Physiology of Increasing Tolerance and Validation of Psychoactive Substance Dependence

Adaptive responses of the organism under regular exposure to a sub-extreme stimulus. Lack of adaptive responses of the body already known in physiology to explain the adaptation mechanisms in response to a further increase in the regular stimulus strength above the sub-extreme level in PAS dependent patients. The pronounced responses by the vegetative nervous system (VNS) in PAS dependent patients indicate the vegetotrophy of most of these substances. Power of their influence is closest to the sub-extreme level. Responsive adaptive reactions of the organism under regular influence of the external factor of the average to subextreme strength were studied by L. Kh. Garkavi and co-authors. Under the influence of sub-extreme stimuli, an activation reaction with the stages of primary and persistent activation is produced, indicating a higher activity of protective systems. The stage of persistent activation is true active resistance, which is stable and long enough up to six months in contrast to the training reaction and in the absence of constant exposure.

a steady increase in the formation and secretion of corticosteroids develops. They increase the amount of circulating blood and blood pressure, have an antihistamine effect, enhance gluconeogenesis, normalize physiological response, etc. The resistance of the organism to the stimulus increases. Prolonged exposure to the stimulus results in the stage of exhaustion, and death may occur.
Doses of PAS above the stress level are lethal [1].
L.Kh.Garkavi and co-authors showed that: "the reactivity of the organism is represented by a number of floors (ranges), which does not exceed ten. In each floor: a weak stimulus causes the training reaction, an average sub-extreme stimulus -the activation reaction, a strong stimulus -the stress. The ranges are separated by the zone of non-reactivity, when increasing the stimulus level above the stress one or decreasing below the training one causes no reaction. Transition to the next range shows again the same order of reactivity: the reactions of training, activation, and stress.
But L.Kh.Garkavi and co-authors could not explain the mechanisms providing non-fatal transition of the organism from one floor (range) of adaptation to a higher one, after the reaction of primary and persistent activation and further enhancement of the effect above the sub-extreme, stress and higher levels.
Indeed, according to pathophysiology, without such adaptation mechanisms increasing the resistance, the body must die from "exhaustion", from failure of adaptation mechanisms, when the organism transits from the first adaptation range to the second.
But this is not observed in a PAS dependent people. This indicates failure of the current level of physiology to explain the mechanisms providing the body transition from one adaptation range to a higher one.
In the history of narcology, attempts were made to explain the increase in tolerance and the accelerated disintegration of PAS in the addict's organism by different causes. They are the occurrence of the state of chronic stress, activation of other states inactive in normal conditions or activation of systems that fulfill other functions, but with an increase in a PAS dose are forcedly involved in detoxification, etc. But all those assumptions have not been scientifically confirmed.
No matter how full modern scientific research explain qualitative changes at the cellular and molecular level that lead to an increase in tolerance in PAS dependent patients, it is clear that these changes can only be of adaptive, not pathological and damaging nature, otherwise they would lead not to an increase in tolerance, but rather to a decrease in it, and the body would die since transition from the first floor of adaptation to the second.
Also, according to the dialectical principle of the mutual transition of qualitative changes to quantitative ones, accumulation of these changes should lead to qualitative and quantitative changes in the neuroendocrine system which is responsible for the adaptation of the whole organism. -"it is possible to investigate separately the changes in any one system or at any one level, for example, molecular. But this is only a part of the changes in the overall complex reaction of the body.
Also, I would like to quote I.N. Pyatnitskaya : "Integral functional reactions to the intoxication of physiological systems are known to be no less important in maintaining homeostasis than biochemical protection". Consequently, we can speak about change of the body's response to a drug. "When excited in neurons, metabolic processes are intensified, the amount of RNA increases, and the synthesis of proteins in neurons is enhanced. In neurons and glia cells surrounding them, these processes are multidirectional. RNA in nerve cells is increased due to the enhancement of its synthesis in a neuron and due to the transport of RNA from glial cells to neurons".

Object and methods of investigation
Histological evidence of the neuroendocrine system hypertrophy under regular exposure to a medium-strength stimulus is Selye's stress research: "adrenal glands bloom". But the adrenal medulla, which is a modified sympathetic ganglion cannot be hypertrophied.
Adaptive, positive, trophic changes, during pauses, allow the sympathetic ANS only to recover itself, not to be exhausted, to maintain productivity for a long time. Hypertrophy appertains to the structures. Therefore, speaking of adrenal hypertrophy, one should keep in mind the adrenal cortex. As early as in 1930s, it was found that chronic morphinization causes hypertrophy of the cortical layer of the adrenal glands in rats, which produces the "adaptation hormones" -glucocorticoids (hydrocortisone, cortisone and corticosterone), increasing the resistance of the organism to intensive stimuli [3].There is no doubt in the Adrenal cortex hypertrophy starts even in the activation reaction, since the process of adrenal hypertrophy is not spasmodic. There is no doubt that due to the mechanism of "advanced excitation", other internal secretion glands "takes a break" for trophic recovery processes, which leads to their hypertrophy and hyperfunctionality. Evidences of adaptive hypertrophy of the endocrine system are L. Kh. Garkavi and co-authors' observations under conditions of training and activation reactions -enlargement of not only the adrenal cortex, but also thymus gland, a prolonged increase in the thyroid and reproductive gland functions [4]. range, everything comes around. It is more correct to call such a process a state of not chronic, but regular, unfinished stress. Stress without the exhaustion stage, no matter how regular it is, cannot be considered as a disease [5]. That allows the body to transit to a higher range of adaptation without death. It becomes clear that increased resistance in persistent activation reaction responding to regular sub-extreme exposure to PAS and the resistance stage in stress responding to the further regular exposure to an increasing dose of PAS are functional manifestations of adaptive hypertrophic changes in endocrine system.

Figure 1
This process is called progredient (or progressive) adaptation.
Beliefs about the unity of form and function, the stereotyped thinking that "if changes in the body are acquired and irreversible, therefore, they are pathological," have led to the erroneous judgment that the body's dependencies on PAS should be considered as diseases. There is the expression "any disease is an adaptation." But the opposite statement that "any adaptation is a disease" in relation to PAS dependencies is inadmissible. It is because neither failure, lack of adaptive capabilities, necessity of compensation for the adaptive capabilities of the body at the expense of any tissues or body systems is observed, nor the disease develops resulted from hypertrophy of Under alcohol exposure, when to achieve euphoria and acquire dependence, abuse with adaptive, qualitative or quantitative

Am J Biomed Sci & Res
Copy@ Baitubayev Ducengali G changes in the mechanisms responsible for the euphoria is required, the accompanying increase in tolerance can be explained by the neuroendocrine system hypertrophy.
Productivity of VNS in the first stage of alcohol dependence explain maintaining the body tone during the week intervals of sobriety, in the absence of alcohol stimulation.
Compensatory stress and production of neurotransmitters or residual neurotransmitter excess, due to VNS productivity, explains adrenergic tension and vegetative disorders in the alcohol withdrawal syndrome.
The productivity of the sympathetic part of VNS against the background of the gradual exhaustion of the parasympathetic department (adrenergic system is more resistant even in ontogenesis) also explain the qualitative change (according to narcotism age) of the sedative PAS (hypnotics, alcohol, opiates) effect on the body, transformation of their initial sedative action into a stimulating one.
The hypertrophy of the endocrine system due to prior narcotization explains the rapid development of alcohol dependence in former opium addicts in alcoholization: rapid increase of alcohol tolerance, the rapid formation of alcohol abstinence syndrome, the development of binge drinking (to develop alcoholism in former drug addicts, it is sufficient to develop only a specific tissue adaptation to alcohol).
Stimulation of the hypertrophic neuroendocrine system and increase in the overall resistance of the organism explain the fact that many stimulants (caffeine), eliminating some effects of ethanol, however, do not change its pharmacokinetics, prolong its intoxicating effect.
Initially the psychomotor agitation in PAS-dependent people getting narcosis can be based on the excitement of the productivity sympathetic department of VNS.
As the PAS dependence develops, functional sufficiency of VNS and the adaptation hypertrophy and hyper functionality of the endocrine system lead to the fact, that neuroendocrine system role as a functional mechanism of protection and adaptation increases and becomes the leading one.

1.
Under regular sub-extreme exposure of the organism to psychoactive substance, physiological adaptation processes develop and lead to the hypertrophy of the endocrine system.

2.
Under regular sub-extreme exposure to psychoactive substance, progredient adaptive hypertrophic changes in the endocrine system lead to an increase in the tolerance of the organism.

3.
In psychoactive substances dependence, due to the adaptive hypertrophy of the endocrine system and the increased resistance, potentially extreme doses have a nonpathogenic sub-extreme effect on the organism.

4.
Dependence of the body on psychoactive substances due to the increased tolerance of the organism and the transformation of the effect of potentially extreme doses into the sub-extreme effect is the adaptation process.

Recommendations
It is necessary to validate the dependence of the body on psychoactive substances not as a disease, but as a state of proqredient adaptation.