1.Basic Concepts
Addiction is a chronic behavioral disorder that manifests itself as an obsessive persistent search and intake of a substance, often despite its negative consequences. In the formation of addiction, on the one hand, compulsive substance searches and applications take up more space in the life of the addict, on the other hand, the repertoire of non-substance-related behavior begins to narrow gradually.
Substance dependence is often the next stage of substance abuse, and these two conditions are defined differently in DSM-IV. As the substance is used more, it causes adaptive changes in the Central Nervous System (CNS) and these changes lead to processes such as tolerance, withdrawal symptoms, physical dependence, sensitization, seeking, and relapse.
1.1. Rewarding Effects of Items
The positive reinforcer effect of a substance is generally used as if it has the same meaning as a pleasurable or rewarding effect. Positive reinforcement is the type of stimulus that increases the probability that the reaction it follows will occur later.
It is true that the rewarding mechanism uses the positive reinforcement mechanism in most cases, but there are also positive reinforcements that do not have a rewarding effect. For example, experimentally, electric shock can act as a positive reinforcement.
In experiments in which operant conditioning mechanisms were used, it was observed that animals learned to apply cigarettes, alcohol, narcotic and similar substances to themselves (Katz and Goldberg, 1988).
The definitions of people as the subjective effects of the substances they are addicted to are “pleasure”, “pleasure”, “enjoyable”. Pleasure doesn’t always have to be the ‘surge’ used to describe amphetamine and cocaine’s stimulus, or the ‘pleasure rush’ for heroin. It can also be seen in more moderate forms such as the reduction of tension, the passing of fatigue, and the improvement of morale.
Another concept related to the rewarding and reinforcing effects of the items is the incentive values of the items. If the reinforcer is the stimulus that emerges at the end of the response, the incentive stimulus is the stimulus that elicits the response. For example, food is a reinforcer, the smell or appearance of food is an incentive.
Two important features of stimulating stimuli are that they act as a trigger in directing the organism to the object and increase the level of arousal necessary for the emergence of reactions. These two features direct the organism to its goal. There is strong evidence that these two features have different neuronal bases (Robinson & Berridge, 2000)
Addiction is a complex phenomenon in which psychological, physiological and individual differences play a role. The theories that try to explain the processes involved in the formation of addiction are discussed below.
1.2.Tolerance
The speed and degree of tolerance may vary for each substance, for each effect of the substance and according to the diversity of the organism exposed to the substance. Three types of tolerance can be mentioned regarding addiction:
metabolic tolerance: as the amount of substance taken increases, the enzyme that metabolizes it also increases; An example of this is the increase in cytochrome 450 enzyme in the liver in alcohol and nicotine intake.
physiological tolerance: reduced number or sensitivity of receptors to the same amount of ingested substance; for example, reduction of GABA activity in the brain with continuous alcohol intake.
behavioral tolerance: Also called Pavlovian “conditional tolerance”. It was observed for the first time during the testing of tolerance to the analgesic effect of morphine in guinea pigs. It was observed that tolerance developed when the tolerance test was performed in the same environment where morphine was applied, and tolerance did not develop when the tolerance test was performed in a medium other than the one in which morphine was administered (Siegel, 1975).
Siegel explained this situation as follows: the organism is conditioned against the drug itself and the accompanying environmental stimuli (conditioned stimulus), against which the organism prepares itself for the drug, tries to adapt (conditioned response), which in turn compensatory against the drug’s effect. elicits reactions.
When the environment is changed, the conditioned state of the stimulus is removed and compensatory responses do not occur. This is why withdrawal symptoms associated with a substance often develop in opposition to the effects of the substance itself. Because the conditioned response develops in a way that compensates for the effect of the substance. For example, heroin use causes constipation, and as a result, diarrhea develops in abstinence.
Also, cross-tolerance phenomena in various situations should be considered.
1.3.Sensitization
Sensitization, opposite to tolerance, is the increase in the effect of a substance as you use it. Although it is frequently seen in CNS stimulants, there are studies showing that it is valid for all addictive substances. Tolerance occurs with continuous application of the same amount of substance, and sensitization occurs with intermittent application. Sensitization may be longer lasting than tolerance.
Psychomotor sensitization is important in the explanation of addiction syndrome in two respects. In many studies, it has been observed that the neurophysiological pathways and mechanisms that form the basis of psychomotor sensitization caused by stimulants and the pathways and mechanisms that form the basis of the rewarding effects of these substances overlap or are the same, Wise and Bozarth, 1987). This mechanism involves the mesocorticolimbic dopamine system, which sends projections from the ventral tegmental area to the nucleus accumbens.
Second, sensitization has been observed not only in the psychomotor stimulant effects of addictive substances, but also in the direct rewarding effects of these substances. In addition, the environment has important effects on sensitization as well as tolerance. Taking the same amount of substance in different environments may result in different levels of response.
In the light of these findings, tolerance and sensitization and their underlying mechanisms seem to be closely related to basic learning mechanisms such as classical conditioning. Therefore, it would be a more accurate approach to consider an organism’s relationship with matter as a product of complex learning mechanisms that have been imparted to the nervous system by the adaptation efforts of species over millions of years, rather than a simple interaction of chemical-physiological systems.
1.4. Withdrawal Symptoms and Physical Dependence
Withdrawal symptoms are the physiological responses to a substance being discontinued or reduced after a long period of time. Those who experience withdrawal symptoms when they quit a substance are told that the substance develops physical dependence. Physical dependence is linked to tolerance. Tolerance to a substance can develop without physical dependence; however, physical dependence and withdrawal symptoms do not appear before tolerance develops. The reason for this is that the organism develops an opposite adaptation, that is, tolerance, to the effects of the substance.
1.5. Psychological Addiction and Searching
Psychological addiction is the behavior of constantly seeking and using the relevant substance in an obsessive manner without physical withdrawal symptoms. Searching often takes the addict to the substance-related environment and stimuli, and ultimately to the substance itself. In studies conducted with brain imaging techniques, it has been observed that the mesocorticolimbic dopaminergic system is activated in the brain of addicts when there are verbal or visual stimuli evoking the relevant substance (Camii and Farre, 2003).
1.6.Relapse
In the withdrawal symptoms of a substance that has been discontinued, even years after getting rid of it, it is common to turn to that substance again. Therefore, this type of behavior should be considered as a part of the addiction syndrome and a method should be developed against it.
2. Neurobiological Basis of Substance Addiction
2.1. Intracranial Self-Stimulation
In the early 1950s, James Old and Peter Milner discovered that electrical stimulation of certain parts of the brain had a positive reinforcement effect. . To obtain this stimulus, animals have learned to press a pedal in operant conditioning boxes. This phenomenon has been called intracranial self-stimulation. In early trials, this phenomenon led to such a strong response pattern that animals pressed the pedal 2,000 times per hour until they became weak to stimulate certain areas of the limbic system.
Old defined this area as the pleasure center. It was named as a reward center by later researchers. Today, researchers are not talking about the “pleasure” or “reward” centers of the brain, but rather the system formed by neuronal pathways underlying positive reinforcement (McKim, 1997). According to this understanding, when the organism performs an action that will meet an important need, the system in question activates the reward mechanism that will enable this action to occur again later.
Although the brain uses such a reward mechanism to induce repetition of a behavior, this mechanism may not be the only one to sustain a behavior. It was mentioned above that positive reinforcers are not always necessarily pleasurable.
According to incentive sensitization theory (Robinson & Berridge, 1993), liking and wanting something is controlled by different systems in our brain. Addictive substances stimulate the craving center directly, and therefore, people continue to seek it with a strong desire, even if they do not enjoy the substance they use in the later stages of addiction.
2.2. Intracranial Self-Stimulation and the Mesocorticolimbic Dopamine System
Intracranial self-stimulation is related to the mesothelencephalic dopamine system in the brain. This system includes dopamine projections that extend from the midbrain (mesencephalon) to some areas of the forebrain (telencephalon). The cell bodies of the neurons that make up the system focus specifically on two nuclei: the ventral tegmental area and the substantia nigra. The axons of dopamine cells found here extend to the forebrain nuclei such as the prefrontal neocortex, limbic system, amygdala, septum, striatum, and especially the nucleus accumbens.
The mesothelencephalic dopamine system includes three pathways: the first extends from the substantia nigra to the striatum, the other extends from the ventral tegmental area to the nucleus accumbens, and the third extends from the ventral tegmental area to the limbic system. The second and third pathways of these have gained more importance among researchers recently, and they have started to be referred to as “mesocorticolimbic” and have become the focus of studies investigating the neurobiological basis of addiction.
Much evidence has been found that the mesocorticolimbic dopamine system plays a central role in both intracranial self-stimulation, the rewarding effect of natural sources of pleasure, and the rewarding effect of addictive substances.
2.3. Natural Sources of Pleasure and Mesocorticolimbic Dopamine System
This system is also related to the rewarding effect of natural sources of pleasure such as eating, drinking and sexuality. Furthermore, Schultz (1997) measured the electrical activity of dopaminergic neurons in the substantia nigra and ventral tegmental area of the monkey brain during a classical conditioning and showed that dopaminergic activity is increased only when an unexpected reward is present.
That is, after conditioning occurs, conditioned stimuli increase dopaminergic activity, not the reward itself.
In addition, the effect of natural sources of pleasure in this system is quantitatively different from the effect of addictive substances. In one study, food increased dopamine release in the nucleus accumbens by 45%, while amphetamine and cocaine increased it by 500% (Hernandez and Hobel, 1988).
2.4. Addictive Substances and the Mesocorticolimbic Dopamine System
Although the primary pharmacological effects of many of the addictive substances (nicotine, alcohol, cannabis, morphine..) seem to stimulate different receptor systems. , it seems that almost all of them ultimately depend on their effects on dopamine transmission in the mesocorticolimbic system.
It has been determined that the amount of dopamine in the nucleus accumbens is greatly reduced during withdrawal symptoms of many substances such as nicotine, alcohol and opiates (Rossetti et al., 1992). Inspired by this finding, some researchers put forward a withdrawal-based hypothesis for addiction (Dackis & Gold, 1985). According to this hypothesis, when these substances are used for a long time, they cause a general depression in the reward system with a decrease in the amount of mesocorticolimbic dopamine. This collapse is observed as depression during withdrawal, and addicts turn to substance use again to get rid of this depressive mood.
The idea that the mesocorticolimbic dopamine system plays a role in the pleasurable rewarding effects of substances has recently been replaced by the idea that this system causes effects that motivate the organism to this pleasurable experience and stimuli related to this experience, rather than the experience of pleasure. That is, people’s enjoyment of these substances may be linked to some other neurotransmitter systems; however, the obsessive desire to repeat this experience is brought about by the activation of the mesocorticolimbic dopamine system, which controls motivation in general.
