What changes in neurobiology in substance abuse and addiction? - Chapter 8

In the United States, the lifetime prevalence of substance abuse and dependence is about 15% of the population. When tobacco is included in this estimate, it comes down to 45%. This prevalence has remained relatively stable over the past ten to twenty years.

Addiction is not always the same as dependence. An addiction is the result of specific neural changes that result from the use of drugs. These are drugs that affect dopamine activity in mesolimbic and mesocortical systems. Not all drugs that provide a dependency produce these neural changes. Alcohol, cocaine, amphetamine, opiates and tobacco do produce this, among other things.

Addiction can occur suddenly or it can develop over the years. The common threat in addiction is the pattern of destruction in the personal and family life of the addict. People with an addiction deny the pain they do to others as well as the negative financial and physical consequences that the addiction has. Alcohol addiction includes comorbid depression, bipolar disorder and anxiety disorders. Treatment of substance abuse is not often successful and is rarely completed on a first attempt.

How can an addiction be diagnosed?

The DSM-IV-tr makes no distinction between drug dependence and drug addiction. Drug addiction disorders are classified by the degree of deterioration and by the presence of tolerance and/or withdrawal symptoms. An individual can thus be dependent of a substance, without having a disorder. The diagnosis of a substance dependency disorder replaces a substance abuse disorder, where it is a requirement that the additional symptoms be present for a longer period of time. If this is not (yet) the case, then there is a substance dependency disorder.

Reward system of the brain

Not all behavioural and neurobiological characteristics of addiction are present in all cases of dependence. An important characteristic is the intense desire or the strong motivation to take drugs, despite the serious adverse consequences. This desire is often even present after years of abstinence. The critical difference between drug dependence and drug addiction is caused by neural changes that result from the use of certain drugs. The reaction of the brain, produced by addictive substances, is due to the effect of the drugs on the reward (reward pathway) of the brain. This system is an evolutionary change that helps to allocate hedonistic values ​​to stimuli. It also provides motivation for seeking sexual partners and for reproduction. The changes because of addictive drugs, benefit the reward system, which keeps the motivation going to search for drugs and to take them.

The critical neural structures where the path consists of: the nucleus accumbens and the ventral tegmental area (ventral tegmental area,  VTA). Research on this system originated by James Olds and his student Peter Milner in 1954. They experimented with electrical stimulation in the septum of rats.

The reward system consists of:

The mesolimbic dopamine system: VTA, medial forebrain bundle, amygdala, lateral hypothalamus and the nucleus accumbens.

The mesocortical dopamine system: VTA and prefrontal cortex.

Electrical stimulation, such as cocaine elicits, increases the availability of dopamine in the VTA and the nucleus accumbens. Natural energizers such as good food, sucrose solution and the availability of a sexual partner also provide this. It is therefore likely that certain drugs activate the same brain areas as these natural energizers and that this activation is correlated with positive feelings.

Drugs and reward roads

Drugs that indirectly (among others, heroin) and directly (e.g. cocaine) increase the dopamine activity in the VTA and the nucleus accumbens, need a high self-administration in laboratory animals. This self-administration consists of a large number of presses of the liver, after which a small amount of drugs end up in specific areas of the brain. However, the increase in dopamine activity in the mesolimbic structures is not sufficient to cause addiction. There are several hypotheses that explain why the speed of drug intake determines the addiction:

The faster drugs enter the brain, the more euphoria. Research has shown that when cocaine or heroin was administered intravenously, this evoked more euphoria than when an equally large dose was given intranasally. However, it appears that euphoria does play an important role in drug intake behaviour but that another factor contributes to the addictive effect of drugs.   

The psychomotor and stimulation sensitization are closely linked to the addictive effects of drugs. Psychomotor sensitization concerns the ability of drugs to increase locomotor activity and drug-seeking behaviour after repeatedly administering the drugs. These behavioural effects are easily conditioned and generated by the context in which the drugs are used. Incentive sensitization is the increase in the stimulating value of drugs and drugs-related signals. These two types of sensitization are caused by neural changes in mesolimbic areas that are the result of rapid drug intake.

Neurological changes after rapid delivery of drugs

Prolonged neural changes cause long-term behavioural changes after using drugs. These changes can probably be explained by drug-induced changes in the gene expression of dopaminergic neurons in the mesolimbic and mesocortical systems.

To find out how drugs can alter this gene expression of specific neurons, a lot of research has been done into inmediate early genes (IEGs). These are proteins that are activated by stimuli that activate intracellular signals. The IEGs activated by drugs can have a strong influence on dopaminergic cell function. An IEG that received a lot of attention because it is activated by addictive drugs is c-FOS. c-FOS proteins are transcription factors that promote synthesis of mRNA under the direction of DNA. This protein can be seen in response to various extracellular signals, including cocaine, amphetamine, nicotine and morphine. If cellular activity increases in response to a drug, c-FOS is seen in larger numbers.

Drug addiction is the result of permanent neural changes. These neural changes adjust the brain response to dopamine. The underlying mechanism for this seems to be activated by CREB c-FOS. c-FOS seems to coordinate the response of dopamine D1 & 2 receptors to repeated drug use by increasing the density and growth of dendrites. The D1 & 2 receptors play an important role in incentive and psychomotor sensibilization that result from the use of addictive drugs. The downregulation of the D1 & 2 receptors causes changes in mesocortical structures, resulting in reduced activity in the frontal lobes. This reduced activity stimulates drug-seeking behaviour without the cortical inhibition mechanism can regulate this behaviour. Addicts are also defined by the absence of impulse control, poor judgment, reduced risk avoidance and inadequate social behaviour.

How is drug addiction treated?

Addiction is one of the most urgent social problems in society. A better understanding of the neurobiology of addiction is therefore necessary for the development of new treatment methods. Many treatments are unsuccessful and the risk of relapse is very high. Treatment consists of (behavioural) therapy with medication. The drugs aim to mimic the effect of the drugs to dampen the desire and the withdrawal symptoms. Behavioural therapy focuses on problematic behavioural patterns and the social and environmental contribution to the use of drugs. There is currently no cure for drug addiction.

Immunization. One of the most promising approaches is preventing the drugs from entering the brain. Here you have two ways, passive and active immunization. Passive immunization means that cocaine is degraded with catalytic antibodies. However, the long-term effects has not yet been demonstrated. Active immunization is that a cocaine-protein inflection ('conjugate'), the formation of cocaine-specific antibodies, is stimulated. It is assumed that a cocaine molecule that sits on an antibody does not pass through the blood-brain barrier so that fewer drugs reach the brain. This effect has been demonstrated by various animal studies. The results of studies with people are mixed.       

Prevent relapse. During periods of stress or when exposed to drugs, the risk of relapse is high. Research has shown that projection of cortical neurons to the nucleus accumbens play an important role in this. For example, evidence has been found that glutaminergic neurons are projected from the prefrontal cortex to the nucleus accumbens. These neurons are activated during stress or when exposed to drugs and regulate the release of dopamine in the nucleus accumbens. Blocking the glutamate AMPA receptors in the nucleus accumbens and the activation of inhibitory glutamate autoreceptors prevent cue-induced drug seeking behaviour (in animals). Medications aimed at these receptors are under development. 

When does someone has an addiction?

To call something an addiction, there must be an underlying pattern of neural change that is similar to the pattern after repeated drug use. Although evidence has been found that video games, gambling and sexual activity increase the dopamine activity in the mesolimbic system, this is not sufficient reason to take an addiction to such behaviour.

Even when excessive playing of video games, excessive gambling and excessive sexual activity turns into compulsive and sometimes life-distorting behaviour, this cannot be called an addiction. Until science can describe the neural changes in the mesolimbic system that accompany these compulsive behaviours, there is little evidence that there is an addiction. This behaviour is maintained by a complex of empowering or motivating expectations and learned consequences.