Acetylcholine and Cognitive Functions
Acetylcholine is a crucial regulator of cognitive behavior, learning processes, and the control of arousal levels. Formed from choline and acetyl-coenzyme A, it acts on muscarinic (m-receptors of the parasympathetic system) and nicotinic (n-receptors of neuromuscular junctions) endings. Pathological changes in cholinergic nuclei of subcortical structures leading to their degeneration are closely associated with severe cognitive impairment observed in Alzheimer's disease and Down syndrome.
In clinical psychiatry, it is important to remember that drugs with pronounced anticholinergic activity (e.g., tricyclic antidepressants or classical antipsychotics) cause a number of somat Vegetative reactions: dry mucous membranes, pupil dilation (mydriasis), urinary retention, accommodation paralysis, and persistent constipation. Overdose of m-receptor blockers, such as atropine, can provoke acute psychosis with altered consciousness, while long-term use of anticholinergics leads to irreversible memory impairment.
Excitation-Inhibition Balance: Glutamate and GABA
Amino acid neurotransmitters form the absolute majority of synaptic connections in the cerebral cortex. The key excitatory agent is glutamate (glutamic acid), which ensures the influx of sodium, potassium, and calcium ions into the cell. Its specific NMDA receptors are responsible for neuronal plasticity and the integrative activity of the brain. However, hyperactivity of this system underlies the development of epilepsy, schizophrenia, and delirium tremens. Excessive excitation leads to excitotoxicity—a catastrophic accumulation of calcium causing the death of nerve cells. To prevent this process, non-competitive NMDA blockers (e.g., memantine) are used.
The counterpart to glutamate is gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter. Activation of GABA receptors, which regulate chloride influx into the neuron, causes systemic protective inhibition: overall performance and memory retention decline, while tissue resistance to hypoxia and stress increases. Tranquilizers (benzodiazepines), barbiturates, general anesthetics, and alcohol actively interact with the GABA receptor complex. The mechanism of action of benzodiazepines involves blocking endogenous peptides (endozepines), which normally close the chloride channel.
Neuropeptides, Opioids, and Hormones in Behavioral Regulation
Neuropeptides functioning as neurohormones exert a tremendous influence on behavioral reactions. Vasopressin, neurotensin, and oxytocin not only cause systemic somatic effects but also directly participate in memory consolidation.
Endogenous opioids (endorphins and enkephalins) serve as the central link in the nervous system's response to pain and stress. Stimulation of mu-receptors produces an analgesic effect and euphoria, whereas activation of kappa-receptors provokes aggressive behavior and hallucinations. It is through this system that the ultimate mechanism of tobacco, alcohol, and drug addiction is realized.
A special place is occupied by substance P, which is involved in the pathogenesis of severe depressions and psychosomatic disorders (bronchial asthma, ulcerative colitis, migraine). Its excess increases pain sensitivity and critically lowers mood due to the suppression of serotonin release. At the same time, adrenocorticotropic hormone (ACTH), whose release in severe depressions is not suppressed during the dexamethasone suppression test, possesses pronounced nootropic activity and improves learning processes.
The role of prolactin should be noted, whose level increases sharply upon the blockade of dopamine receptors by antipsychotics. This causes specific side effects: menstrual irregularities, gynecomastia, potency disorders, and increased appetite (which, combined with sedative action, often leads to weight gain).
Role of Neurosteroids and Purines in the Psyche
Neurosteroids act as powerful modulators of synaptic transmission. Estrogens and progesterone enhance the response at dopamine receptors, which is one of the mechanisms of premenstrual syndrome, menopausal disorders, and postpartum psychoses. Dehydroepiandrosterone (DHEA) demonstrates pronounced antidepressant properties, and its concentration directly correlates with the level of physical and mental health.
The purinergic system, which utilizes adenosine derivatives (ATP, ADP), is responsible for energy balance and the economical expenditure of brain resources. Methylxanthine derivatives (caffeine, theophylline) block purine receptors and inhibit the enzyme phosphodiesterase. This leads to the accumulation of cAMP and uncontrolled energy expenditure, which clinically manifests as pronounced psychomotor agitation.
Briefly: answers to topical questions
What somatovegetative side effects are caused by drugs with pronounced anticholinergic activity?
Drugs with pronounced anticholinergic activity that block m-cholinergic receptors can cause the following somatovegetative side effects:
- dry mouth;
- tachycardia;
- urinary retention;
- constipation;
- mydriasis;
- accommodation paralysis.
In which brain structures does the degeneration of cholinergic nuclei occur in Alzheimer's disease?
In Alzheimer's disease, the degeneration of cholinergic nuclei occurs in the basal forebrain nuclei. The main structure undergoing destruction is:
- Meynert's nucleus (basal nucleus) — neurons in this area normally synthesize acetylcholine.
Diffuse cholinergic projections to the entire cerebral cortex and hippocampus originate here. The death of neurons in these structures leads to a marked decrease in acetylcholine content in the hippocampus and neocortex, which forms the basis of cognitive impairment and severe memory dysfunction in this disease.
In the pathogenesis of which neurological and mental diseases is hyperactivity of the glutamate system involved?
Hyperactivity of the glutamate system and overexcitation of NMDA receptors are involved in the pathogenesis of a number of mental and neurological diseases. These include:
- Psychoses — including schizophrenia and delirium tremens.
- Epilepsy — associated with an imbalance of glutamate and GABA.
- Alzheimer's disease — a degenerative process accompanied by excitotoxicity.
- Amyotrophic lateral sclerosis — damage to motor neurons is associated with the effect of glutamate on neuronal death receptors.
- Cerebral ischemia — an excess of glutamate triggers a cascade of reactions leading to cell death.
What is the molecular mechanism of action of benzodiazepine tranquilizers on the GABA receptor?
The molecular mechanism of action of benzodiazepine tranquilizers involves the allosteric modulation of the GABA-A receptor complex. The drugs bind to specific benzodiazepine receptors (on the γ-subunit of the complex), which causes conformational changes in the structure of the GABA receptor. This increases its sensitivity to the endogenous neurotransmitter (GABA) and blocks the action of endozepines. As a result, the frequency of chloride channel opening increases, leading to a massive influx of chloride ions into the neuron. This results in the hyperpolarization of the neuronal membrane and the development of a pronounced inhibitory effect in the central nervous system.
How do the clinical effects of mu- and kappa-opioid receptor stimulation differ?
The clinical effects of mu- (μ) and kappa- (κ) opioid receptor stimulation differ primarily in their psychotropic action.
| Characteristic | μ-opioid receptors | κ-opioid receptors |
|---|---|---|
| Psychotropic effect | Cause pronounced euphoria | Cause dysphoria (discomfort), hallucinations, and aggressive behavior |
| Analgesia | Pain-relieving effect | Spinal analgesia (suppression of pain impulse transmission) |
| Additional effects | - | Sedative action, miosis, slight decrease in GI motility |
Both receptor types provide analgesia, but stimulation of μ-receptors leads to a euphoric effect, whereas activation of κ-receptors is accompanied by a negative emotional background.
What side effects are caused by elevated prolactin levels during antipsychotic therapy?
Elevated prolactin levels (hyperprolactinemia) during antipsychotic therapy cause a number of endocrine side effects. The main clinical manifestations include:
- Galactorrhea — milk discharge from the mammary glands (predominantly in women).
- Menstrual irregularities — in women.
- Gynecomastia — enlargement of the breast glands in men.
- Potency disorders — in men.
- Increased appetite — a possible concomitant manifestation.
These disorders are associated with the blockade of D₂-receptors of the tuberoinfundibular system (hypothalamus and pituitary gland) by typical antipsychotics.
Which classes of psychoactive substances and drugs interact with the GABA receptor complex?
The following interact with the GABA receptor complex:
- benzodiazepines;
- barbiturates;
- ethanol;
- volatile general anesthetics;
- steroids, including allopregnanolone and pregnenolone.
Drugs that activate the GABA system also include sedatives, in particular derivatives of benzodiazepine and barbituric acid, sodium oxybate and other agents, as well as sodium thiopental.
To understand excitotoxicity, imagine an "overheated engine": glutamate hyperactivity opens channels, an excess of calcium floods the cell and "burns out" the neuron, causing irreversible damage in ischemia and dementia.
Class and exam questions
What is the mechanism of action of benzodiazepines?
Benzodiazepine tranquilizers block the action of specific endogenous peptides (endozepines), which naturally cause the closure of the chloride channel in the GABA receptor complex.
Why does body weight increase when taking classical antipsychotics?
Blockade of receptors by antipsychotics causes a sedative effect and increased appetite. In addition, blockade of dopamine pathways leads to an increase in prolactin, which also contributes to changes in eating behavior.
What function does the dexamethasone suppression test perform in psychiatry?
Normally, the administration of dexamethasone suppresses ACTH release. The absence of such suppression is an important diagnostic marker in severe endogenous depressions and Cushing's syndrome.
How does glycine affect the glutamate system?
Glycine modulates the function of NMDA receptors, enhancing the neuronal response to glutamate. Without the presence of glycine, glutamic acid receptors remain refractory to excitation.
What else to study on this topic
- Mechanisms of neuronal excitotoxicity and the use of non-competitive NMDA blockers
- Specifics of GABA receptor interaction with steroids and barbiturates
- The opioid system: differential diagnosis of mu and kappa receptor effects
- The role of substance P in psychosomatic medicine and the treatment of pain syndromes
- The effect of non-steroidal anti-inflammatory drugs on the efficacy of tranquilizers
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