The Deficits in the Neurobiology of Reward & Cognitive Control Systems in Addiction

In order to understand the effects of addiction, it is crucial to first comprehend exactly what addiction is. Addiction is a powerful thing; it takes over an individual’s life. Addiction consumes vulnerable individuals who need to repeat previous experiences of pleasure. Addiction to a drug is the most commonly thought of addiction. With drugs, recreational use develops into addiction when a “a fundamental motivational shift takes place whereby a drug is no longer taken to derive pleasure from it but to satiate intense craving and to relieve the distress of not having the drug” (Baler and Volkow, 2006). Addiction is an uncontrollable and compulsive urge for a drug. It encompasses a never-ending cycle of intoxication, withdrawal, and craving that ends in excessive use of the drug. Addiction is characterized by “(a) compulsion to seek and take the drug, (b) loss of control in limiting intake, and (c) emergence of a negative emotional state when access to the drug is prevented” (Koob and Le Moal, 2005). 

Addiction does not let up because of health and social consequences (O’Sullivan). According to neuroscientists, addiction is a chronic disease of the brain. The most important aspect of the disease is relapse. Features and signs of addiction include taking risks, making bad decisions, being insensitive to consequences, having surprising relapses, and refusing to admit the severity of the individual’s drug consumption. Many individuals that are addicted to drugs stop social, occupational, and/or recreational activities because of their dependence on their drug of choice. Repetitive drug use causes significant changes to the brain to occur, making cognitive intervention much more difficult (Baler and Volkow, 2006).

What is the neurobiology of reward reinforcement and cognitive control?

The control and reward areas of the brain are complicated domains. What makes addicts crave their drug of choice? What is the neurobiology behind the addiction cycle and reward and control systems? 

According to Berridge and Robinson in The Neural basis of Drug Craving: An Incentive-sensitization Theory of Addiction, the theory of drug cravings includes four major parts (1993). First, addictive drugs are able to stimulate the transfer of dopamine in an individual’s system. Incentive salience is a process that changes the way an individual can view a stimulus, making it seem more pleasurable than it really is. This leads into the second part of the theory that states that the systems of the brain apply the incentive salience to their drug of choice, making the way they see the drug much more attractive than the actual reality. Next, in some addicted individuals actual changes to the brain processes can occur, making them long-lastingly more vulnerable to wanting that certain drug – even if they are in a period of abstinence. Lastly, even if the individual no longer feels pleasure when taking the drug, they still feel the wanting and craving of the drug because the neural processes of the person have changed. The incentive salience might be the process that procures addictive behavior in individuals. 

What are the brain mechanisms behind this? The subcortical ventral striatum plays a role in the incentive salience a certain drug has on a person; this affects the wanting a person has for the addictive substance. The behavioral and emotional effects take place in the prefrontal cortex. 

Reward is an “operational concept for describing the positive/negative value that a creature ascribes to an object, behavioral act, or an internal physical state” (Schultz et al, 1997). There are natural and healthy rewards for an individual like food and sex. The natural reward system has been cracked; people have figured out how to stimulate the reward system with unnatural rewards. A study on rats in the 1950s where the rat was given electrical stimulation in certain brain regions, which has become the “brain reward circuitry” (Wise, 2005). The drugs that individuals use to complete this circuit affect the parts of the brain that the reward system exists in. The major parts of the brain that are included in processing reward-related stimuli are nucleus accumbens, ventral tegmental area, the striatum, hypothalamus, and the amygdala. The system elements majorly correlated in reward function are the dopamine systems of the brain and the incentivized salience of stimuli. The ventral striatum has been a larger focus in the study of addiction because it is the major spot where dopamine systems exist in the brain. In the ventral striatum, it’s not the actual dopamine being released; it is the anticipation and waiting for the dopamine and stimulus to enter the brain. The reward is delivered in subparts of the ventrial striatum and complete other parts of the brain, more specifically the insula and ventromedial and orbitofrontal cortices. Drugs up the release of dopamine in the nucleus accumbens, where the usual dopamine firing takes place but the process is sped up significantly. This mechanism is what signals reward.  Most drugs cause a fast and large dopamine in the midbrain areas, parts of the basal ganglia. Both of these parts of the brain are interconnected with reward, conditioning, and the formation of habits. Studies have identified a key involvement of the prefrontal cortex (PFC) both through its regulation of the reward system and its involvement in higher function, such as self-control. The motivation the user has for reward can be a driving force in their addiction; this can be attributed to striatal hypoactivity.

The cognitive control system is characterized by “a loss of control, difficulty in avoiding drug use in the presence of strong motivations (cravings) to consume” (O’Sullivan). Cognitive control includes inhibitory control, self-monitoring, attentional control, control over habits, and delaying gratification decision making. Most of the cognitive processes are considered to be the executive functions of an individual. Most of the cognitive control happens in the prefrontal cortex because most typically, it is executive function taking place. This system has been tested using individuals to perform tasks and activities like multitasking, task-switching, memory updating, response sequencing, monitoring, and manipulation (Garavan and Weierstall, 2012). Being the executive function center of the brain, the process of making decisions happens in the prefrontal cortex and the subcortical regions of the brain that are also involved in reward and motivation.  The majority of addicted individuals fail to self-regulate, resulting in dependence on addictive drugs. The drugs cause alterations to appear after drug use in the function parts of the brain. The dysfunction caused by drugs might impair normal cognitive function and inhibitory control over an individual’s behavior. This can lead to more judgment impairments and increased impulsivity (Berridge and Robinson, 2003).  For example, after an individual uses a drug for a long time, the implicit want for the drug can override the expectations of liking the drug or not. The implicit incentive salience that a drug gives a person outweighs anything else in their lives. The response inhibition of the user, or lack thereof, makes them unable to stop behavior even when the environment demands it. This salience can be attributed to hedonic and reinforcement processes that addictive drugs can give a dependent individual. 

What makes drug use cause deficits in the neurobiology of the reward and cognitive control systems?

There has been a recent shift in focus in research that now is putting the spotlight on chronic administration and the acute and long-lasting neuro-adaptive changes in the brain that can lead to relapse (Koob and Volkow, 2010). How does recreational drug use transform into the loss of control and to susceptibility to relapse? Understanding impulse control disorders and compulsive disorders is one of the aspects of drug addiction. Impulse control disorders are correlated with positive reinforcement. The disorder is when a person is experiencing an increased sense of negative emotions (tension, arousal etc.) before engaging in the act and during engagement experiences relief or pleasure. With compulsive disorders, an individual experiences stress and anxiety before committing the behavior and relief from said stress by engaging. Engaging in the impulsivity and compulsivity cycles leads to the addiction cycle. As the drug dependent individual falls deeper into their addiction, it relies on automaticity to release the compulsive feelings to drive the behavior. What in neurobiology causes these deficits where the individual is unable to perform cognitive control? Koob and Volkow performed a study and looked into the changes that were caused in the brain reward and stress systems due to prolonged drug use. “Many have argued that by means of associative learning, the enhanced incentive salience state becomes oriented specifically toward drug-related stimuli, leading to escalating compulsion for seeking and taking drugs” (Koob & Volkow, 2010; Kalivas & Volkow, 2005). Having to maintain the incentive salience state involves the activation of neural structures, leading to drug dependent individuals becoming susceptible to relapsing. 

The neuroadaptations from prolonged drug exposure are dependent on the drug as they can produce different results. It is also dependent on the stage of the addiction. When the frequency and amount of drug taken increases, this marks the transition to addiction. Another factor is when the individual moves from impulsivity to compulsivity, that is when the drug use goes from recreational and occasional to dependence and addiction. The behavior goes from impulsivity to compulsivity in a three stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation (Koob and Le Moal, 1997). There is a study that evaluates the studies down on the addiction cycle in human and animal clinical studies, which will show the deficits in research in human models and if the results from the animal models will be able to fill those gaps (Koob and Volkow, 2010). 

Through the study of animal models, it was found that in the Binge (or Intoxication) Stage, the brain stimulation of reward is spread across all of the neural circuits of the brain. It was found that all drugs reduce brain stimulation reward thresholds. Due to studying the binge stage, it was found that in addition to norepinephrine and dopamine, other non dopaminergic systems are involved in the stimulation of the brain’s reward system (Hernandez et al, 2006). The first stage of addiction tends to focus on the acute rewarding properties that a drug has on the brain, such as dopamine, opioid peptides, GABA, glutamate, neuropeptide Y and glucocorticoids (Koob and Le Moal, 2005). Each of these has a specific drug that is reinforced by it. Dopamine has an effect on psychostimulants, opioid peptide receptors reinforce opioids, and GABA and opioid peptides reinforce alcohol. Once a person becomes addicted to drugs, the natural reward system in their brain is significantly harder to fire and becomes less rewarding. The dopamine originates in the ventral tegmental area and then the nucleus accumbens and the extended amygdala, which makes the drug be able to reinforce the critical effects of the drug. Though most of the evidence from the animal models was found using self-administration tactics, the results from the clinical study of humans is more or less the same. Brain imaging studies in humans confirm that increases in dopamine from drugs that happen in the striatum are associated with reward, just like in the animal models. 

In the Withdrawal (or Negative Affect) Stage, the negative emotional states that stimulate the negative reinforcement processes are activated in the extended amygdala (Heimer and Alheid, 1991). This stage is the reduction of motivation for natural rewards. The extended amygdala has an important part in pain processing, more specifically the emotional factor of it. One of the main characteristics of this stage is that since dopamine systems are changed in the first stage of addiction, it can increase sensitivity to chosen drugs in this stage. Animal studies have shown that there is a reduced level of dopamine in the system, along with activity and serotonergic neurotransmission. There is also reduced activity in the other elements that are reinforced when a drug stimulus is produced: opioid peptide, GABA, glutamate, and neuropeptide Y in the extended amygdala and the nucleus accumbens (Koob and Le Moal, 2005). This low dopamine in the neural circuit can cause a reduced sense of motivation, which is one of the key elements of withdrawal. During the development of drug dependency anti-reward circuits start to happen, which is another example of a neuroadaptation. When the function of the reward system reduces and anti-reward systems start to form, that is when the compulsivity begins when it comes to taking drugs. It drives the cycle of addiction forward. This part of the cycle is produced by the anti-reward systems, making the only way to feel rewarded again is to take the drug again. In human clinical studies, the response to a drug withdrawal can differ significantly depending on the drug and amount of the drug a person takes. Some drugs, such as opiates or alcohol, can cause such severe withdrawal symptoms that they could be hazardous to an individual’s health, or potentially, fatal. Very few studies have been carried out on humans while they were experiencing these bad withdrawal symptoms. A study that had been done on a human did not reflect that the dopamine decreases happened in the nucleus accumbens, which had been reported to be true after a study on rodents. It is unclear whether this means that rodents and humans react to withdrawal differently or if the technology was not detailed enough to reflect what was happening in the human brain. 

After an addict experiences withdrawal, the next stage, Preoccupation (or Anticipation), comes into play. The preoccupation/anticipation (Craving) stage of addiction is the key element in the addiction cycle. This stage is when the individual starts to exhibit drug-seeking tendencies after the withdrawal from the drug. According to studies, this has been the hardest to measure. With deficits in the research for arguably the most key stage of addiction, it makes it hard to develop treatment and medications. Koob and Volkow, in Neurocircuitry of Addiction, found that in animal models craving can be separated into two groups. There is “drug-seeking induced by drug or stimuli paired with drug-taking and drug-seeking induced by an acute stressor or a residual negative emotional state, often a state of stress, termed protracted abstinence” (Koob and Volkow, 2010). In the human studies, it was determined that the heightened awareness of the conditioned cues is what elicits the anticipation in this stage of addiction. These conditioned cues can be as simple as emotional states; anxiety can be a hugely influential emotion used to generate a relapse in problem drug behavior. This is caused through awakening of the reward processing circuits of the brain, creating a ‘drug use reminder’ (Koob and Volkow, 2010). 

This stage of the cycle is the most difficult part, whether human or animal model, because even after the physical withdrawal symptoms disappear, the craving of the drug is still there because the brain circuits in the individual are telling them to want that drug. This has been a very challenging task as far as treatments go because of the actual deficit in research and evidence of effects in human models.  

This drug addiction cycle causes neuroadaptations in the brain and the circuit systems, changing behavior and function of the drug dependent individual as a result of a failing prefrontal system. The main deficit that addicts face is impulse control. Some addicts are unable to distinguish between small and immediate gratification rewards vs. larger rewards in the future. The majority of addicts opted for the immediate reward, suggesting that there are decision-making deficits in the frontal cortical regions of the brain (Koob and Volkow, 2008). Other deficits of drug addiction are memory and conditioned learning. 

What kind of deficits can these neuroadaptations cause in an addict?

Not only is addiction a “break with homeostatic brain regulatory mechanisms that regulate the emotional state of the animal... Leaving a residual neuroadaptive trace that allows rapid ‘readdiction’ even months and years after detoxification and abstinence” (Koob and Le Moal, 2008). The brain experiences a long-lasting effect of their reward circuits having reduced function, increase in anti-reward systems, and loss of cognitive control functions. These changes can have severe behavior impacts on the addict. Through a study reported by Canales on animals, evidence proposed that the neurogenesis in humans can become severed (2007). With deficits like this being caused in humans, how can treatment be approached? It was found that in order to attempt to regulate the hippocampus and other pairs of the brain, there needs to be a disruption in the memory formation of drugs and situations (Lee, 2008). 

Deficits in the Research of Reward and Cognitive Control Systems

Many factors can affect the results of an individual’s addiction making it very hard to pin down a specific answer on the outcome of the reward system in addicted individuals such as the choice of drug, the addiction severity, and what stage the addiction is at. Without transparent and constant data on the subject, there will continue to be deficits in the research of the reward circuitry. Even with specific data on animal models, the human model becomes a lot more complex due to outside factors such as environments and social groups. 

Even when studies are limited to a concentration on the frontal lobe, it is still difficult to conclude where the cognitive processes exactly take place in the frontal lobes. There are multiple regions that play a key role in brain memory and function. With new studies being conducted and conflicting data in animal vs. human models, it can be hard to focus on a result. With new evidence from the lack of inhibitory control in an addict even when it’s not relative to the studies of distracting stimuli in cocaine users it can be difficult to come to an exact conclusion (Dalley et al., 2007). 

Deficits in the Research on Addiction Recovery

One of the major features and the hardest problem to treat for addiction is relapsing. According to a well-known hypothesis, prolonged drug use causes brain adaptations (molecular, cellular, and neurochemical) (Hope and Shaham, 2005). These adaptations are behind many aspects of addiction, which includes being susceptible to relapse for a long time after exposure to prolonged drug use. In the study, The Role of Neuroadaptations in relapse to drug seeking, Shaham and Hope conclude that even though neuroadaptations caused by drugs are involved in relapse to seeking drugs, such as cocaine, based on the data they cannot come to the conclusion that these neuroadaptations are the main cause of relapse vulnerability. If clinical experiments and studies cannot explain what happens to the brain after dependent drug use, why does it not fully explain why drug-addicted individuals are so likely to relapse, if it’s not because of the neuroadaptations?

A substantial deficit in the research of addiction is the focus on addiction recovery in an individual. There tends to be a focus on studying what causes addiction over focusing on the recovery of the disease. This bias creates a lack of knowledge about how to stop addiction. It may be assumed that addiction recovery relies on reversing the changes that the drug caused the brain to make. This is a very ambiguous claim. Weierstall and Garavan propose in The neurobiology of reward and cognitive control systems and their role in incentivizing health behavior (2012) that there are numerous neurobiological mechanisms that play a role in recovery from addiction. They propose that it is more than reversing the effects of the drug on the brain. There are many more psychological processes involved. The prefrontal cortex is one of the central areas to focus on when tackling addiction.  

How can these deficits be addressed? Why are current research methods not providing the necessary information?

Most headway that has been gained in the study of neurobiology of addiction has used animal models. At least all the ones that include the administration (and self-administration) of different addictive drugs. Some drugs that have been studied using animal models include alcohol, nicotine, THC, stimulants, and opioids. While these models can provide insight into the complex subject of addiction, animal models are not the best way to study approaches to recovery (Garavan & Weierstall, 2012). When studying animals, the researcher is able to force the animal model to abstain from taking the drug. This provides a look into withdrawal effects and some brain activity, but it does not really provide an accurate depiction of what addiction recovery in humans would look like. The human addict is able to express willpower, or rather lack thereof, when participating in abstinence to their drug of choice, making relapse more common in humans. 

In Decision Making, Impulse Control and Loss of Willpower to Resist Drugs: A Neurocognitive Perspective, Bechara (2005) proposes that in future studies of addiction decision making should be looked into, prior to and post drug use. He argues that not every individual that tries drugs becomes dependent or addicted. Is there a predisposed quality or mechanism that some people have and others do not that makes them more sensitive to the risks of drug addiction? Can development of neurocognitive provide an indicator for risks of addiction in individuals? He provides testable hypotheses for researchers to test in future studies. 

What can be done about this lack of concrete evidence in human models? Obviously, it’s unethical and illegal to administer drugs to individuals but by conducting studies on addicts in different stages of their addiction and of all different drug type addictions headway will be made. It is clear that there are deficits in the research due to animal models not being able to give a clear view of the human condition in the sense of addiction.  

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