Читать книгу The End of addiction - Dr Volker Hitzeroth - Страница 9

Historically, society believed that substance-related problems were associated with “moral degenerates” and “social misfits”. More recently, however, advances in technology and research have identified much of the neuroscience behind the addiction process. These findings suggest that drug use and drug dependence are neurobiological processes within the brain itself, rather than simply “bad people” making “bad choices”. Such research has contributed to the development of the “disease model of addiction” hypothesis. This evidence leaves no doubt that addiction can be classified as a brain disease, similar in many ways to Parkinson’s disease or even other chronic illnesses like diabetes mellitus and high blood pressure.

The past decade or two have provided us with a more coherent understanding of the addiction process. Researchers are also able to identify the neurological centre responsible for pleasure and reward. This brain centre is critical when it comes to the pleasurable experiences associated with drug and alcohol abuse. Any understanding of drug and alcohol use and abuse has to start with a basic understanding of the neuroscience behind pleasure and reward. Knowing what goes on in the brain helps us to understand why people use, abuse and become dependent on drugs. We may even come to appreciate why people use a drug in larger amounts and over a longer time than was intended, why any attempt to reduce or control drug use is difficult, why so much time, effort and money is spent to obtain drugs, why important activities are neglected and why drug users continue using the substance despite knowing that it may be causing physical and psychological problems.

Our brain is made up of different cells. In fact, there are four different types of brain cells. These are neurons (nerve cells), astrocytes, oligodendrocytes and ependymal cells. Each cell type has a different function. We are primarily interested in the neurons, which are responsible for the transmission of nerve impulses throughout the body and brain and hence for the communication function of the brain. Neurons use electrical and chemical impulses to communicate signals from one part of the brain or body to another. The vast amount of communication that happens throughout our body every second has necessitated the formation of certain larger neuron pathways in order to facilitate easier signal transmission across different parts of the brain and nervous system.

In order to communicate effectively the body makes use of many different chemical substances, all with different functions. The most common chemical neurotransmitters in the brain are dopamine, serotonin, noradrenalin, glutamate, GABA (gamma-aminobutyric acid) and acetylcholine, among many others. Each of these chemical neurotransmitters is used by a particular type of cell; dopamine by dopaminergic neurons and serotonin by serotonergic neurons, for example. It therefore follows that we have not only dopaminergic cells, but also dopaminergic pathways where the majority of dopaminergic cells cluster together to facilitate dopaminergic communication throughout the brain and nervous system. Of course, there are also serotonergic, glutaminergic and many other chemical pathways, too.

When we study pleasure and reward scientifically we are primarily interested in dopamine. Recent research indicates that dopamine is the primary neurotransmitter responsible for pleasurable and rewarding experiences. Dopaminergic neurons and pathways are clearly also of importance in the neurobiology of pleasure and reward (and also addiction and dependence). All neurotransmitter pathways start at some point in the brain and end at another point within the nervous system. In between they pass through relay stations which are called nuclei. Each nucleus has a different name and function. (The system can be compared to a railway line starting in Cape Town and ending in Pretoria, with numerous train stations in between.)

Initially, researchers identified four different dopaminergic pathways spread throughout the brain. These were:

1 The nigrostriatal dopaminergic pathway which starts in the substantia nigra and projects to the striatum.

2 The mesolimbic dopaminergic pathway which starts in the ventral tegmental area (VTA) and projects to the nucleus accumbens.

3 The mesocortical dopaminergic pathway which starts in the ventral tegmental area and projects to the prefrontal cortex.

4 The tuberoinfundibular dopaminergic pathway which starts from the hypothalamus and projects to the anterior pituitary gland.

More recently two more dopaminergic pathways have been identified. These are:

1 The thalamic dopaminergic pathway.

2 The insertohypothalamic pathway.

Of these six pathways it is the mesolimbic pathway that has been associated with pleasure, motivation and reward. It is for this reason that the mesolimbic pathway has also been implicated in addictive behaviour.

The mesolimbic pathway starts in the ventral tegmental area (VTA) of the brain stem. This is a very deep-seated and early brain structure. From the VTA the pathway projects to the nucleus accumbens in the ventral striatum, which is part of the limbic lobe of the brain (also a deep-seated, primitive, early brain structure). When dopamine is released in the nucleus accumbens, pleasurable sensations are experienced. This pathway has therefore been called the “pleasure pathway” of the brain. Stimulating it will release dopamine and make us feel good, happy and rewarded. It may also make us want to repeat the behaviour in order to re-experience such pleasurable feelings.

In our natural world such normally occurring pleasurable experiences include eating a tasty meal, drinking a good wine, sexual activity, winning a race, receiving praise and recognition, as well as listening to beautiful music or reading an interesting book. All of these activities release dopamine in the nucleus accumbens, and therefore are inherently pleasurable. It is for this reason that we generally feel good, happy and motivated when we experience these normal and naturally rewarding experiences.

The mesolimbic pathway is influenced by numerous different neurotransmitters and their pathways. A specific part of the brain that also influences this “pleasure pathway” is the amygdala, which plays an important role in controlling and modulating emotions.

Figure 3.1 The pleasure pathway

Interestingly, the brain already has a number of chemical substances that naturally stimulate the dopaminergic mesolimbic pathway. Our brain has thus developed natural systems to make us feel good. These natural chemical substances include the following:

1 Dopamine itself, which can generally be said to be the equivalent of amphetamine and cocaine.

2 Acetylcholine, which is equivalent to nicotine.

3 Anandamide, the equivalent of cannabis.

4 Numerous endorphins that are equivalent to opioids (and thus heroin).

It is these brain chemicals that make us feel good when we engage in naturally pleasurable activities. Various naturally occurring drugs do this through a number of different mechanisms, but they all ultimately seem to result in the stimulation of dopamine in the nucleus accumbens. Similarly, all drugs of abuse ultimately influence the mesolimbic dopaminergic pathway either at its beginning, along its projection or at its end. All drugs of abuse somehow increase dopamine release along this pathway with subsequent feelings of pleasure, satisfaction and reward (the so-called drug-induced high). It is for this reason that the mesolimbic pathway is often referred to as the “final, common pathway” of pleasure and reward.

Specific drugs and their effect on the pleasure pathway

Opioids

The opioid system is a naturally occurring system in our brains and bodies. The naturally occurring opioids are called endorphins and they are released from the arcuate nucleus and project to the VTA and the nucleus accumbens. Natural (and external) opioids act on three types of receptors, namely the mu, delta and kappa receptors. The mu receptor is primarily responsible for the pleasurable experiences associated with opioid use. External opioids like heroin or codeine-containing pain medications also act on the mu receptor. Through a complicated neurobiological cascade opioids increase dopamine in the mesolimbic pathway, which is the final common pleasure pathway. Subsequently, there is a feeling of pleasure and reward.

Amphetamines

The amphetamine group of drugs has a more direct effect on dopamine in the VTA and nucleus accumbens. They cause dopamine to be released from specific neurons in the pleasure pathway, resulting in an increase in the dopamine levels with subsequent feelings of pleasure and reward. (It should, however, be remembered that some amphetamines have effects on other neurotransmitter systems in the brain, including the serotonergic, noradrenergic and GABA systems. You will also recall that ecstasy has some serotonergic/hallucinogenic effects as well.)

Figure 3.2 Natural and drug influences on the pleasure pathway

Cocaine

Cocaine also has a more direct effect on dopamine release in the mesolimbic pathway. While amphetamines release dopamine directly, cocaine generally inhibits the reuptake of dopamine once it has been released. Due to this inhibition, dopamine cannot be removed from the particular neural space and the levels of dopamine rise, causing a pleasurable and rewarding experience. Like amphetamines, cocaine also affects other neurotransmitter systems in our brain, such as the serotonergic, noradrenergic and GABA systems.

Nicotine

The nicotine inhaled when smoking cigarettes affects the acetylcholinergic system through specific nicotinergic receptors. Nicotine specifically interacts with two important cholinergic receptors. These are the alpha-4-beta-2-nicotinic acetylcholine receptor and the alpha-7-nicotinic acetylcholine receptor. When external nicotine enters the body, it finds its way to these receptors and through a process of chemical reactions leads to dopamine release in the nucleus accumbens, and consequently a feeling of pleasure and reward.

Alcohol

Despite having been consumed by humans across the globe for thousands of years, the effect of alcohol on the brain is the least understood. Alcohol affects numerous different chemical systems in a variety of ways, most of which finally also have an effect on the VTA and the nucleus accumbens, with a subsequent increase in levels of dopamine in the pleasure pathway.

Cannabis

When cannabis is inhaled, it binds with the cannabinoid receptors which occur naturally in our bodies. There are two types of cannabinoid receptors, namely type I and type II receptors. The cannabinoid type I receptor is primarily situated in the brain, while the cannabinoid type II receptor is found mostly in the spleen, thymus and immune system. The active ingredient in cannabis is called delta-9-tetrahydrocannabinol, commonly abbreviated as THC. This chemical is metabolised to another chemically active metabolite, 11-hydroxy-THC. Through a process of chemical reactions this metabolite finally leads to a release of dopamine in the nucleus accumbens and a pleasurable sensation. You will recall that cannabis also has other effects, including stimulant and depressant effects.

Hallucinogens

The group of hallucinogen drugs affects numerous neurotransmitters in the brain, including serotonin, noradrenalin and dopamine. Hallucinogens seem to specifically target the serotonin type 2a receptor, but also have an effect on dopamine release in the pleasure pathway.

Phencyclidine (PCP)

Phencyclidine has a relatively direct effect on dopamine. It stimulates dopamine release and inhibits its reuptake in the pleasure pathway. Phencyclidine seems to do this via a sequence of chemical reactions, including in the glutaminergic and serotonergic systems.

Inhalant drugs

The inhalant group of drugs also releases dopamine in the nucleus accumbens with subsequent feelings of pleasure and reward.

So far we have learnt that there are three components of the pleasure pathway, namely the VTA, mesolimbic pathway and nucleus accumbens. The majority of pleasurable experiences (whether induced by drugs or natural events) result from dopamine release in the common pleasure pathway. This explains why some people cross over from one substance to another once they stop their initial primary drug of abuse. Such examples include an alcohol-dependent person who increases his smoking habit during the alcohol withdrawal phase. A heroin addict is likely to request more benzodiazepine tablets when detoxing from heroin, and a benzodiazepine-dependent patient might use more alcohol when he is weaned off the benzodiazepine medicine. A person who stops smoking cigarettes may increase his coffee intake.

The reason for such crossover behaviour is that the original primary drug of abuse has now been either reduced or stopped, the feelings of pleasure and reward have subsided and there is an urge to re-establish them. By taking a different chemical substance which also acts on the common pleasure pathway, this can be rectified. Various drugs therefore have a similar biochemical effect at the common pleasure pathway (that is, an increase in dopamine levels) and can be partially or wholly substituted.