10 Substance Use Disorders

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S E C T I O N

X SUBSTANCE USE DISORDERS

CHARLES P. O’BRIENMARIAN W. FISCHMAN

Although the prevailing view for many decades was thatdrug dependent patients simply suffered from character weakness, the persuasive data emerging from modern brainimaging techniques and the application of molecular biol-ogy methods to animal models of compulsive drug use indi-cate that this position is no longer tenable. The integrationof a number of new technologies has allowed investigatorsto combine behavioral and neurobiological approaches tomore completely evaluate multiple aspects of this difficultproblem.The following 16 chapters detail advances in the biology of substance use disorders, concentrating on those occurringduring the 1990s, the decade of the brain. The section con-centratesonadvancesmostrelevanttoneuropsychopharma-cology, integrating neurobiology, behavioral biology, andpharmacology. Knowledge of the pathophysiology of druguse disorders has greatly increased with the identificationand cloning of receptors for the major drugs of abuse. Thereis also a much greater understanding of the brain circuitsinvolved, including those common to different classes of drugs. The efficacy of treatment has also increased throughthe availability of effective medications for alcohol, heroin,and nicotine, as well as behavioral approaches used withcocaine abusers. Also, there is greater acceptance of thechronic disease model, which focuses on functional im-provement as the realistic goal of treatment, rather than‘‘cures.’’The terminology used in this section deserves some com-ment. There is general agreement that there are degrees of

Neuropsychopharmacology: The Fifth Generation of Progress.

Edited by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, andCharles Nemeroff. American College of Neuropsychopharmacology



2002.

severity ranging from occasional drug use to a dangerousbut moderately severe state called ‘‘abuse’’ in the AmericanPsychiatric Association Diagnostic and Statistical Manual(DSM), to a severe compulsive state known as ‘‘depen-dence’’ or ‘‘addiction.’’ There is disagreement, however, onthe usefulness of the term ‘‘addiction’’ to denote this severestate that occurs only in the minority of users who losecontrol and become compulsive drug users with a chronicrelapsingclinical course.TheDSM-III RevisionCommitteenarrowly voted not to use the term ‘‘addiction’’ because of its prejudicial connotations, opting instead for ‘‘depen-dence.’’ This was continued in the current version, DSM-IV. The other point of view is that the term ‘‘dependence’’creates confusion because it is already used to designate thestate marked by drug-specific withdrawal symptoms thatnormally occur when regular drug use is abruptly termi-nated(‘‘physical’’dependence).Dependencealsohasalong-standing use as a personality disorder descriptor completely unrelated to drug use. Most important, patients withchronic pain receiving opiates often show signs of toleranceand withdrawal symptoms without any behavior that couldbe categorized as abuse. Physicians who are confused by ‘‘dependence’’ defined as a normal response and ‘‘depen-dence’’ as a disorder have been known to mistakenly with-hold pain medication to ‘‘prevent addiction.’’ We haveopted to use the DSM terminology for the title of this sec-tion,but thereaderwillfind thatthereis someinconsistency among the chapters in the use of the terms ‘‘addiction’’ and‘‘dependence’’ reflecting the current variance in the fieldover proper terminology.

95

NEUROCIRCUITRY OF ADDICTION

PETER W. KALIVAS

Addiction can be defined as drug-induced changes in thecentral nervous system (CNS) that produce maladaptive al-terations in spontaneous behavior and in the behavioral re-sponsetoreadministrationofthat drug. Maladaptivebehav-iors include those identified as criteria for addiction in theDSM-IV. In general what most psychiatric metrics describeas addiction associated behaviors is the emergence of behav-iors to obtain drug reward at the expense of engaging inbehaviors to seek natural rewards, ranging from biologicalrewards such as sex to cultural rewards such as stable per-sonal relationships. The substitution of drug reward for nat-ural reward suggests that the neuropathology of addictionmay reside in the same neural systems that mediate thedetection and acquisition of natural rewards. This postulateforms a primary premise in the search for the neurobiologi-cal basis of addiction, and has revealed a circuit consistingof interconnections among limbic cortex, basal ganglia, andbrainstem nuclei that is pathologically modified by repeateddrug administration. The drug-induced changes in thestructure and function of this circuit are progressive, andto some extent parallel the development of the behavioralcharacteristics of addiction.Over the last decade neurobiologists have come to de-scribe the behavioral transition to addiction as a drug-induced neuroplastic process (1–3). In parallel with thedevelopment and expression of addictive behaviors, theneurobiology of these two components of the transition toaddiction can be described as: (a) the sequence of molecularevents that establish the neuroplastic changes leading to ad-diction, and (b) the neuroplastic changes themselves. Ac-cordingly, a number of molecular neuroplastic alterationshave been identified in the brain after repeated drug admin-istration, and some of these appear to be important in thedevelopment and/or expression of addictive behaviors.However, the process of identifying drug-induced changesis accelerating and producing a deluge of information thatis proving increasingly difficult to integrate into a coherentsequence of neuroplastic changes that mediate addiction. In

Peter W. Kalivas:

Department of Physiology and Neuroscience, MedicalUniversity of South Carolina, Charleston, South Carolina

partthedifficultyofintegrationarisesbecausetheveracityof each molecular neuroplastic event must be tested in animalmodelsofaddiction;alabor-intensiveprocessoftenemploy-ing imprecise tools for selective

in vivo

manipulation of cellbiology. Moreover, this problem is compounded by the factthat the neuroadaptations associated with use of a drug of abuse are not entirely predicated on the pharmacology of the drug. It has become increasing clear that in addition todrug pharmacology, the environmental regulation of thedrug-induced changes is a critical factor in the developmentand expression of addiction (4–6). Althoughacriticalroleforenvironmentinthemanifesta-tion of addicted behaviors has been obvious for decades inthe behavioral evaluation of addiction in humans and ani-mal models, only recently has the drug–environment inter-face been directly evaluated as critical in the cellular neuro-adaptations mediating addiction (7,8). The realization thatthe neuroplasticity defining addiction arises as a collabora-tion between repeated drug administration and environ-mental associations is contributing to the construction of atemplate to help organize and integrate the emerging tideof data that describes the cellular adaptations potentially mediating addiction. Figure 95.1 illustrates how learningtoassociateenvironmentalstimuliwiththemolecularactionof a drug impinges on brain circuitry to elicit neuroplasticchanges producing addiction. Figure 95.1 is used to orga-nize this chapter into the three current arenas of investiga-tion into the neurobiology of addiction: (a) the molecularsite of action by a drug and the immediate consequences of drug administration to intracellular signaling and synaptictransmission; (b) the circuitry involved in learning and how this integrates with the molecular action of drugs of abuse;and (c) the overall circuitry of reward that contains bothmolecular sites of drug action and learning circuits, andforms the site of pathologic change mediating addiction.

PHARMACOLOGYMolecular Binding Site of the Drug

The molecular site of action and the immediate sequenceof cellular events have been successfully decoded for many

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