Pathogenesis of drug addiction and substance abuse

Key components and the reward phenomenon

The development of dependence is a multistage process consisting of four key components:

1. Pathological craving for repeated PAS intake.
2. Development of psychological dependence.
3. Development of tolerance.
4. Development of physical dependence.

The pathogenesis is based on the reinforcement phenomenon. Psychoactive substance intake causes a massive release of neurotransmitters from storage depots. Anatomically, this process is mediated through the structures of the reward system: the limbic system and the brainstem (specifically, the locus coeruleus — locus ceruleus, located in the floor of the fourth ventricle).

Initially, the release of neurotransmitters leads to pronounced positive emotions, euphoria, and increased performance. However, this effect is transient: catecholamines are rapidly metabolized, their reserves are depleted, and a reward deficit occurs (fatigue, psycho-emotional discomfort, depressed mood). A pathological system is formed whose goal is to obtain a new dose of PAS to recreate a state of comfort.

Mechanisms of tolerance development

Tolerance is manifested by a decrease or complete elimination of the effects of the habitual dose of PAS, which forces the patient to constantly increase the amount of the administered substance. The triggering factor is repeated PAS intake. The process is realized through two main pathways:

• Metabolic pathway (acceleration of breakdown). The body activates cellular microsomal enzyme systems and cytosolic dehydrogenases. As a result, the destruction and inactivation of the psychoactive substance are intensified.
• Membrane-receptor pathway (decreased sensitivity). An excess of cholesterol and saturated fatty acids accumulates within the phospholipids of neuronal cell membranes. Membranes become more viscous and lose fluidity. Consequently, receptors become fixed within the thickness of the plasmalemma, their mobility drops, and they become less accessible to the neurotransmitters of the reward system.

Psychological and physical dependence

Psychological dependence is based on discomfort (depression, profound anguish, anxiety) that occurs when PAS intake stops. The substance becomes a prerequisite for a sense of satisfaction and mental uplift.

To compensate for the continuous massive release and enzymatic breakdown of neurotransmitters, the reward system undergoes remodeling: the synthesis of dopamine and norepinephrine is accelerated many times over, and the turnover of catecholamines speeds up.

Physical dependence is a state in which PAS withdrawal causes not only psychological discomfort, but also profound acute disruptions in the functions of the central nervous system and internal organs. At this stage, periodic or continuous administration of the substance is required by the body to alleviate severe physical disorders.

Abstinence syndrome (withdrawal syndrome)

Abstinence syndrome develops upon PAS withdrawal against the background of already established physical dependence. Its pathogenesis includes several mechanisms:

1. Accumulation of catecholamines. Upon abrupt PAS withdrawal, the rate of neurotransmitter synthesis remains high by inertia, while their utilization drops (due to the lack of stimulus for release). An excess of dopamine and other catecholamines accumulates in brain tissue.
2. Membrane hypersensitivity. In the state of intoxication, membrane viscosity was optimal for neurons (adaptation). Upon PAS withdrawal, receptors "float up" to the surface of the plasmalemma. Their accessibility increases sharply, leading to generalized central nervous system hypersensitivity.
3. Imbalance of neurotransmitter systems (especially in chronic alcoholism). The activity of the excitatory glutamatergic system increases, while the inhibitory GABAergic system is critically suppressed.

Clinical presentation includes psychiatric changes (anxiety, irritability, anguish), pain syndrome (myalgia, leg cramps, gastrointestinal pain), dyspepsia (nausea, vomiting, diarrhea), and autonomic reactions (blood pressure fluctuations, tachycardia, sweating, insomnia).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Anatomy and physiology of the reward system (role of the locus ceruleus)
• The role of microsomal enzyme systems in xenobiotic metabolism
• Membrane theory of dependence: the effect of higher fatty acids on plasmalemma fluidity
• Clinical manifestations of reward deficit in the early stages of dependence
• Pathophysiology of autonomic disorders in withdrawal syndrome

Other topics in «Chapter 18. Drug Addiction. Substance Abuse. Poisoning»

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