Panasenko O. I. , Buryak V. P., Samura T. O., Melnik I. V., Kremzer O. A., Kravchenko T. V., Postol N. A., Voloch N. H., Panasenko T. V.

Zaporozhye State Medical University

THE THEORY OF EARSY DRUG DEPENDENCE

Most general attempts to isolate a defining property of addiction have focused on one or another form of drug dependence. As might be suspected, the definition of dependence has not proved much easier than the definition of addiction. Dependence is defined as a condition that develops with habitual drug intake and that is revealed by a distress syndrome when habitual intake is discontinued or pharmacologically blocked. The classic physiological dependence syndromes are associated with opiates, alcohol, and barbiturates. The cramps, sweating, nausea, convulsions, and other symptoms associated with withdrawal from chronic, high-dose usage of these agents are dramatic and can be objectively measured; thus dependence on these substances is termed physiological or physical dependence. The concept of physical dependence offers the basis of a theory of addiction that is not circular, because dependence is defined in terms that are separate from the compulsive drug seeking that identifies addition. Identifying physical dependence as the common denominator of addictions to different substances is not merely defining a new word to reflect the same thing. Thus the notion of physical dependence offers a potential explanation of addiction that meets the first criterion for a heuristic theory; it is not merely renaming the phenomеnot it attempts to explain. However although its lack of circularity gives the concept of physical dependence potential heuristic value, physical dependence has not proved to have actual heuristic value as the foundation of a general theory of addiction. Several facts are inconsistent with the view that physical dependence is either a necessary or a sufficient condition for addiction. One is that the relief of withdrawal distress is minimally effective in treating addictive syndromes [1]. Another is that the dependence syndromes associated with different drug classes are not homologous. The classic pattern of withdrawal symptoms associated with depressant drugs such as opiates, barbiturates, and alcohol is different from the patterns of withdrawal symptoms that are seen with stimulant drugs such as cocaine, amphetamine, or nicotine [2]. Indeed, even the withdrawal syndrome seen with the barbiturates is not homologous to that seen with the opiates [4]. In response to these and other problems, dependence theory has gone through a succession of unsuccessful rations. The first major attempt to modify dependence theory was an attempt to define a so-called Psychic dependence syndrome that would extend to all classes of addictive drugs where physical dependence syndromes had failed to do so [5]. With the realization that some habit-forming drugs are not associated with a single, classic withdrawal syndrome, attempts have been made to extend the concept of dependence by defining it in terms of drug craving or compulsive drug self-administration, rather than in terms of a syndrome of withdrawal symptoms. To distinguish it from the physiological dependence objectively demonstrated in the case of opiates, alcohol, and barbiturates, dependence defined in terms of craving and self-administration is termed psychic dependence. As will be immediately obvious to those who have thought seriously about the mind-body problem, the dichotomy between psychic and physiologic dependence has proved troublesome. To distinguish psychic dependence from physiologic dependence is to deny the very obvious fact that there is a physiological basis for psychological dependence.

The central problem with this notion is that the concept of psychic dependence is circularly defined; psychic dependence is defined in terms of the very phenomena – craving and compulsive self-administration – that define addiction. Thus the concept of psychic dependence can offer no explanation of addiction. Whereas physiologic dependence was defined independently, in terms of physiological consequences of habitual intake, psychic dependence is defined circularly, in terms of the intake which it is then argued to cause. Thus the concept of psychic dependence, unlike the concept of physiologic dependence, offers no advantage over the concept of addiction itself; it is no easier to define and it does not advance understanding of the phenomenon. The concept of psychic dependence merely renames the problem; it has no heuristic value whatsoever.

In light of the circularity of the concept of psychic dependence, some workers have returned to the notion that all addictive drugs produce dependence syndromes that can be identified by objective physiological consequences of drug withdrawal [6]. Whereas nicotine, amphetamine, cocaine, and caffeine do not produce the classic dependence syndrome associated with opiates, alcohol, and barbiturates, they do produce withdrawal distress and physiological withdrawal symptoms of their own. If we take the production of any form of withdrawal distress and any physiological withdrawal symptoms as the defining properties of dependence, then it can be said that these drugs are dependence producing. If we take the self-medication of withdrawal distress as a cause of drug self-administration, then dependence can logically serve as a partial explanation of addiction. Inasmuch as the subjectively experienced and subjectively reported withdrawal distress is as unpleasant as many illnesses for which medication is readily prescribed and taken, and inasmuch as physiological withdrawal symptoms – unlike psychic dependence – are demonstrated in ways other than by self-administration itself, the concept of physical dependence offers a non-circular, and thus potentially heuristic, definition of addiction. It is tempting, then, to return to the concept of physical dependence using a broader definition of dependence than was used in early dependence theories. Thus there is no homology between dependence of the opiate type and dependence of the barbiturate type. What we know about the mechanism of the one is not necessarily useful in understanding the other. If there is no unity to the concept of physical dependence even within the class of depressant drugs, then it seems clear that there can be no unity to the dependence concept as applied across various drug classes. Although these are good reasons to turn away from dependence theory, there are now even stronger reasons to question the utility of physical dependence as a general explanation of addiction. Of the various problems associated with dependence theory, the most damaging is that dependence does not seem to offer a good or complete explanation of compulsive drug self-administration even when prototypical dependence-producing drugs like opiates or alcohol are considered. Dependence theory attempts to explain drug taking in terms of dependence; drug taking is seen as motivated – once addiction is established – by the need to alleviate withdrawal distress. Dependence theory does not explain why drug self-administration habits get established in initially nondependent subjects; nor does it explain why relapse rates are so high in adequately detoxified ex-addicts. Dependence theory does not attempt to explain the development of addiction or re-addiction; it merely attempts to explain why drug-seeking and drug-taking habits are so strong once they are established.

However, even this aspect of dependence theory has been seriously challenged. For example, alcohol-dependent humans and monkeys will undergo voluntary abstinence periods, failing to initiate alcohol self-administration at times when withdrawal symptoms are strong but subsequently initiating such self-administration at times when withdrawal signs are minimal. Thus withdrawal distress does not necessarily compel an individual to take a drug. Even in the case of opiates, the case where dependence theory was perhaps most firmly rooted, dependence and habitual intake can now be clearly dissociated. It has been demonstrated empirically that opiate dependence is not a necessary condition for either establishing or maintaining compulsive opiate self-administration. The data to support this assertion will be discussed in some detail, because if dependence theory fails in the case of opiate self-administration, then it seems clear that the notion of dependence cannot serve as a heuristic explanation of addiction to substances, such as cannabis, nicotine, cocaine, or amphetamine, that produce weak or atypical dependence signs at best.

The theory relates the reinforcing effects of drugs and brain stimulation to unconditioned psychomotor stimulant effects of those agents that result from activation of dopaminergic fibers of the medial forebrain bundle, its inputs, or its outputs. A serious problem for the ultimate success of the theory is the fact that dopamine receptor blockade does not have immediate effects on the psychomotor activation caused by a click that has been paired with food in a free-feeding task despite its having immediate and potent effects on the psychomotor activation caused by similar cues in a partial-reinforcement operant task. Moreover, dopamine blockers have no appreciable effects on the "priming" effects of stimulation in animals that have been trained to run an alley and lever-press or simply to run in a running wheel for such stimulation. It seems that the conditioned psychomotor stimulant effects of reinforces can be maintained for a significant period without the support of the dopamine system. The relation between unconditioned and conditioned psychomotor actions of reinforcing drugs is not addressed by the present theory but has major significance for both the understanding and the treatment of addiction [3].

REFERENCES

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2. Clarke's Analysis of Drug and Poisons. Fourth Edition / Edited by Anthony C. Moffat, M David Osselton - Head, Centre for Forensic Sciences, School of Conservation Studies, Bournemouth University, UK, Brian Widdop. – London: The Pharmaceutical Press. 2011. – 2609 p.

3. Clinical Toxicology: Principles and Mechanisms. Frank A. Barile, Boca Raton. Florida: CRC Press, 2004. – 474 p.

4. Fundamentals of analytical toxicology / Edited by R. T. Flanagan. – New York: John Wiley and Sons, 2007. – 532 p.

5. Handbook of Toxicology. Second Edition / Edited by Michael T. Derelanko, Mannfred A. Hollinger. – Florida: CRC Press LLC, 2000. – 1380 p.

6. Immunotoxicology Strategies for Pharmaceutical Safety assessment. Editor by Danuta J. Herzyk, Jeanine L. Bussiere. – London: Royal Medial Academy, 2012. – 898 p.