Textbook - BIOLOGICAL CHEMISTRY - Gubsky Yu.I. - 2000

Chapter VI. BIOCHEMISTRY OF PHYSIOLOGICAL FUNCTIONS AND SPECIALIZED TISSUES

CHAPTER 33. BIOCHEMISTRY OF THE NERVOUS SYSTEM. MOLECULAR PSYCHOBIOLOGY

33.3. NEUROCHEMICAL MECHANISMS OF PSYCHOTROPIC DRUG ACTION

Psychotropic (psychoactive) agents are pharmacological preparations used to treat disorders of human mental activity.

The fundamental possibility of using BIOLOGICALLY ACTIVE SUBSTANCES (BAS) that affect synaptic transmission in the Central Nervous system as medications is due to the fact that certain Mental Illnesses and psycho-emotional disorders are largely (or entirely, in some pathologies) determined by dysfunctions in specific neurotransmitter-receptor systems of the human Brain. For example, the Pathogenesis of Schizophrenia and related schizoaffective psychoses is associated with the hyperfunction of dopaminergic nuclei; states of psycho-emotional tension, anxiety, and fear with The stimulation of adrenergic structures; Sleep cycle disturbances with serotonergic system dysfunction; and pain syndromes with the state of the opioid receptor antinociceptive system and opioid Neuropeptides, etc.

An Analysis of the general MOLECULAR AND CELLULAR mechanisms by which physiologically active compounds—particularly drugs—affect the Organism, as well as the Structure and Molecular Organization of transmitter and receptor structures in interneuronal synapses, allows us to identify the key links of synaptic transmission in the brain that are regulated and corrected by psychotropic drugs of various orientations (Yu.I. Gubsky, 1997):

1) enzymatic Synthesis and degradation of the neurotransmitter;

2) deposition of the neurotransmitter in vesicles of presynaptic terminals;

3) release of the neurotransmitter into the synaptic cleft;

4) interaction of the neurotransmitter with postsynaptic ionotropic and/or metabotropic receptors, triggering the corresponding sequence of biochemical and biophysical reactions in the membrane, Cytoplasm, and Organelles of the sensitive neuron;

5) interaction of the neurotransmitter with presynaptic membrane structures responsible for its reuptake and enzymatic degradation.

The most common groups of psychotropic drugs include neuroleptics (antipsychotics), antidepressants, and anxiolytics.

Neuroleptics (antipsychotic drugs, antipsychotics) are medications used to treat psychoses, primarily schizophrenia, as well as other endogenous (organic) and exogenous (psychogenic) mental disorders manifested by severe psycho-emotional disturbances with delusions, hallucinations, and agitation.

Given the social significance of schizophrenia—a disease that affects up to 1 % of the population according to modern studies (H.I. Kaplan, B.J. Sadock, 1994)—a vast body of scientific literature is devoted to studying neurotransmitter disturbances in this group of mental disorders. It is believed that the greatest significance in the pathogenesis of schizophrenia belongs to the genetically determined hyperactivity of dopamine systems in the mesocortical and mesolimbic tracts, whose neuronal Cell bodies are localized in the substantia nigra and the ventral tegmental area.

Accordingly, the neurochemical mechanisms underlying the therapeutic effects of neuroleptics are based on their antagonistic action against dopamine D₂ receptors (and, more recently, D₃ and D₄ receptors), which are localized predominantly in the brain's limbic system. The greatest positive effect in schizophrenia is produced by compounds derived from phenothiazine (such as Chlorpromazine /Aminazine/) and butyrophenone (such as Haloperidol).

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Antidepressants are psychopharmacological agents used to treat depressions of various origins. This group of drugs is also known as thymoleptics, meaning "mood-elevating agents."

The neurochemical basis for the central nervous system effects of antidepressants of various chemical structures is their ability to stimulate monoaminergic transmission in the brain, achieved by increasing the synaptic concentration of norepinephrine and/or serotonin.

Based on their neurochemical and pharmacological Mechanisms of action, antidepressants are divided into two subgroups:

- monoamine reuptake inhibitors;

- monoamine oxidase (MAO) inhibitors.

Monoamine reuptake inhibitors block the reuptake system of norepinephrine, serotonin, or dopamine by presynaptic nerve endings, which promotes their accumulation in synapses and stimulates the monoaminergic neurotransmitter signal. This group includes heterocyclic antidepressants, which are molecularly structured as compounds consisting of several (three or four) heterocyclic rings (such as Imipramine and Amitriptyline).

Depending on their predominant effect on the reuptake and METABOLISM of a specific monoamine in synapses, heterocyclic antidepressants are divided into classes of compounds with targeted noradrenergic, serotonergic, or dopaminergic action.

MAO inhibitors are compounds that block The activity of monoamine oxidase with varying degrees of selectivity and reversibility. This enzyme catalyzes the Oxidative Deamination of monoamines—primarily norepinephrine and serotonin—within the Mitochondria of brain Neurons.

Most antidepressants are non-selective inhibitors of monoamine oxidases A and B, which increase the levels of monoamines with diverse structures and physiological activities in the brain, including norepinephrine, epinephrine, dopamine, serotonin, tyramine, and phenylethylamine. A distinction is made between irreversible MAO inhibitors (Iproniazid) and reversible ones (Pirazidol).

Anxiolytics are medications that exert a calming effect by relieving states of psychological and emotional tension and anxiety (from the English word anxiety). This group of drugs is also referred to as tranquilizers (from the Latin tranquillium meaning calmness) or ataractics (from the Greek ataraxia meaning calmness or equanimity).

Nowadays, derivatives of benzo-1,4-diazepine (benzodiazepines or BDDs) are the most widely used anxiolytics, or tranquilizers. Due to their anxiolytic and stress-protective properties, they rank among the most frequently prescribed medications worldwide.

The first benzodiazepine medication was Chlordiazepoxide, introduced into clinical practice in 1960. Later, pharmaceutical companies synthesized several thousand BDD derivatives, of which a few dozen are currently in clinical use. The most common among them include Alprazolam, Lorazepam, Oxazepam, Diazepam, and others.

The neurochemical mechanisms underlying the central pharmacological effects of benzodiazepines are linked to their interaction with GABA receptors (specifically the GABA_A subtype) located on the postsynaptic membranes of GABAergic neurons in the brain, which potentiates the inhibitory effects of γ-aminobutyric acid.

The interaction of benzodiazepines with BD-binding receptor sites on the "GABA_A receptor–chloride channel" membrane complex allosterically activates the GABA_A receptors themselves. This, in turn, triggers the opening of chloride channels and the hyperpolarization of the postsynaptic membrane, thereby executing the inhibitory effects of benzodiazepines.

Research has established the presence of an endogenous Ligand for BD receptors in the human brain: a low-molecular-weight (MW 15 kDa) neuropeptide known as DBI ("diazepam binding inhibitor"), which exhibits anxiogenic activity. High concentrations of DBI have been detected in human brain regions responsible for controlling behavioral responses to emotional and stress stimuli. This suggests that the protein acts as an endogenous modulator of reactions associated with The regulation of anxiety, fear, and aggression.