Key syndromes of the middle stage
The complex of pathological changes in the middle stage of substance use disorder includes a number of specific clinical and pathophysiological manifestations. Five main syndromes determining the severity of the patient's condition are distinguished:
- Syndrome of physical dependence on the psychoactive substance. The body completely restructures its functioning to accommodate the constant presence of the drug. The main consequence of this adaptation is the inevitable development of withdrawal when attempting to stop intake.
- Syndrome of progressively increasing tolerance. Tissue sensitivity to habitual doses of the substance drops rapidly. The patient is forced to constantly increase the amount of the administered drug, often reaching toxic doses.
- Syndrome of incorporation of psychoactive substances into metabolism. The drug and its breakdown products (metabolites) integrate into natural biochemical cycles, becoming an essential link in them.
- Personality degradation. A profound destruction of the psyche occurs, along with the loss of social ties and moral-ethical guidelines.
- Disorders of organ and tissue function. Chronic intoxication leads to systemic damage to internal organs.
Pathogenesis of withdrawal syndrome
Withdrawal syndrome is the main marker of established physical dependence. Its pathogenesis is based on a profound neurotransmitter imbalance in the brain.
The key link in the development of withdrawal is the accumulation of dopamine and other biogenic amines in nervous tissue. This process is triggered in response to the cessation of psychoactive substance intake. Excess catecholamines concentrate predominantly in the structures of the brain's reward system.
The severity of the clinical picture of withdrawal syndrome has a clear correlation with the concentration of dopamine in systemic circulation:
- If the blood dopamine level exceeds the physiological norm by 2 times, the patient develops a severe presentation of withdrawal syndrome.
- If the dopamine concentration increases by 3 times compared to the norm, the condition becomes critical: acute psychosis develops, accompanied by severe disorders of the body's basic vital processes.
In addition to the dopaminergic crisis, changes in the activity of other brain neurotransmitter systems play a crucial role. Prolonged hypercatecholaminemia exerts an inhibitory effect on a number of protective and inhibitory pathways. Specifically, a marked decrease in the activity of the opioidergic, serotonergic, cholinergic, and GABAergic systems is recorded. Such total depletion of the neurotransmitter apparatus severely exacerbates the course of withdrawal and creates an irresistible urge in the patient for the immediate administration of a new dose of the psychoactive substance.
Mechanisms of tolerance and integration of psychoactive substances into metabolism
The need to constantly increase the dose of the drug is explained by the development of the syndrome of psychoactive substance (PAS) incorporation into metabolism. This phenomenon is based on structural rearrangements at the cellular level.
Repeated and regular administration of PAS provokes profound changes in the structure of neuronal membranes, including synaptic contact areas. The main biochemical shifts occur in the lipid phase of cell membranes. A pathological excess of cholesterol and free fatty acids (FFAs) begins to accumulate there.
The change in lipid composition directly affects the physicochemical properties of the membrane. The main consequence of this process is a decrease in the mobility of receptors embedded in the membrane. The receptor apparatus loses its ability to adequately respond to chemical signals. It is precisely this decrease in receptor mobility that underlies the increase in tolerance to PAS, making a further dose increase inevitable to achieve the desired effect.
Briefly: answers to topical questions
What biogenic amines, besides dopamine, accumulate in nervous tissue during the development of withdrawal syndrome?
In addition to dopamine, noradrenaline and other catecholamines accumulate in brain tissue during the development of withdrawal syndrome.
Accumulating biogenic amines:
- Noradrenaline — its synthesis is enhanced in the reward system, and upon substance withdrawal, the rate of synthesis remains high by inertia.
- Other catecholamines — their excess in the structures of the reward system acts as a key factor in the development of the clinical picture of withdrawal.
What stages of substance use disorder exist besides the middle stage?
In addition to the middle stage, sources on addiction stages indicate:
- Initial stage — psychological dependence, the "phenomenon of revival".
- Terminal stage — muscle atrophy, weight loss, trophic disorders, persistent hepatitis, personality impoverishment.
The five syndromes of the middle stage can be memorized by the acronym P-T-I-D-O: Physical dependence, Tolerance, Incorporation into metabolism, Degradation, Organ disorders.
Class and exam questions
What is the main cause of withdrawal syndrome development in the middle stage of substance use disorder?
Withdrawal occurs because the body is fully adapted to a specific level of the psychoactive substance. When its concentration decreases or intake stops completely, a massive release of catecholamines occurs in the brain, which triggers the severe clinical picture of withdrawal syndrome.
How does blood dopamine concentration affect the severity of the patient's condition during withdrawal?
There is a direct correlation: a 2-fold increase in dopamine levels compared to the norm causes a severe presentation of withdrawal syndrome. If the level increases 3-fold, the patient develops acute psychosis and dangerous life-support disorders.
Why do the activities of GABAergic and serotonergic systems decrease in substance use disorder?
The suppression of these systems, as well as the opioidergic and cholinergic systems, occurs under conditions of prolonged hypercatecholaminemia. This neurotransmitter imbalance worsens the course of withdrawal and creates an acute need for the immediate administration of the drug.
What is the biochemical mechanism of increasing tolerance to psychoactive substances?
During regular PAS intake, an excess of cholesterol and free fatty acids accumulates in the lipid phase of neuronal membranes. This leads to a decrease in receptor mobility within the membranes, causing sensitivity to the substance to drop, and requiring increasingly larger doses for the patient.
What else to study on this topic
- Mechanisms of hypercatecholaminemia formation upon PAS withdrawal
- The role of the reward system in the pathogenesis of dependence
- The effect of drugs on the opioidergic and cholinergic systems
- Pathophysiology of personality degradation in chronic intoxication
- Organ disorders against the background of toxic PAS doses
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