The most conclusively individual differences in the spectrum of psychotropic action of psycho - depressants are revealed when their influence on the emotional state of one to the same quality, consistently occurring in the same animal, is compared.
A very good-natured cat was taken into the experiment, easily responding to affection, not prone to emotions of rage and fear, easily getting along with partners and occupying an independent position in the group by virtue of its physical capabilities. Immediately after stimulation of the dorsal parts of the hypothalamus, the Animal had a long-lasting change in the emotional sphere, which could be classified as anxiety according to our terminology.
The cat looked around, pressed and turned the auricles to the sides, moved restlessly around the camera, or sat motionless with the legs straightened. Optic fissure dramatically expanded, pupils increased in diameter, breathing became frequent and uneven. The cat reacted to any afferent influences by a “panic” reaction, not like a manifestation of fear, or aggression. Against this background, so-called positive emotions were completely suppressed: there was no hunting, no games, all signs of pleasure disappeared, no peace in behavior, reactions to caress were suppressed.
Stimulation of this "point" had obviously " punishing " properties. Even minimal irritation caused a refusal to eat, which lasted from 5-10 to 30 minutes (depending on the strength of the irritation) in the period after stimulation. The negative state usually lasted somewhat longer than other indicators characterizing changes in the emotional sphere.
The transformation of the behavior and spectrum of the emotional activity of an experimental animal was differentiated by the partners in the group. The animals rose from their seats, looked around anxiously, but without additional provocation did not show aggression. At the same time, the experimental animal, in any movement of the partners, saw for itself a danger and a threat, kept its maximum condition from the partners and vigorously controlled any of their actions. The doses of drugs that affect the evoked emotional changes, but do not exhibit psychopathological effects on normal behavior are compared.
The most complete normalization of the emotional state and behavior is caused by chlordiazepoxide (3 mg / kg) and diazepam (1.5 mg / kg.) For the tranquilizing effect, diazepam is somewhat more effective than chlordiazepoxide . In addition, it has a more distinct "activating" effect. This completely coincides with the data on the psychotropic activity of these compounds in the clinic.
In diazepam more pronounced anxiolytic, anxiolytic effect is more pronounced activating component, which allows its use in hyposthenic symptoms, while chlordiazepoxide gives the best effect when hypersthenic symptoms, having a stronger inhibitory effect, including in conflict situations
Soothing effects of tranquilizers.
Chlordiazepoxide to a greater extent suppresses the " punishing " properties of electrical stimulation and more intensively activates the manifestation of positive emotions. According to clinical observations, a significant euphorizing effect of chlordiazepoxide is known , which raises concerns about the development of addiction and dependence.
With regard to the effect of both tranquilizers on the “ parasitic ” effects, the literature data are not completely identical. As N. A. Patkipa (1974) believes , chlordiazepoxide does not have a direct influence, and the perception of a punishing stimulus. It is not the perceptive, but the emotional component of negativity that is suppressed. In this case, an increase in the activity of the incentive systems is essential, which is manifested by the “ euphorizing ” effect.
Data on the effect of benzodiazepine tranquilizers on aggressiveness, a state of rage are not the same . According to Randall and Schaliek (1960), chlordiazepoxide (2 mg / kg) and diazepam (0.2 mg / kg) have a calming effect on aggressive cats, making them more contact, playful, sociable, eliminating the manifestations of alertness. Interspecific aggressiveness of cats chlordiazepoxide does not inhibit .
The rage reaction caused in cats by the introduction of carbachol into the hypothalamus is suppressed by diazepam. Aggression, caused by isolation or destruction of the septal zone (rat), is suppressed only by neurotoxic doses. According to Fox et al . (1972), benzodiazepine anxiolytics increase in aggressiveness grouped mice, but aggressiveness, induced by electrical stimulation, chlordiazepoxide depressing (Quenezer, Feldman, Moore, 1974). Not by chance one of the latest reviews on this topic is entitled so: “The effect of benzodiazepi on aggression - decrease or increase”?
To a certain extent, the heterogeneity of the method of inducing aggression, the use of different types of animals and dose ranges are the reason for the inconsistency of experimental data. However, besides this, the so-called "activating" effect, which is reduced to the elimination of inhibition, fear, helps to identify aggressive and reactive behavior in general.
The effect of elrokvil to some extent, approaches benzodiazepiovy derivatives. However, its tranquilizing effect is not very strong, it develops in parallel with the increase in positive emoshsh . The “ punishing ” properties of electrostimulation persist longer than the qualitative, emotional coloration caused by this effect.
Elroquil N (2-dimethylamino) -ethyl-3-chlorophenothiazine, a phenothiazine derivative containing only two carbon atoms in the side chain, has, according to experimental data, a selective ataractive action without a hypnotic and all - sedative action. According to preliminary clinical observations, it weakens tension, fear, gives an improvement in well-being without euphoria, impairment of consciousness, and adequacy of behavior ( Elze , 1968). Effective also in unbalanced, aggressive behavior, bad mood.
In the experimental conditions, a distinct anti - aggressive action of elrokvil was not found. He does not have a "taming" effect on aggressive animals. The anti - conflict effect was minimal, and in a certain dose range the drug could even increase the number of conflict situations in the group of animals. The evrophilic effect of elrokvil is not accompanied by a decline in social relationships in the group.
As in the case of chlordiazepoxide , an increase in the general level of positive emotional manifestations (without a general sedative effect and adynamia) enhances the animal's desire to satisfy its needs, and any interference (from other animals in the group or the experimenter) causes a defense or aggressive response.
Effect of anticholinergics on fear
The tranquilizing effect of metamizil is reduced not only to the suppression of the induced emotional state, but also to the general impoverishment of the entire spectrum of emotional activity. At the same time, the “negativity” associated with the direct activation of the brain decreases slightly, the elements of diffuse “anxiety” remain, and even from this small dose, the adequacy of behavior is disturbed.
The ability of central anticholinergics to suppress experimentally induced states of fear has been studied in sufficient detail. In clinical terms, amisnil and megamizil are used to treat neurotic conditions, but the range of their indications is rather narrow.
In some patients, these drugs cause an increase in anxiety, anxiety. It has been shown that amisil and megamisil also cause the first phase of their action to cause a state of discomfort, anxiety, and fear, and only in the second phase does peace occur. In rabbits when administered intravenously, amisyl also causes anxiety in the first 10–15 minutes. This first phase can be eliminated by prior administration of sympatholytic drugs.
Perhaps it can be put into relation with the ability to release amizila and brain tissue norepinephrine from synaptic vesicles and inhibit and ktivnost monoaminokeydazy.
Data on the effect of central anticholinergics on the " punishing " effects of brain electrical stimulation are contradictory. The hypothesis of cholinergic brain systems "punishment" is not confirmed by all.
By the nature of the spectrum of activity, metamizil is more close to mazeptil than to other tranquilizers. Mazheptil does not eliminate the negativity of irritation, does not restore the adequacy of behavior, does not resolve (in these doses) the conflicts of zoosonial relationships. Specific antipsychotic properties of this antipsychotic are not detected on this model,
Under clinical conditions, mazeptil ( thioproperazine ) compared to other neuroleptics of the phenothiazine series has a less general effect of learning and even shows an indirect activating effect in combination with the emotional-volitional revival of Sh. P. Korolenko et al ., 1970).
As follows from the above, the study of the individual spectrum of psychotropic activity of tranquilizers according to the method developed by us gives a fairly close correlation with the characteristics of the same preparations established by the clinical conditions, which makes it possible to evaluate this method of psychopharmacological analysis as quite promising.
As for neuroleptics, the model of the emotional state of anxiety-fear used by us reveals the features associated with the tranquilizing properties of these compounds, however, it is not quite adequate for determining their main, antipsychotic action.
The tranquilizing action of neuroleptics such as haloperidol , epotarazina , mazheptil is not selective, but develops in parallel with their common psychotropic, including psychodisleptic, action. Lepopex can be defined in this plan as a special drug. Its tranquilizing action is independent, it develops selectively with the introduction of small doses of the drug.
In such anxiolytic doses leponeks still does not change the original spectrum of emotional activity and does not cause disorders such highly sensitive to the action of other neuroleptics psychophysiological processes as the adequacy evaluation of the situation, initiative, and others. The spectrum psychotropic action of small doses leponeks resembles the action tranquilizers benzodiazepine, whereas at high doses are features characteristic of neuroleptics.
Preliminary clinical evidence suggests that this drug also has an antipsychotic and tranquilizing effect, promotes re-socialization, and gives a good effect in behavioral disorders with productive symptoms.
Study of the impact on the behavioral act
Behavior, like any other physiological category, passes through certain stages and I am the fetters of evolutionary development. More primitive forms of behavior are organized according to the type of stimulus- trigger response. This stereotypical, "innate" behavior, carried out on the basis of genetically fixed programs ( stimulus bound behavior ).
But already at this level, vital reactions of the type “approximation - avoidance” are formed. At higher stages of phylogenetic evolution, adaptive behavior, based not only on specific but also on individual experience, is becoming increasingly important. These complex programs of behavior are not the stereotypical nature and organized is already not just the type of "stimulus-response".
And, finally, the highest form of adaptive behavior is determined by the symbols of the signals in images, on the basis of processing and synthesis of information, extrapolation, goal-setting. Such elementary rational behavior is inherent not only in anthropoids, but in lower organized animals. In the process of both filo and ontogenesis, more complex forms of behavior are built on simpler ones and relations between them are established according to the type “element - system”.
It has not been sufficiently studied at which stages of development such subjective perceptions of organisms as emotions are included in the integration of behavior. To understand the motivations of behavior, this is important, since the behavior is ultimately determined by the nature of the reinforcement.
The study of the action of psychotropic drugs on complex forms of interaction of living organisms with the environment and other individuals of their species, that is, on their behavior, is the subject of study of many laboratories. This problem is solved in different directions: ethological, psychological, neurochemical and neurophysiological. The latter aspect, in turn, is divided into the analytical direction (determination of the action of psychotropic drugs on individual functional or structural elements of the brain) and systemic.
It does not require special evidence that the psychopharmacological study of such complex forms of the biological and social existence of animals, which is their behavior, is fully possible only on an animal that is not damaged by vivisection interventions, in conditions of relative freedom of manifestation and identification of its actions.
However, it is absolutely necessary to differentiate and isolate from the general chain of behavioral manifestations of individual components corresponding to certain neurophysiological processes, identify behavioral equivalents to those large neurophysiological categories that are included in the architecture of the functional system of a behavioral act, and determine the nature and direction of the various psychotropic drugs these elements of the system.
Psychopharmacological analysis of behavior.
The systems approach is very fruitful for the psychopharmacological analysis of behavior because the basal neurophysiological mechanisms underlying it are still not widely known and not available for direct study. The use of categories of analytical neurophysiology to explain the substance and characteristics of the psychotropic effect of individual bale compounds is not yet adequate.
But the meaning of the therapeutic use of such compounds in psychopathology is the normalization of the impaired system of behavior regulation. And while the essence of psychopathological phenomena is also not deciphered, the description of the peculiarities of the action of different classes of psychotropic compounds can be most fully realized in the terminology of the systems approach.
In turn, a psychopharmacological analysis of the functional system of a behavioral act allows one to penetrate such processes of nervous activity that are inaccessible for research and identification by other techniques that are at the disposal of neurophysiology.
The use of pharmacological methods contributes to the specification of certain provisions that are important for the neurophysiology of behavior, and is thus one of the aspects of studying the systemic organization of behavior. At this point, in particular, according to I. P. Pavlov, the “mutual utility” that exists between physiology and pharmacology is felt.
Interest in the system analysis of psychopharmacological compounds is not a tribute to fashion, but a natural and inevitable stage in the scientific development of pharmacology. If we trace the stages that the neurophysiology of the brain has gone through over the past two decades, then psychopharmacology has completely repeated them, which is reflected in the regular evolution of views on the principal mechanisms of action of psychotropic drugs.
After the disclosure of the physiological role of the reticular formation, the approval of ideas about its ascending and descending systems, many neuropharmacological studies were performed to identify the effect of certain neuropsychotropic drugs on the reticular formation. Many valuable facts were obtained, but it was not possible to adequately explain the effect of psychotropic drugs and the characteristics of individual drugs.
The system of the reticular formation is related to the regulation of the level of wakefulness, it is certainly associated with. basal background activity of many brain processes, but is not a substrate of mental processes of the brain and behavior regulator. However, many non-specific aspects of psychotropic drugs are associated with effects on the reticular formation.
The analysis of psychotropic drugs from the standpoint of their influence on the conduction of nerve signals on specific and diffuse afferent systems provided a wealth of formal data on the shift of certain bioelectric phenomena. But these studies, mostly performed on anesthetized or immobilized animals, did not differentiate what information the afferent systems convey and what these electrophysological phenomena reflect for the functional processes .
In addition, as evidenced by the achievements of modern neuropsychology, brain processes are not organized according to the principle of cable networks or the “telephone station”, so this way is certainly inadequate for studying the psychotropic effect itself.
Studying Intracentric Relations
The study of intracentral relations between different structures of the brain in their electrophysiological aspect reflects the influence of psychotropic drugs on the functional connections between individual elements of the brain. But with their local electrical activation and registration of evoked potentials in other zones (or the total bioelectric effects of large brain substrates), the functional meaning of these shifts, their connection with specific processes of regulation of behavior or mental functions also escapes.
The period of revival of interest in the pharmacological study of conditioned reflexes was marked by an abundance of data on the effect of psychotropic compounds on the conditioned reflex reaction itself , on the relationship between the processes of excitation and inhibition depending on the functional state of the central nervous system.
However, they differed little from the data of the first, while the progressive period of development of pharmacology of higher nervous activity, initiated by I. P. Pavlov and his students. Such studies, of course, are of interest for screening, for determining specific features in the action of various groups of psychotropic compounds, but they contribute little to the further study of both the mechanism of their action and the study of the organization of behavioral reactions.
According to V. Fedorov (1951), the inclusion of new pharmacological compounds in the range of studies did not enrich the pharmacology, since the researchers limited themselves only to the fact that the magnitude of the positive and inhibitory reflexes were increased or decreased.
With all the objectivity and great importance of this method for the development of the physiology and pharmacology of higher nervous activity, the conditioned-reflex principle cannot be considered fully adequate for studying the specific effect of psychotropic drugs. This is especially true for firmly automated, fixed reactions proceeding in a “stimulus-response” scheme. The psychotropic effect could not be qualified in terms of the classical theory of higher nervous activity.
The use of psychophysiological methods for the selection and evaluation of psychotropic drugs (various instrumental methods, behavioral reactions caused by the stimulation of deep brain structures, combinations of both methods, etc.) gave a new “explosion of information”, an endless stream of pharmacological studies that filled periodicals (see the reviews Dews , Morse , 1961; Cook , Kelleher , 1963, and others).
These methods are widely used for the screening of new compounds, their quantitative evaluation, and the identification of the dose – effect relationship. But the results of such psychopharmacological studies are descriptive in nature and reveal the neurophysiological or psychophysiological essence of these changes.
Ethological analysis of psychotropic drugs
Ethological analysis of psychotropic drugs acquired the right of citizenship after the establishment of ethology as a science of animal behavior. Patient and detailed studies of ethologists revealed a greater complexity of individual, intraspecific and interspecific zoosocial relationships of animals that do not fit into the simplified patterns of conditioned reflex behavior.
It became obvious that many psychophysiological categories well studied in humans, and in the same fundamental quality, exist in animals. Naturally, the study of the effects of pharmacological substances on mental functions cannot but take into account the modern achievements of ethology. However, the rather primitive and superficial use of ethological techniques in psychopharmacology gives rise to many contradictions in explaining the facts. The treatment of behavioral manifestations recorded by different researchers for the evaluation of pharmacological effect, as has been shown in previous chapters, far ne is flawless, is largely subjective.
Assessment of psychopharmacological effects on behavior, developing on the basis of motivational, emotional, situational, or other factors, is usually qualified in an alternative form. At the same time, the idea of qualitative or quantitative shifts of individual functional components of behavior, which basically can have different neurophysiological mechanisms, is lost.
In itself, an increase in factual material through the detalization of an infinite number of individual signs of a behavioral act available to registration is not a solution to the problem and only creates the illusion of greater objectification.
It is clear that the further development of experimental, psychopharmacology in its ethological and neurophysiological aspect requires a single methodological basis, which would contribute to the generalization of the mass of individual facts from the position of a general biological concept. At present, the most reasonable and promising theoretical base is system analysis.
The concept of a functional system (P. K. Anokhin) as the principle of organizing the set of neuronal brain elements into a single system for integrating and implementing complex forms of the body’s response is especially productive for the analysis of goal-directed behavior. The application of these ideas to psychopharmacology allows the evaluation of the pharmacological effect not only on the nomenclature of individual fragmentary manifestations of a behavioral act, but also in semantic categories, a functional system for controlling behavior. And this is not just a semantic problem.
The selection of basal categories (processes) involved in the organization of complex forms of adaptive behavior, their detailed study of neuropharmacological and psychopharmacological methods is a guarantee of success and effectiveness of further experimental study of the organization of mental activity. And without this, progress in psychopharmacology is impossible.
In this regard, it is important to carry out a psychopharmacological analysis of each of the links of the functional system of emotional or motivational behavior, highlighting the fundamental importance of the individual stages of the formation of this system for the implementation of subsequent behavior and determining the preferential neurochemical ( mediator ) mechanism associated with the implementation of this link.
Psychotropic drugs, whose pharmacological action is based on interfering with certain neurochemical processes of the brain, split the integral functional system of a behavioral act, have a predominant effect on its individual links, which determines the characteristics of the psychopharmacological spectrum of individual drugs.