.


Drug addiction can be defined as a chronically relapsing disorder, characterised by compulsion to seek and take the drug, loss of control in limiting intake, and emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) when access to the drug is prevented. From a diagnostic perspective, the term addiction is now encompassed by the term substance use disorders.

In 2013, DSM-51combined what was previously conceptualised as two separate and hierarchical disorders (substance abuse and substance dependence) into one construct, defining substance use disorders on a range from mild to moderate to severe, with the severity of an addiction depending on how many of the established criteria apply.

Although much of the early research with animal models focused on the acute rewarding effects of drugs of abuse, focus is shifting to the study of chronic drug administration-induced brain changes that decrease the threshold for relapse, which corresponds more closely to human imaging studies of individuals who have substance use disorders.

One of the main goals of neurobiological research is to understand changes at the molecular, cellular, and neurocircuitry levels that mediate the transition from occasional, controlled substance use to loss of control in drug intake and chronic addiction.2 

Because only some substance users make this transition, neurobiological factors that influence the diverse individual differences in drug responses have also attracted increasing interest. Cogent arguments have been made that addictions are similar to other chronic relapsing disorders—with individual differences in responses to the same exogenous challenges and limited effi cacy of treatment—such as diabetes, asthma, and hypertension.3

The purpose of this Review is twofold. First, we aim to elaborate a heuristic framework based on the neuropsychopharmacological and brain imaging phenotype of addiction in the context of three functional domains (incentive salience, negative emotional states, and executive function) mediated by three major neuro-biological circuits (basal ganglia, extended amygdala, and prefrontal cortex). Second, we aim to identify neurochemically defined mini circuits that can independently or interactively mediate functional neuroplasticity within the three major circuits to produce incentive salience and compulsive-like habits, negative emotional states of low reward and excessive stress, and compromised executive function.

Building on previous identification of the three overall domains, this Review provides a framework for integration of the ever-expanding neuroplastic complexity of motivational systems that are involved in addiction and for identification of new targets for diagnosis, treatment, and prevention of addiction.

Addiction can be conceptualised as a three-stage, recurring cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (craving)—that worsens over time and involves neuroplastic changes in the brain reward, stress, and executive function systems.46 Derived from a confluence of information from social psychology of human self-regulation failure, psychiatry, and brain imaging, these three stages provide a heuristic framework for the study of the neurobiology of addiction.4,5 A definition of impulsivity is “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others”.7 

A definition of compulsivity is the manifestation of “perseverative, repetitive actions that are excessive and inappropriate”.8 Impulsive behaviours are often accompanied by feelings of pleasure or gratification, but compulsions in disorders such as obsessive-compulsive disorder are often performed to reduce tension or anxiety from obsessive thoughts.8 

In this context, individuals move from impulsivity to compulsivity, and the drive for drug-taking behaviour is paralleled by shifts from positive to negative reinforcement (figure ​(figure1).1). However, impulsivity and compulsivity can coexist, and frequently do so in the different stages of the addiction cycle.8

Understanding of the neurobiology of addiction has progressed through the study of animal models10 and, more recently, through brain imaging studies in individuals with addiction. Although no animal model of addiction fully emulates the human condition, they permit investigations of specific signs or symptoms that are associated with the psychopathological condition.

If the model adequately mimics the phenomenology observed in humans as they transition from experimentation to addiction, then it is more likely to have construct or predictive validity.11 The phenomena under study can be models of different systems (genetic, epigenetic, transcription, cellular, and network), psychological constructs (positive and negative reinforcement), symptoms outlined by psychiatric nosology (craving, hypohedonia, and dysphoria), and stages of the addiction cycle.4 

Recently developed animal models take advantage of individual and strain diversity in responses to drugs, incorporate complex environments with access to and choices of alternative reinforcers, and test effects of stressful stimuli, allowing the investigation of neuro biological processes that underlie the risk for addiction and environmental factors that provide resilience against vulnerability. Animal models have also started to explore the influence of developmental stage and sex in drug response to better understand the greater vulnerability to substance use disorders when drug use is initiated in adolescence, and the distinct drug use trajectories that are observed in men and women.

The neurobiological mechanisms involved in the stages of the addiction cycle can be conceptualised as domains, with a focus on specific brain circuits, the molecular and neurochemical changes in those circuits during the transition from drug taking to addiction, and the way in which those changes persist in the vulnerability to relapse.12 Equally convincing, animal models of the specific stages of the addiction cycle can be paralleled by human laboratory models13 and studied with neuroimaging.14

Molecular and genetic treatment targets within brain circuits associated with addiction

The neuroplastic changes outlined previously are triggered and sustained by molecular and cellular adaptations that can presumably also interact with genetic and environmental vulnerability to addiction. In the binge/intoxication stage, both signal transduction mechanisms and changes in gene transcription have been identified. For example, chronic exposure to a wide variety of abused drugs upregulates cAMP formation, cAMP-dependent protein kinase A (PKA) activity, and PKA-dependent protein phosphorylation in the nucleus accumbens.

Numerous interventions that tonically activate nucleus accumbens cAMP/PKA signalling promote escalations in drug self-administration or compulsive-like drug-seeking behaviour, and the upregulation of a postsynaptic Gs/cAMP/PKA signalling pathway in the nucleus accumbens might constitute a critical neuroadaptation that is central to the establishment and maintenance of the addicted state.136,137

These changes in signal transduction can trigger longer-term molecular neuroadaptations via transcription factors that modify gene expression. A well characterised example is that chronic exposure to various drugs of abuse increases the activation of cAMP response element binding protein in the nucleus accumbens and deactivates it in the central nucleus of the amygdala.

Introduction of cAMP response element binding protein in the nucleus accumbens decreases the reinforcing value of natural and drug rewards, and this change plausibly contributes to withdrawal/negative affect stage-related decreases in reward pathway function, which leave a drug-abstinent individual in an amotivational, dysphoric, or depressed-like state.138,139 

These substance-related changes in susceptibility to negative emotional states might begin early: alcohol use during adolescence might lead to epigenetic modifications that alter amygdalar gene expression and dendritic density, increasing susceptibility to anxiety-like behaviours and alcohol ingestion in adulthood.140

Substance-induced changes in transcription factors can also produce competing effects on reward function.141 For example, repeated substance use activates accumulating levels of ΔFosB, and animals with elevated ΔFosB exhibit exaggerated sensitivity to the rewarding effects of drugs of abuse, leading to the hypothesis that ΔFosB might be a sustained molecular trigger or switch that helps initiate and maintain a state of addiction.141,142 

Next-generation sequencing methods have shown that repeated cocaine exposure leads to histone modifications that act in a combinational fashion to create chromatin signatures that strikingly alter pre-mRNA splicing, an effect that is necessary for the expression of cocaine-induced conditioned place preference.143

The heightened risk of cue-induced cocaine seeking (incubation of craving) that occurs during prolonged withdrawal (protracted abstinence in humans) has provided new insights into the molecular basis of vulnerability to relapse. During incubation in animal models, AMPA-type glutamate receptors are recruited. Specifically, the infralimbic medial prefrontal cortex-to-nucleus accumbens shell circuit recruits calcium-permeable AMPA receptors,144 and the prelimbic medial prefrontal cortex-to-nucleus accumbens core circuit recruits non-calcium-permeable AMPA receptors.

The blockade of metabotropic glutamate 1 receptors in the nucleus accumbens blocks cue-induced incubation reinstatement and cocaine-primed reinstatement; as a result, these receptors are potential therapeutic targets.145,146

The kinase mammalian (mechanistic) target of rapamycin complex 1 (mTORC1) belongs to the phosphoinositide 3-kinase (PI3K)-related kinase (PIKK) family and plays a key role in the dendritic translation of synaptic proteins. As such, mTORC1 plays a major role in the molecular mechanisms associated with learning and memory147 and is involved in several brain disorders, including epilepsy, Parkinson’s disease, Alzheimer’s disease, and addiction.148,149 Exposure to drug and alcohol cues activates the mTORC1 pathway in the hippocampus, frontal cortex, nucleus accumbens, and amygdala.149 

Even more compelling, blockade of the mTORC1 pathway systemically blocked the reconsolidation of cocaine memories,150 and blockade of mTORC1 in the amygdala blocked the reconsolidation of alcohol memories;151 these results suggest a potential molecular target for the treatment of relapse.

Heritability of addictions is 40–60%, much of which is caused by genetic variations that affect underlying neurobiological mechanisms, and thus is consistent with there being common pathways to different addictions.152 Genes have been identified that convey vulnerability at all three stages of the addiction cycle, and salient candidates are discussed within this conceptual framework. However, a more comprehensive analysis is beyond the scope of this Review. In the binge/intoxication stage, several genes have been identified in animals as key to drug responses, and their modifications strongly affect drug self-administration.37,153155

Notably, in animal models, dopamine D1 receptor knockout rats will not self-administer cocaine37 and μ opioid receptor knockout mice will not show the rewarding effects of opioids.153 In humans, only a few specific genes have been identified with polymorphisms (alleles) that either predispose an individual to or protect an individual from drug addiction,156 but the number is growing.

For example, genome-wide association studies have implicated two acetylcholine receptors, the α4 nicotinic receptor subunit157 and α5 nicotinic receptor subunit,158 in the vulnerability to nicotine dependence and a single-nucleotide polymorphism associated with regulating the trafficking and gating properties of AMPA-selective glutamate receptors (CNIH3) in opioid dependence.159

Some of the polymorphisms associated with vulnerability for the binge/intoxication stage interfere with drug metabolism. For example, specific alleles for genes that encode alcohol dehydrogenase (ADH1B) and acetaldehyde dehydrogenase (ALDH2; enzymes involved in the metabolism of alcohol) are reportedly protective against alcoholism.160 Intriguingly, an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1) has been identified in the ventral tegmental area.161 

GABA co-release is modulated by binge-like doses of alcohol administered to mice, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. Similarly, polymorphisms in the genes for cytochrome P450 2A6 and 2D6 (enzymes involved in nicotine and opioid metabolism, respectively) are reportedly protective against nicotine addiction.162

From the perspective of the withdrawal/negative affect stage, in humans, two single-nucleotide poly morphisms in the CRF1receptor gene (CRHR1) were associated with binge drinking in adolescents and excessive drinking in adults.163 Moreover, homozygosity at one of these single-nucleotide polymorphisms (rs1876831, C allele) was associated with heavy drinking in relation to stressful life events in adolescents.164

From the perspective of the preoccupation/anticipation stage, a genetic knock-in mouse that bio logically recapitulates a common human mutation in the gene for fatty acid amide hydrolase (C385A[Pro129Thr], rs324420) presented a reduction of fatty acid amide hydrolase expression associated with the variant allele that selectively enhanced fronto-amygdala connectivity and fear extinction learning and decreased anxiety-like behaviours; this result suggests another possible molecular genetic target for neuroplasticity in the preoccupation/anticipation and withdrawal/negative affect stages.165

Although such approaches do not guarantee that these genes convey vulnerability in the human population, they provide viable candidates for exploring the genetic basis of endophenotypes that are associated with addiction.


Source:
Aarhus University

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