Tag Archive: Alkohol


1,6 Millionen alkoholkranke Menschen leben in Deutschland – Professoren, Obdachlose, Mütter, Mediziner. Das Therapiekonzept ALITA könnte vielen helfen – doch niemand will dafür bezahlen

Weinflaschen © Photocase.de/Flaccus

Kerstin Saller* ist 56 Jahre, 18 davon hat sie im Alkohol ertränkt. Um von der Flasche loszukommen, lässt sie sich in Suchtkliniken behandeln. Immer wieder. Und immer wieder wird sie rückfällig. „Irgendwann wurde mir klar, dass ich es auf diesem Weg nicht packe“, erzählt sie im Gespräch mit NetDoktor. Doch dann hat Kerstin Glück: Sie ist eine von 180 Alkoholkranken, die an einer zweijährigen Studie des Max-Plank-Instituts in Göttingen teilnehmen. Die letzte Chance. Erprobt wird ein neues Konzept zur Alkoholtherapie. ALITA heißt es und steht für Ambulante Langzeit-Intensivtherapie für Alkoholkranke. „Alles was hilft, ist erlaubt – das war unser Motor“, erklärt Prof. Hannelore Ehrenreich, die Entwicklerin des Modells, gegenüber NetDoktor. Die Medizinerin besitzt jahrelange Erfahrung mit Alkoholkranken, und von diesen gibt es in Deutschland viele. Rund 1,6 Millionen Menschen hängen an der Flasche, bei 3,2 Millionen ist der Konsum im roten Bereich, so die Zahlen der Bundeszentrale für gesundheitliche Aufklärung (BZgA).

Täglich auf Trab

In den kritischen ersten Wochen ist die Betreuung sehr intensiv. „Denn viele Alkoholiker greifen gleich am ersten Tag nach dem Entzug wieder zur Flasche“, weiß die Suchtexpertin. Täglich müssen die Patienten zu einem Gespräch in die Ambulanz. Erscheint ein Patient nicht, telefonieren die ALITA-Betreuer hinterher oder suchen ihn sogar zu Hause auf. „Aggressive Nachsorge“ nennen Ehrenreich und ihr Team das. Auch wenn ein Rückfall droht, sind die Betreuer da – 24 Stunden täglich, 365 Tage im Jahr. „Diese intensive Betreuung war für mich die letzte Rettung“, bestätigt Kerstin. Klassische ambulante Modelle sehen Therapiesitzungen nur ein- bis zweimal wöchentlich vor. Für viele Alkoholkranke reicht das nicht aus.

Unter der Käseglocke

Auch stationäre Therapieansätze für Alkoholkranke haben Schwachstellen, aber andere. Die Patienten werden abgeschirmt vom problematischen Alltagsleben. „Die Klinik“, sagt Kerstin, „wirkt wie eine Käseglocke“. Auf das Ende der Therapie folgt dann der Realitätsschock. Einsamkeit, Familienstress, Arbeitslosigkeit, Geldsorgen, Frust und … der erneute Griff zur Flasche. Kerstin erzählt: „Eine ambulante Therapie ist zwar erstmal härter, aber man lernt von Anfang an im Alltag ohne Alkohol zurechtzukommen.“

Künstliche Alkoholvergiftung

Bei ALITA ist neben der intensiven Betreuung auch die Kontrolle wichtig. Ein täglicher Urintest zeigt, ob der Patient Alkohol getrunken hat oder nicht. Vor den Augen der Betreuer schluckt er täglich ein Mittel mit dem Wirkstoff Disulfiram (Antabus). Es verhindert, dass Alkohol im Körper abgebaut wird. Wer sich jetzt einen genehmigt, bekommt die Symptome einer Alkoholvergiftung: knallroter Kopf, Herzrasen, Schwindel und Übelkeit.

„Wir bleuen den Entzugspatienten die Wirkung des Mittels immer wieder ein“, sagt Ehrenreich. In ihrem Konzept ist das Medikament ein wichtiger Verbündeter im Kampf gegen die Sucht. Entscheidend ist die psychische Wirkung. Kerstin sagt: „Ich hatte die drohenden Folgen dauernd im Hinterkopf, das hat geholfen, dem nächsten Schluck zu widerstehen.“

Jedenfalls ist sie seitdem trocken – so wie rund 50 Prozent ihrer Mitstreiter. „Eine solche Erfolgsquote gibt es sonst weltweit nicht“, betont Ehrenreich. Bei anderen Therapieangeboten seien nach zwei Jahre nur noch 5 bis 30 Prozent trocken, so ihre Erfahrung.

Bürokratisches Tauziehen

Trotzdem gibt es ALITA für Alkoholkranke in Deutschland nicht. Ein wesentlicher Grund ist offenbar das bürokratische Tauziehen zwischen Krankenkasse und Rentenversicherung, bei dem es ums Geld geht. Normalerweise zahlen die Kassen den medizinischen Part (Entzug und manchmal Entwöhnung). Alle therapeutischen Maßnahmen für die Wiedereingliederung ins Berufsleben (also die Nachsorge) übernehmen die Rentenversicherer.

Eine solche Aufteilung gibt es aber beim ALITA-Konzept nicht, weshalb sich keine der Parteien so recht zuständig fühlt. „Unser Gesundheitswesen ist an vielen Stellen wurmstichig und veraltet“, kritisiert die Ärztin Ehrenreich. „Jeder hält an seinen Pfründen fest.“

Kein Interesse an ALITA

Auf Nachfragen von NetDoktor gab der Bund der Rentenversicherer an: Man sehe keine Veranlassung, ein weiteres Therapiekonzept aufzunehmen, sie hätten schon Angebote, die genauso wirksam seien. Konkret benennen konnten die Verantwortlichen allerdings auf Rückfrage keines.

Der Verband der Krankenkassen entdeckte ein anderes Haar in der Suppe. So wurde während der ALITA-Studie in einigen Fällen ein Medikament eingesetzt, das heute in Deutschland nicht mehr verordnet wird. Ein ausreichender Grund, um das gesamte Projekt abzuschmettern.

Schmuddelkinder der Gesellschaft

Erschwerend kommt hinzu, dass Alkoholiker keine Lobby, aber dafür ein denkbar schlechtes Image haben: Sie sind die Schmuddelkinder des Gesundheitssystems. Zu dieser Krankheit mag sich kaum einer bekennen.

So gibt es die Anonymen Alkoholiker seit Jahrzehnten, von anonymen Diabetikern hat noch niemand etwas gehört. Viele Privaten Krankenkassen haben Alkoholentzugstherapien sogar ganz aus dem Leistungskatalog gestrichen. „Das geht soweit, dass Ärzte, die sich mit Alkoholikern befassen, von Kollegen scheel angesehen werden“, berichtet Ehrenreich.

Therapie aus eigener Tasche

Einige Suchtmediziner setzen die Therapie zumindest in Grundzügen ein. Die Drogenhilfe Provivere in Hamburg bietet das Konzept Plan A an, das auf ALITA basiert – allerdings nur für Selbstbezahler. 18.000 Euro müssen die Patienten für die zweijährige Therapie berappen. Das Westfälische Zentrum für Psychiatrie in Bochum setzt das Konzept in Grundzügen im Rahmen ihrer Alkoholambulanz um – einen 24-Stunden-Service wie ALITA ihn eigentlich vorsieht, kann das Team jedoch nicht leisten. „Darunter leidet vermutlich auch die Erfolgsquote“, bestätigt der Leiter der Ambulanz, Dr. Alfred Wähner, gegenüber NetDoktor.

Dass ALITA dauerhaft wirkt, dafür ist Kerstin der beste Beweis. Sie versucht sich unverdrossen als freiberufliche Ernährungsberaterin zu etablieren. Zwar ist die Situation der Hartz-IV-Empfängerin alles andere als rosig – trotzdem hat die Droge die Macht über sie verloren. Sie sagt: „Ich verschwende heute keinen Gedanken mehr an Alkohol.“

 

Christiane Fux

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1. Einleitung
Einheimische Deutsche bringen mit Aussiedlern nicht selten exzessiven Alkohol- und illega-len Drogenkonsum sowie Kriminalität in Verbindung. Damit meinen sie oft die jungen Russ-landdeutschen, die immer wieder im Blickpunkt der Medien stehen. Gerade die Medien sind es, die das Bild der Aussiedler in der Öffentlichkeit bestimmen, zumal die große Mehrheit der Bundesbürger über keine persönlichen Kontakte und Erfahrungen verfügt. Da Medien nur Ausschnitte der Realität zeigen und diese entsprechend den Interessen ihres Publikums aufbe-reiten, bleibt die mediale Darstellung des Drogenkonsums junger Aussiedler rudimentär.
Deshalb sind empirische Untersuchungen erforderlich, die Erkenntnisse über die Drogenprob-lematik bei Aussiedlern liefern. Seit einigen Jahren mehren sich Studien zu dieser Bevölke-rungsgruppe, dennoch fehlt es in Bezug auf den Drogenkonsum weiterhin an Daten. Dieser Missstand ist auch darauf zurückzuführen, dass diese Zuwanderer nach der Einreise die deut-sche Staatsangehörigkeit erhalten und deshalb in den meisten Statistiken nicht gesondert er-fasst werden. Ziel des vorliegenden Beitrags ist, die Einflüsse des Substanzgebrauchs im sozi-alen Umfeld der jungen Russlanddeutschen darzustellen. Solche Einflüsse wurden bei Aus-siedlern bislang lediglich ansatzweise (Strobl et al. 1999) untersucht.
Der vorliegenden Beitrag beschränkt sich auf die jungen Russlanddeutschen, da diese seit den 1990er Jahren das Gros der Aussiedler stellen.1 Ferner sind es diese Heranwachsenden, die immer wieder mit Drogen in Verbindung gebracht werden. Die Befragung war auf die Stadt Frankfurt am Main begrenzt.2 Dies hatte forschungsökonomische Gründe, hing aber auch mit der besonderen Situation in dieser Stadt zusammen: Frankfurt zählt neben Hamburg und Ber-lin zu den „Drogenhauptstädten“ der Bundesrepublik (vgl. Stöver 2001: 15)3 und zeichnet sich durch eine vorbildliche Integration von Zuwanderern aus.

Weiter geht es hier: zdun_drogen_russlanddeutsche

INHALT
Zusammenfassung
1. Einleitung
1.1. Zum Frühverlauf der Schizophrenie
1.2. Zur Komorbidität von Psychose und Sucht
1.2.1. Epidemiologie
1.2.2. Erklärungsansätze zur Komorbidität
1.2.3. Probleme in der Therapie komorbider Patienten
1.3. Fragestellungen dieser Arbeit
2. Material und Methoden
2.1. Untersuchungsrahmen
2.2. Art der Datenerhebung
2.3. Beschreibung der Gesamt-Stichprobe
2.4. Beschreibung der Stichprobe der berücksichtigten Patienten
2.5. Zusammenfassung
3. Ergebnisse
3.1. Psychopathologie im Verlauf
3.2. Bestimmung der Parallelisierungszeitpunkte
3.3. Das Konsummuster zwischen 1988 und 1997
3.4. Varianzanalyse zum Konsummuster
3.5. Das Konsummuster an den Parallelisierungszeitpunkten
3.6. Einfluß von subjektiver Symptomatik und Diagnose-Zeitpunkt
4. Diskussion
4.1. Methodische Fragen
4.2. Diskussion der Ergebnisse
4.3. Fazit und Ausblick

weiterlesen: PsychoseundSucht_Studie

Abhängigkeit (Allgemeines)
Die Frage nach den Ursachen, die zu einer Abhängigkeit führen, ist auch eine Frage
nach der Motivation, überhaupt eine Substanz zu sich zu nehmen, bzw. eine
diesbezügliche Handlung auszuführen, zunächst eingeschränkt auf den
Drogenkonsum: Warum werden Drogen genommen?
Drogen sind neben den illegalen Substanzen auch legale Alltagsdrogen (Nikotin,
Koffein, Alkohol, Chinin, Capsaicin, Kakao) und zudem das breite Spektrum mehr
oder weniger psychoaktiver Medikamente.
Der menschliche Körper selbst produziert eine große Zahl solcher Substanzgruppen,
um unser Wohlbefinden, unsere physischen und psychischen Befindlichkeiten
maßgeblich zu steuern. Eine physische Beeinflussung korreliert daher bei einem
mehr oder weniger regelmäßigen Abusus (Missbrauch) psychotroper Substanzen
letztendlich mit einem tiefen Eingriff in das körpereigene Regelkreis-System (s.a.
Kybernetik) der Hormone und Neurotransmitter, infolgedessen der psychologische
Zustand eines Individuums verändert und gestört wird. Die Zufuhr körperfremder
(exogener) Stoffe (i.e.S. der eigentlichen Droge) und deren Verstoffwechselung
respektive Metabolismus hat dabei oft große Ähnlichkeit mit jenen Stoffen, die der
eigene Körper produziert, um in spezifischen Situationen allerdings nur kurzzeitig
eine notwendige Befindlichkeit sicherzustellen. Im Normalfall ohne Drogenkonsum
kommt es jedoch niemals zu einer Dauerausschüttung von diesbezüglich initiierten
Hormonen und Neurotransmittern, die eine derartige (drogeninitiierte) Gefühlslage
hervorrufen würden. Durch die Dauerausschüttung solcher Botenstoffe im Gehirn
(besonders Substanzen mit eminentem Pons-Passage-Wirkprofil) und den primär
hormonellen und additiv dopaminergen Auswirkungen auf das vegetative
Nervensystem (s.a. Sympathikus/Parasympatikus) kann durch anhaltenden Konsum
ein nachhaltiger Gewöhnungseffekt (Toleranzbildung) eintreten. Der regelmäßige
Missbrauch führt besonders bei potenten Wirkstoffen zum Ceiling-Effekt, den
Drogenabhängige fürchten wie der Teufel das Weihwasser.

Die Rohstoffabhängigkeit
übernimmt zunehmend alle vorgesehenen Bindungsstellen (Rezeptoren) des Körpers
und unterwirft dessen Funktionalität und Befindlichkeit – ohne die Droge – nachhaltig.
Zudem ist es nicht immer nur der chemischen Substanz, sondern vor allem auch
ihren symbolischen Attributen geschuldet, auf welche Droge die Wahl des Einzelnen
fällt. „Manche Drogen besitzen aus den verschiedensten Gründen ein jugendliches,
andere ein Außenseiter-Image, und bei wieder anderen bemüht sich die Industrie
offenbar nicht völlig erfolglos, ihnen ein Image von Freiheit und Abenteuer zu
verleihen.“ (Leitfaden Drogentherapie,S.41/Campus Verl.1997).

weiter lesen: 070101_Lexikon_Neurobiologie

A) ALLGEMEINE GRUNDLAGEN 2
1. Verhaltensbiologie 2
2. Das Gehirn – Strukturen, Prozesse und Funktionen 3
2.1 Anatomie (Makroanatomie) 3
2.2 Struktur hirnlokaler Netzwerke (Mikroanatomie,
Histologie) 9
2.3 Die Nervenzelle und ihre Verknüpfungen 11
2.4 Die Nervenzelle – chemische Impulse 15
2.5 Innerzelluläre molekulare Signalketten 17
2.6 Neurophilosophie – das „Gehirn-Geist“-Problem
und das „Mikro-Makro“-Problem 19
B) NEUROBIOLOGIE DER SUCHT 20
3. Drogen 20
4. Neurochemische Dynamik 24
5. Neuroanatomie der Sucht 28
5.1 Die zentrale Rolle des Dopamin-Systems 28
5.2 Das Gesamtbild der funktionellen Architektur des
süchtigen Gehirns 30
5.3 Hirn-Schädigungen als Konsumfolge 31
C) LITERATUR 32

Weiter lesen: 001_070402_BAS_Skript_Neurobiologie_der_Sucht_Tretter

Most definitions of drug addiction or substance dependence include (i) descriptions of „overwhelming involvement with the use of a drug (compulsive use)“ (1) and (ii) a number of symptoms or criteria that reflect a loss of control over drug intake and a narrowing of the number of different behavioral responses toward drug-seeking (2). Drug addiction can be equated with substance dependence as defined by the American Psychiatric Association (3). However, it is important to distinguish between what is termed substance use, substance abuse, and substance dependence (addiction) (4).

In humans, most drug users do not become drug abusers or drug-dependent (4). Similarly, stable drug intake can be observed in animals without pronounced signs of dependence, even with intravenous drug administration under limited-access situations. Many factors such as availability (route of administration), genetics, history of drug use, stress, and life events contribute to the transition from drug use to drug addiction. The current challenge is to discover what neurobiological elements convey the individual differences in vulnerability to this transition to drug addiction.

In this article we will draw from recent formulations in behavioral neuroscience and other disciplines to construct a framework to view addiction as a continuous process of hedonic homeostatic dysregulation. Multiple sources of reinforcement are identified in the spiralling cycle of addiction, and the symptoms of this hedonic dysregulation form the well-known criteria for substance dependence or addiction (2, 3). Critical neurotransmitters, hormones, and neurobiological sites have been identified that may mediate the hedonic dysregulation and may provide the substrates that convey both vulnerability to, and protection against, drug addiction (5) (Fig. 1).


Fig. 1. Diagram describing the spiralling distress-addiction cycle from four conceptual perspectives: social psychological, psychiatric, dysadaptational, and neurobiological. (A) The three major components of the addiction cycle, preoccupation-anticipation, binge-intoxication, and withdrawal-negative affect, and some of the sources of potential self-regulation failure in the form of underregulation and misregulation. (B) The same three major components of the addiction cycle with the different criteria for substance dependence from DSM-IV incorporated. (C) The places of emphasis for the theoretical constructs of sensitization and counteradaptation. (D) The hypothetical role of different neurochemical and endocrine systems in the addiction cycle. Small arrows refer to increased functional activity. DA, dopamine, CRF, corticotropin-releasing factor. Note that the addiction cycle is conceptualized as a spiral that increases in amplitude with repeated experience, ultimately resulting in the pathological state known as addiction. (fuer groesseres Bild unten gucken!)


Spiralling Distress and the Addiction Cycle

Important elements that may be involved in the failure to self-regulate drug use, as well as other behaviors such as compulsive gambling and binge eating, have derived from social psychology (6). It is of interest to conceptualize how these regulation failures ultimately lead to addiction in the case of drug use or an addiction-like pattern with nondrug behaviors. Lapse-activated causal patterns, that is, patterns of behavior that contribute to the transition from an initial lapse in self-regulation to a large-scale breakdown in self-regulation, can lead to spiralling distress (6). Spiralling distress describes how, in some cases, the first self-regulation failure can lead to emotional distress, which sets up a cycle of repeated failures to self-regulate, and where each violation brings additional negative affect (6). For example, a failure of strength may lead to initial drug use or relapse, and other self-regulation failures can be recruited to prevent an exit from the addiction cycle. Here, spiralling distress will be used to describe the progressive dysregulation of the brain reward system within the context of repeated addiction cycles (Fig. 1A).

Psychiatry and experimental psychology, in effect, address the same addiction cycle (Fig. 1B), and neurobiology has begun to identify the neurobiological elements that contribute to the break with hedonic homeostasis, known as addiction. Although animal models provide a critical part of the study of the neurobiology of addiction, no animal models incorporate all the elements of addiction. Alternatively, animal models can be established and validated for different symptoms or constructs associated with addiction (7). There is much evidence for valid animal models of many of the criteria in the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (3) and the sources of reinforcement associated with addiction (7).

Neurobiology of Drug Reinforcement

The focus for the neurobiological mechanism for the positive-reinforcing effects of drugs of abuse has been the mesocorticolimbic dopamine system and its connections in the basal forebrain (8, 9). For cocaine, amphetamine, and nicotine, the facilitation of dopamine neurotransmission in the mesocorticolimbic dopamine system appears to be critical for the acute reinforcing actions of these drugs [for reviews, see (8, 9)]. Multiple dopamine receptors including D-1, D-2, and D-3 have been implicated in this reinforcing action (10, 11). Neuropharmacological studies support both a dopamine-dependent and a dopamine-independent contribution to the positive-reinforcing effects of opiates such as heroin (8, 9, 12). Ethanol appears to interact with ethanol-sensitive elements in multiple neurotransmitter receptor systems, and these interactions may contribute to ethanol’s positive-reinforcing actions (13). The neurotransmitters and receptor systems implicated include actions on the gamma -aminobutyric acid (GABA), glutamate, dopamine, serotonin, and opioid peptide systems, all of which are within the mesocorticolimbic dopamine system and its connections to the nucleus accumbens and amygdala (13). Limited study has implicated the release of dopamine in the nucleus accumbens in the positive-reinforcing actions of tetrahydrocannabinol (THC) (14).

A major question still challenging drug abuse research, however, is whether the neurobiology of reward and drug reinforcement changes with chronic use and during the manifestation of an abstinence syndrome when the drug is no longer self-administered. Historically, substance dependence has focused on the manifestation of an abstinence syndrome upon abrupt cessation of drug administration that was characterized by physical signs such as the well-documented tremor and autonomic hyperactivity of ethanol withdrawal and the discomfort and pain associated with opiate withdrawal. However, recent conceptualizations of abstinence symptoms have begun to focus on aspects of abstinence that are common to all drugs of abuse and may be considered more motivational in nature and perhaps are best described as a negative affective state (5, 15, 16). These symptoms include various negative emotions such as dysphoria, depression, irritability, and anxiety (3, 15, 16).

Consistent with these clinical observations, animal studies in which intracranial self-stimulation was used as a measure of reward function have revealed pronounced decreases in reward (or increases in the reward threshold) associated with withdrawal from all major drugs of abuse tested to date (Fig. 2). These effects vary with dose and duration of exposure to the drug, but can last as long as 96 hours after withdrawal from the drug in rodent models (15, 16).


Fig. 2. Changes in reward threshold associated with chronic administration of three major drugs of abuse. Reward thresholds were determined by a rate-independent discrete trials threshold procedure for intracranial self-stimulation (ICSS) of the medial forebrain bundle. (A) Rats equipped with intravenous catheters were allowed to self-administer cocaine for 12 hours before withdrawal and reward threshold determinations. Elevations in threshold were dose-dependent with longer bouts of cocaine self-administration yielding larger and longer-lasting elevations in reward thresholds (51). Asterisks refer to significant differences between treatment and control values. Values are mean ± SEM. (B) Elevations in reward thresholds with the same ICSS technique after chronic exposure to ethanol of about 200 mg% in ethanol vapor chambers (52). (C) Elevations in reward thresholds measured with the same ICSS technique after administration of very low doses (in milligrams per kilogram of body weight) of the opiate antagonist naloxone to animals made dependent on morphine with two, 75-mg morphine (base) pellets implanted subcutaneously (53). (fuer groesseres Bild unten gucken!)


The significance of drug abstinence syndromes remains controversial as a basis for compulsive use (1, 7), but increasing evidence both in animal and human studies suggests that the presence of a negative affective state may not only signal the beginning of the development of dependence (17), but may contribute to vulnerability to relapse and may also have motivational significance. Rats made dependent on opiates and ethanol show increases in drug self-administration (18). Thus, exposure to sufficient amounts of drug to produce dependence as measured by elevations in reward thresholds can increase the motivation for a drug. This increase could result from additive or even synergistic sources of positive and negative reinforcement (19) and may contribute to the addiction cycle.

Neural Substrates for Sensitization and Counteradaptation of Reward

At the neurobiologial level, two neuroadaptive models have been conceptualized to explain the changes in motivation for drug-seeking that reflect compulsive use: counteradaptation and sensitization. Counteradaptation hypotheses (20) were intimately linked to the development of hedonic tolerance by the formulation known as opponent process theory (21). In contrast, sensitization, a progressive increase in a drug’s effect with repeated administration, has been conceptualized to be a shift in an incentive-salience state (21).

Both of these conceptual positions focus on neurobiological changes at the molecular, cellular, and system levels, and both may involve what have been described as „within-system“ and „between-system“ changes (8). At the neurochemical level, changes associated with the same neurotransmitters implicated in the acute reinforcing effects of drugs that are altered during the development of substance dependence would be examples of within-system changes.

Counteradaptive, within-system neurochemical events include decreases in dopaminergic and serotonergic neurotransmission in the nucleus accumbens during drug withdrawal (22). At the molecular and cellular levels, changes in opiate receptor function during withdrawal from chronic opiates and decreased GABAergic and increased glutamatergic transmission during ethanol withdrawal have been observed [(23), and Nestler and Aghajanian (24) in this issue)]. Sensitization to the locomotor stimulant effects of psychomotor stimulants and opiates also appears to involve within-system activation of the mesolimbic dopamine system. There appears to be a time-dependent chain of adaptations within the mesolimbic dopamine system that leads to the long-lasting changes produced by sensitization (25).

Changes in other neurotransmitter systems that are not linked to the acute reinforcing effects of the drug but are recruited during chronic drug administration have been conceptualized as between-system adaptations. Examples of between-system counteradaptations include increases in dynorphin function in the nucleus accumbens during chronic cocaine administration, increases in anti-opioid peptides associated with chronic opioid administration, and augmentation of brain stress systems such as corticotropin-releasing factor (CRF) associated with cocaine, opiates, ethanol, and THC (15, 16, 26).

Recent neuroanatomical, neurochemical, and neuropharmacological observations have provided support for a distinct brain circuit within the basal forebrain that may mediate both the within-system and between-system neurochemical changes associated with drug reward. The extended amygdala (27) is a hypothesized macrostructure consisting of several basal forebrain structures that share similarities in morphology, neurochemistry, and connectivity (27). Support for the role of the extended amygdala in the acute reinforcing effects of drugs of abuse can be found in a series of in vivo microdialysis and neuropharmacological studies that showed selective activation of dopamine in the shell of the nucleus accumbens by most of the major drugs of abuse (28). In addition, GABAergic and opioidergic mechanisms in the central nucleus of the amygdala may participate in the acute reinforcing actions of ethanol (29). Also, the central nucleus of the amygdala may function in counteradaptation of the brain reward system during the development of drug dependence. Chronic administration of drugs can alter both CRF and proopiomelanocortin gene expression in the amygdala (30). An increased CRF response in the central nucleus of the amygdala is associated with acute withdrawal from ethanol, opiates, cocaine, and THC (31).

Limited data suggest a specific role for parts of the extended amygdala in sensitization. The mesolimbic dopamine system is clearly involved, but no specific subregion has been delineated. Glucocorticoids can activate the mesolimbic dopamine system by increasing dopamine synthesis, decreasing dopamine metabolism, and decreasing catecholamine uptake (5). The participation of a specific subprojection of the mesolimbic system in sensitization is under investigation.

Relapse: Neural Substrates and Vulnerability

Relapse and vulnerability to relapse are key elements in the maintenance of a chronic relapsing disorder such as addiction [see O’Brien (32), this issue]. Animal models predictive of relapse are being developed. Studies suggest that stresslike stimuli and neuropharmacological agents that activate the mesocorticolimbic dopamine system can rapidly reinstate intravenous drug self-administration that has been previously extinguished (33), and drugs that modulate dopamine receptors can block reinstatement of cocaine self-administration in rats (11). Naltrexone and acamprosate decrease relapse rates in alcoholics (34) and can modify excessive drinking in rodents in various models (35). Thus, a rich source for study of the neurobiological mechanisms of relapse will be the same neurotransmitters and neurocircuitry implicated in the within- and between-system adaptations of sensitization and counteradaptation.

The vulnerability to relapse will have both genetic and environmental bases resulting in a susceptible host, from a medical perspective (36). Animal studies have begun to address both these contributions. While genetic vulnerability is beyond the scope of this review, there are rodent strains that show preferences for drinking ethanol, and there is mounting evidence of alterations in the same reward neurotransmitters that may form the basis of such preferences (37). In addition, new techniques such as quantitative trait loci analysis and the study of knock-out and transgenic mice are revealing potential genetic sites associated with vulnerability (38).

Environmental factors involved in vulnerability have largely focused on the role of stress. An atypical responsivity to stress in former opiate- and cocaine-dependent subjects has been well documented and hypothesized to be linked to chronic relapse (39). Exposure to repeated stressors also increases the propensity to develop initial intravenous drug self-administration (acquisition) (40) and can facilitate reinstatement of drug self-administration after extinction (relapse) (33). These effects appear to be directly linked to activation of the hypothalamic pituitary adrenal axis. Suppression of stress-induced corticosterone secretion abolishes the enhanced behavioral responsiveness to amphetamine and morphine produced by different stressors (41). Consistent with these observations, repeated administration of corticosterone can substitute for stress and increase the behavioral effects of psychostimulants (41). It is hypothesized that glucocorticoid hormones function in the long-term maintenance of the sensitized state and may even represent a within-system change (41). In addition, vulnerability to drug-taking may be influenced by a history of drug experience and the presence of competing nondrug reinforcers altering the response to drug reinforcers (42).

The combination of genetic and environmental factors can dramatically change an animal’s response to drugs. A comparison of rats that show a high and low locomotor response to forced exposure in a novel environment revealed that high responders (HRs) show a greater propensity to develop intravenous drug self-administration compared with low responders (LRs) (43). This greater sensitivity to drugs in HRs shows a correlation with dysregulation of the hypothalamic pituitary adrenal axis (a prolonged secretion of corticosterone in response to stress) and with a higher sensitivity to the behavioral and dopamine-activating effects of glucocorticoids (41) (Fig. 3). Indeed, stress has been hypothesized to cause HR rats to express enhanced responses to drugs (43, 44). What is largely unknown is how these genetic and environmental factors combine to contribute to the development of what constitutes substance dependence (addiction) in humans. In addition, identification of the vulnerability for different parts of the addiction cycle using animal models will provide clues to relapse vulnerability in human addicts. With the use of animal models, studies of the interaction of genetics, of stress, and of the initial response to drugs on various features of the addiction cycle other than drug-taking will be informative.


Fig. 3. (A) The effects of adrenalectomy on cocaine self-administration in rats. Animals were trained to self-administer cocaine by nose-poking and subjected to a dose-effect function. Adrenalectomy produced a flattening of the dose-effect function, with decreases of cocaine intake at all the doses (54). (B) Corticosterone-induced changes in extracellular concentrations of dopamine in high-responding (HR) and low-responding (LR) animals. HR animals that drank the corticosterone solution (100 mg/ml) in the dark period showed a faster and higher increase in accumbens dopamine than LR animals (55). (fuer groesseres Bild unten gucken!)


Homeostasis of Reward, Self-Regulation, and „Natural“ Addictions

The concept of homeostasis contends that an organism maintains equilibrium in all of its systems, including the brain reward system, that is, the organism uses physiological and cognitive or behavioral capabilities to function within the appropriate limits of physiology with the help of its own resources. Environmental factors that challenge homeostasis are met with counter actions. Allostasis refers to the concept of physiology where an organism must vary all of the parameters of its internal milieu and match them appropriately to perceived and anticipated environmental demands in order to maintain stability (45). If the threats to the system continue to produce disequilibrium, the process of allostasis continues to regulate where the organism must mobilize enormous amounts of energy to maintain apparent stability at a now pathological „set point.“ The system is at the limit of its capability, and thus a small challenge can lead to breakdown (45). This is the beginning of spiralling distress and the addiction cycle. When the organism has reached a state of dysregulation so severe that it cannot recover by mobilizing its own resources, allostasis has reached the point of what is normally considered illness. The state of dysregulation of the reward system may produce loss of control over drug intake, compulsive use, or drug addiction. The mechanisms that contribute to this allostasis are normal mechanisms for homeostatic regulation of reward that have spun out of the physiological range (that is, sensitization and counteradaptation).

Addiction Cycle: Sensitization and Counteradaptation

The role of sensitization in dependence has been elaborated where a shift in an incentive-salience state, described as „wanting,“ progressively increases with repeated exposure to drugs of abuse (21). This shift is largely attributed to a pathological overactivity of mesolimbic dopamine function and, as such, represents a break with homeostasis. Other factors such as increased secretion of glucocorticoids may function in the long-term maintenance of this sensitized state (41).

Early theories of counteradaptation with chronic drug administration were based on the concept of homeostasis (20) and later extended to hedonic processes in opponent process theory (21) (Fig. 4). This theory may explain the affective withdrawal component of the addiction cycle and also may explain how repeated drug-taking can lead to spiralling distress. Indeed, the onset of a negative affective state can be used to define addiction (17). In addition, the negative affective state may have motivating properties in maintaining drug-seeking behavior, not only by direct negative reinforcement (that is, the drug is taken to relieve the negative state) but also by changing the set point for the efficacy of reinforcers and thus add motivational effectiveness to both positive drug effects and conditioned positive drug effects (7, 15, 16, 21). At least two common neurochemical elements, activation of limbic CRF systems and a decrease in mesolimbic DA function, are common neurochemical correlates of the early parts of drug withdrawal (15, 16, 31).


Fig. 4. Diagram illustrating an extension of Solomon and Corbit’s opponent-process model of motivation to incorporate the conceptual framework of this article (21). All panels represent the affective response to the presentation of the stimuli (that is, drug administration). (A) The original description of the affective stimulus, which was argued to be a sum of both an a-process and a b-process and represents the initial experience with no prior drug history. (B) The same affective stimulus in an individual with an intermittent history of drug use that may result in sensitized response. The shaded line illustrates the sametrace of the initial experience in (A). The dotted line represents the sensitized response. (C) Change in the affective stimulus hypothesized to exist in the heavily dependent individual (that is, after chronic exposure) where there is a major change in the hedonic set point. This represents a change sufficient to be considered a major break with hedonic homeostasis. The light dotted line represents the sensitized response observed in (B). (D) The hypothesized state of protracted abstinence and enhanced vulnerability to relapse with a history of chronic continuous experience. The change in this panel reflects the change in the affective response in an organism with a history of depen-dence where there is both a change in set point that is long-lasting and a residual sensitization. The bar to the right of each diagram illustrates the total peak-to-peak contrast between the lowest point in negative affect to the highest point in positive mood produced by a drug at any point in the addiction cycle. An alternative hypothesis still under consideration is that even during an intermittent sensitization pattern of drugtaking, the affective after-reaction (b-process) also may get progressively larger and larger (21). „On“ refers to the „time on“ of the hedonic stimulus, in this case the drug action. „Off“ refers to the „offset“ of the drug action. (fuer groesseres Bild unten gucken!)


At first glance, the two processes of sensitization and counteradaptation may appear to make opposite predictions about the course of drug dependence and the neurobiology of drug dependence. However, if drug dependence is viewed in the context of spiralling distress, then it is possible that both processes are active, although perhaps not concurrently, at different parts of the cycle (Figs. 1 and 4). The neurobiology of a heavily dependent person (Fig. 4C) will be very different from that of a nondependent person (Fig. 4A) and may reflect a state of severe allostasis (with a change in set point) and the part of the addiction cycle associated with negative affect and spiralling distress (Fig. 1C). For example, enhanced dopaminergic and opioidergic neurotransmission may be involved in the preoccupation-anticipation stage and result in sensitization (Figs. 1C and 4B), but compromised dopamine, serotonin, and opioidergic neurotransmission, as well as increases in stress neurotransmitters, may be responsible for the negative affective state of withdrawal (Figs. 1D and 4C). The combination of a change in hedonic set point produced by repeated counteradaptation and a separate mechanism for sensitization would provide a dramatic motivational force for continuing drug dependence (Fig. 4, C and D).

This view is similar to that of incentive motivational theory (46) and incorporates some aspects of incentive-salience theory (21). Under the current formulation, counteradaptation creates a need state that may or may not easily be labeled by subjective responses but, rather, reflects a chronic break with homeostasis such as a decrease in hedonic set point. Sensitization, in contrast, creates a facilitated incentive motivation or incentive salience that reflects enhanced responses to drug incentive stimuli (that is, wanting or craving).

According to this formulation, sensitization is assigned a relatively minor role in the ongoing process of spiralling distress, but a more important role in triggering the beginning of instability (vulnerability to drug-taking, as in the form of cross-sensitization to stress) or retriggering of instability as in the process of relapse (reentrance into the cycle of spiralling distress). Indeed, a dependent person is almost by definition already sensitized. However, there is little evidence of sensitization in drug-dependent people, and most clinical evidence points to tolerance, not sensitization. Human addicts consume enormous amounts of ethanol, opiates, and even stimulants that would easily be toxic to nonaddicted individuals (47). In addition, most of the animal studies of sensitization have focused either on locomotor activity as a dependent variable or in the drug reward domain on acquisition of drug self-administration (21). If sensitization is to gain a role as extensive as that outlined herein, more data will be required to show a link between these measures of enhanced sensitivity to drugs of abuse (locomotor activity and acquisition of drug self-administration) and other measures of dependence.

Implications for the Concept of Addiction and Treatment

The present conceptualization of addiction has important implications for the treatment of drug addiction. The social psychological components of failure to self-regulate may impact on different parts of the addiction cycle (Fig. 1A), and these different components may be reflected in changes in different components of reward neurocircuitry (Fig. 1D). For example, failure of strength may reflect increases in stress system activity, whereas failure of monitoring or attention may reflect cognitive changes that are influenced by the widely distributed brain monoamine systems.

The present conceptualization also provides a framework for studying the components of addiction most often neglected in animal studies. The role of neurobiology in different processes, such as social psychological self-regulation failures, positive and negative reinforcement, sensitization, and counteradaptation, changes dramatically over the course of transition from drug use to abuse to addiction. In addition, different drugs may act differentially on parts of the spiralling distress-addiction cycle. Young, type II alcoholics (48) may be more involved in the preoccupation-anticipation and binge components than terminal alcoholics, where a major need state has usurped most other sources of motivation. In contrast, users of opiates and nicotine may assume this need-state component at a much earlier stage (49). Studies of the neurobiology of such differences will be critical for future interventions at both the prevention and treatment levels.

There is clearly a neurobiological basis for multiple sites of treatment intervention. Eliminating affective withdrawal and the reward need state are critical (such as methadone for opiate addiction), as well as eliminating the changes that lead to facilitated incentive salience (such as naltrexone for alcohol addiction). Various forms of behavioral therapies and psychotherapy have been shown to be effective in treating addiction, particularly in combination with pharmacotherapy [(34) and O’Brien (32), this issue]. These therapies ultimately act on the same dysregulated hedonic circuitry to help return and maintain it within homeostatic boundaries. In addition, vulnerability to addiction can be conveyed at any part of the spiralling distress of the addiction cycle and should not be simply relegated to initial drug responses.

Although beyond the scope of the present review, dysregulation of hedonic homeostasis can also occur with compulsive use of nondrug reinforcers. Similar patterns of spiralling distress-addiction cycles have been observed with pathological gambling, binge eating, compulsive exercise, compulsive sex, and others (6). The same neurobiological dysregulations and breaks with homeostasis may be occurring within the same neurocircuitry implicated in drug dependence. With the advent of more sophisticated measures of brain function in humans, such questions may be pursued.

The implications of this homeostatic view for everyday existence forces one to return to social psychology, but with a biological perspective. The brain hedonic system may be a limited resource (50). One can expend this resource rapidly in a binge of drug-taking or other compulsive behavior, but at a great risk for entrance into the spiralling dysregulation of the addiction cycle. Alternately, one can adopt a more regulated, „hedonic Calvinistic“ approach (51) where use of the reward system is restricted within the homeostatic boundary (that is, without the development of subsequent negative affect). Such an ascetic view may or may not fall within certain cultural norms, but probably makes biological sense.

REFERENCES AND NOTES

  1. J. H. Jaffe, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, A. G. Gilman, T. W. Rall, A. S. Nies, P. Taylor, Eds. (Pergamon, New York, ed. 8, 1990), pp. 522-573.
  2. World Health Organization, International Statistical Classification of Diseases and Related Health Problems (World Health Organization, Geneva, 10th revision, 1990).
  3. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington, DC, ed. 4, 1994).
  4. 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).
  5. G. F. Koob and E. J. Nestler, J. Neuropsychiatry Clin. Neurosci. 9, 482 (1997) [Abstract/Free Full Text] ; P. V. Piazza and M. Le Moal, Brain Res. Rev., in press.
  6. 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)].
  7. 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 [ A. Markou, et al., Psychopharmacology 112, 163 (1993) [CrossRef] [Medline] ; G. F. Koob, in Psychopharmacology: The Fourth Generation of Progress, F. E. Bloom and D. J. Kupfer, Eds. (Raven Press, New York, 1995), pp. 759-772; G. F. Koob et al., J. Psychopharmacol., in press].
  8. G. F. Koob and F. E. Bloom, Science 242, 715 (1988) [Abstract/Free Full Text] .
  9. R. A. Wise and P.-P. Rompre, Annu. Rev. Physiol. 40, 191 (1989) ; M. Le Moal and H. Simon, Physiol. Rev. 71, 155 (1991) [Free Full Text] ; G. F. Koob, Trends Pharmacol. Sci. 13, 177 (1992) [CrossRef] [Medline] ; F. E. Pontieri, G. Tanda, F. Orzi, G. Di Chiara, Nature 382, 255 (1996) [CrossRef] [Medline] .
  10. W. L. Woolverton, Pharmacol. Biochem. Behav. 24, 531 (1986) [CrossRef] [ISI] [Medline] ; G. F. Koob, H. T. Le, I. Creese, Neurosci. Lett. 79, 315 (1987) [CrossRef] [ISI] [Medline] ; J. Bergman, J. B. Kamien, R. D. Spealman, Behav. Pharmacol. 1, 355 (1990) [Medline]; S. B. Caine and G. F. Koob, Science 260, 1814 (1993) [Abstract/Free Full Text] .
  11. D. W. Self, W. J. Barnhart, D. A. Lehman, E. J. Nestler, Science 271, 1586 (1996) [Abstract] .
  12. G. Di Chiara and R. A. North, Trends Pharmacol. Sci. 13, 185 (1992) [CrossRef] [Medline] ; T. S. Shippenberg, A. Herz, R. Spanagel, R. Bals-Kubik, C. Stein, Ann. N. Y. Acad. Sci. 65