Drug Abuse: Hedonic Homeostatic Dysregulation
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A recent Institute of Medicine report [Institute of Medicine Pathways of Addiction (National Academy Press Washington DC 1996)] used a three-stage conceptualization of drug-taking behavior that applies to all psychoactive drugs whether licit or illicit: use abuse and dependence. “Use” of drugs is the taking of drugs in the narrow sense to distinguish it from a more intensified pattern of use. “Abuse” refers to any harmful use regardless of whether the behavior constitutes a disorder in the DSM-IV of the American Psychiatric Association. “Dependence” refers to “substance dependence” as defined by DSM-IV or “addiction” as defined by International Classification of Diseases (ICD 10).
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Underregulation can be defined as a “failure to exert control over one's self.” Conflicting or inadequate standards would be a breakdown in the basis for self-regulation. Reduction in monitoring is a failure of a person to evaluate one's self and actions against relevant standards. Inadequate strength is analogous to the common-sense concept of willpower and is a conflict between the power of impulse/tendency to act and the self-regulatory mechanism to interrupt that response and prevent action. Misregulation can be defined as “exerting control in a way that fails to bring about the desired result or leads to some alternative result.” Misregulation probably most often involves some kind of deficiency in knowledge especially self-knowledge. These knowledge deficiencies include false beliefs distorted beliefs overgeneralizations and misdirected control efforts. Lapse-activated causal patterns are the patterns of behavior that translate an initial lapse (break in self-regulation) into a large-scale indulgence or major binge. Many factors contribute to these patterns of behavior including underregulation emotional responses stress zero-tolerance beliefs spiralling distress and others [R. F. Baumeister T. F. Heatherton D. M. Tice Eds. Losing Control: How and Why People Fail at Self-Regulation (Academic Press San Diego 1994)].
The use of animal models to characterize the neurobiology of specific aspects of human disorders is a reorientation to the “top-down” approach. Here specific behaviors are explored at the system level the cellular level and ultimately the molecular level with hypothesis testing based on an understanding of the mechanism of the behavioral response [
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Russell argued “The notion of dependence on a drug object role activity or any other stimulus-source requires the crucial feature of negative affect experienced in its absence. The degree of dependence can be equated with the amount of this negative affect which may range from mild discomfort to extreme distress or it may be equated with the amount of difficulty or effort required to do without the drug object etc.” This appearance of negative affect could have motivational significance or simply be a signal of a change in set point [M. A. H. Russell in Drugs and Drug Dependence G. Edwards M. A. H. Russell D. Hawks M. MacCafferty Eds. (Saxon House/Lexington Books Westmead UK 1976) pp. 182–187].
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In reference to opponent process theory the a-processes (positive hedonic effects) were proposed to occur shortly after presentation of the reinforcer and to show tolerance. In contrast the b-processes (negative hedonic effects) appear after the a-process has terminated are slow to decay and get larger with repeated exposure. More recent data and conceptualizations suggest that the b-process actually may appear shortly after the beginning of the a-process and may ultimately result in a change in hedonic set point (Fig. 4). In reference to sensitization theory sensitization has been defined as the increased response to a drug that follows its repeated intermittent presentation and may be a potential source of significant differential vulnerability to certain concepts of the addiction cycle. Sensitization theory invokes a shift to a state of incentive salience (defined as a hypersensitive neural state that produces the experience of “wanting”). This state of incentive salience is hypothesized to be produced by drug-induced sensitization of the mesocorticolimbic dopamine system. Thus the pathologically strong craving or “wanting” encountered during protracted abstinence would be hypothesized to be due in large part to an overactive mesocorticolimbic dopamine system. Sensitization has largely been characterized as an enhanced motor response to drugs of abuse with repeated administration though recent work has extended these effects to a progressive increase in the reinforcing value of the drugs at least during initial acquisition of drug-seeking or conditioned drug effects (Figs. 1 and 4). Sensitization is also more likely to be evident with intermittent rather than continuous administration of drugs which favors the development of tolerance and sensitization is long-lasting (up to weeks after injection) [
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The extended amygdala includes the medial (shell) part of the nucleus accumbens bed nucleus of the stria terminalis the central medial amygdala and the sublenticular substantia innominata region. The afferent and efferent connections of the extended amygdala make it well situated for mediating not only basic drug reward but also the neuroadaptive changes associated with sensitization and counteradaptation. Afferent connections include projections from the limbic cortices hippocampus basolateral amygdala midbrain and lateral hypothalamus. Efferent connections include the ventral pallidum ventral tegmental area various brainstem projections and a large projection to the lateral hypothalamus [
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D. Smith personal communication.
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The concept of limited energy within a hedonic system can be traced at least as far back as Carl Jung where the psyche was regarded as a relatively closed system. This limited energy was expressed by the term “libido ” which basically described a general life instinct or psychic energy. Jung wrote “Since our experience is confined to relatively closed systems we are never in a position to observe an absolute psychological entropy but the more the psychological system is closed off the more clearly is the phenomenon of entropy manifested (a system is absolutely closed when no energy from outside can be fed into it)” [C. G. Jung The Structure and Dynamics of the Psyche {translation from Über die Energetik der Seele [On the Driving Force of the Soul] vol. 8 of Über psychische Energetik und das Wasen der Traume [On Psychological Energy and the Meaning of Dreams] (Rascher Zurich 1948)} (Princeton Univ. Press Princeton NJ ed. 2 1969)].
The theological system of Calvin and his followers is marked by a strong emphasis on the sovereignty of God the depravity of humankind and the doctrine of predestination. Calvinism is characterized by a strict disciplined lifestyle where morality is tantamount and there is a strong sense of church unity. Calvinists and later Puritans with regard to personal life demanded of themselves a reformation of character the rejection of idle recreations and vain display and sober obedient godliness [S. E. Ahlstrom A Religious History of the American People (Yale Univ. Press New Haven and London 1972].
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Deroche V., Marinelli M., Le Moal M., Piazza P. V., ibid. 281, 1401 (1997).
Supported in part by NIH grants AA06420 and AA08459 (G.F.K.) from the National Institute of Alcohol Abuse and Alcoholism; NIH grants DA04043 DA04398 and DA08467 (G.F.K.) from the National Institute on Drug Abuse; and INSERM grants (M.L.M.). We thank the following individuals for their comments and discussions of the data and concepts discussed herein: S. Ahmed M. Cador V. Deroche M. Heilig C. Heyser P. Karli M. Lewis A. Markou P. Piazza A. Roberts G. Schulteis G. Simonnet T. Wall and F. Weiss. We also thank P. Brennan M. Arends and the Molecular and Experimental Medicine Word Processing Unit (L. Miller and J. Robertson) for their help with manuscript preparation. This is manuscript number 11020-NP from The Scripps Research Institute.