Place in pathogenesis and essence of the initial stage
The pathogenesis of substance use disorders and toxicomania distinguishes three strictly consistent stages of development: the initial stage, the stage of physical dependence, and the final stage.
The initial stage has several synonyms reflecting its clinical essence: adaptive, psychasthenic, neurasthenic, or the stage of psychological dependence.
The main characteristic of this period is the formation of a persistent psychological craving for psychoactive substances (PAS). The patient begins to use the substance as a universal and primary tool for solving any psychoemotional tasks: increasing mental and physical performance, achieving psychological comfort, and eliminating depressive thoughts. Gradually, a specific complex of four pathogenic syndromes is formed.
Syndrome of psychological dependence and its pathogenesis
The basis of this syndrome is the onset of acute psychological discomfort, a sense of dissatisfaction, and depression when the concentration of PAS in the blood decreases. These distressing sensations are completely eliminated only when a new portion of the substance enters the body.
The pathogenesis of psychological dependence includes several main links:
- Neurotransmitter depletion: due to continuous repeated intake of PAS, there is a gradual decrease in neurotransmitter stores directly in neurons and their terminals.
- Decreased activity of the reward system: an acute deficiency of dopamine and other catecholamines occurs in the neurons of the brainstem and limbic system. As a result, the natural maintenance of a comfortable psychoemotional state is disrupted.
- Psychoemotional disorders: a distressing sense of bitterness and internal discomfort develops, along with a sharp drop in mental and physical energy.
- Formation of craving: an irresistible, obsessive need for re-stimulation of the body with the substance appears.
At this stage, the body tries to resist. Dopamine deficiency is temporarily compensated for by the activation of enzymes that synthesize catecholamines: tyrosine hydroxylase, dihydroxyphenylalanine decarboxylase, and dopamine beta-hydroxylase. This leads to an acceleration of catecholamine metabolism in the nervous system. However, over time, these adaptive mechanisms inevitably become depleted.
Neurasthenic and psychasthenic syndromes
Depletion of the nervous system manifests as a number of clinical symptoms. Patients exhibit:
- Increased irritability and emotional lability.
- Rapid fatigue during both physical and mental work.
- Marked memory impairment and various sleep disorders.
- Sensory disorders: paresthesias (false sensations of numbness or tingling) may occur, as well as hypoesthesia (decreased sensitivity) and hyperesthesia (increased susceptibility to stimuli).
Syndromes of tolerance and adaptation
In addition to psychological dependence, two other key syndromes are prominently manifested in the initial stage:
- Syndrome of progressively increasing tolerance to PAS. The essence of this phenomenon is that to maintain the habitual comfortable state, the patient requires a constant increase in the dose of the substance taken. Previous amounts no longer produce the expected effect.
- Syndrome of adaptation to the negative effects of PAS. This is characterized by the complete leveling and disappearance of the protective unpleasant reactions of the body that naturally occurred previously upon initial drug or alcohol intake. Nausea and vomiting, pseudo-allergic reactions, severe headache, and other symptoms of intoxication disappear without a trace in the patient. The body ceases to perceive the substance as an acute poison, which paves the way for the further progression of the disease.
Briefly: answers to topical questions
What are the cellular and receptor mechanisms for the development of tolerance to PAS?
The cellular and receptor mechanisms for the development of tolerance to PAS consist of desensitization and a decrease in receptor density on the cell membrane. The basis of habituation, i.e., the decrease in the effect of a substance upon its repeated or prolonged use, lies in the physiological adaptation of receptors.
Key mechanisms:
- Desensitization — a decrease in receptor sensitivity to the acting substance.
- Down-regulation — a decrease in the number (density) of receptors on the cell membrane.
For example, the weakening of the effect of morphine occurs precisely due to the simultaneous decrease in sensitivity and the total number of opioid receptors.
The four main syndromes of the initial stage are easy to remember by the acronym PANT (Psychological dependence, Adaptation to negative effects, Neurasthenia, Tolerance [its continuous growth]).
Class and exam questions
How many total stages are distinguished in the pathogenesis of substance use disorder?
The pathogenesis consistently develops through three stages: initial, physical dependence (middle), and final.
Why does depression occur upon PAS withdrawal in the first stage?
This is due to the depletion of one's own neurotransmitter stores and dopamine deficiency in the brain's reward system. The body loses the ability to maintain a comfortable state without external stimulation.
How does the nervous system attempt to compensate for the shortage of dopamine?
The enzymes of catecholamine synthesis (tyrosine hydroxylase, dihydroxyphenylalanine decarboxylase, and dopamine beta-hydroxylase) are temporarily activated, accelerating their metabolism. However, this adaptive mechanism is rapidly depleted.
What does adaptation to the negative effects of PAS mean?
This is the complete leveling of the body's natural protective reactions to the toxin. The patient ceases to experience nausea, vomiting, pseudo-allergic reactions, and headache in response to substance intake.
What else to study on this topic
- Stage of physical dependence (addictive, middle stage)
- Final stage of substance use disorder and toxicomania
- Mechanisms of neurotransmitter system depletion during chronic PAS intake
- The role of the limbic system and brainstem in the formation of dependence
- Pathogenesis of withdrawal syndrome (abstinence syndrome)
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