Alcoholism has many definitions that vary from social frameworks to a psychiatric framework embedded in the diagnosis of Substance Dependence on Alcohol defined in the Diagnostic and Statistical Manual of the American Psychiatric Association,
4th edition (DSM-IV; American Psychiatric Association 1994
). Alcoholism, and more generically drug addiction, can be defined as a chronically relapsing disorder characterized by (i) compulsion to seek and take the drug (alcohol), (ii) loss of control in limiting (alcohol) intake, and (iii) emergence of a negative emotional state (e.g., dysphoria, anxiety and irritability) reflecting a motivational withdrawal syndrome when access to the drug (alcohol) is prevented (defined here as dependence: Koob and Le Moal 1997
). Clinically and in animal models, the occasional but limited use of alcohol with the potential
for abuse or dependence is distinct from escalated alcohol intake and the emergence of a chronic alcohol-dependent state. The thesis argued in the present synthesis is that alcoholism, similar to drug addiction, is a reward deficit disorder, and the “emergence of a negative emotional state” plays an important role in defining and perpetuating alcoholism. Alcoholism also involves substantial neuroadaptations that persist beyond acute withdrawal and trigger relapse and deficits in cognitive function that can also fuel compulsive drinking. However, the argument here is that the core deficit that sets up vulnerability to relapse in alcoholism, and possibly even deficits in cognitive function, is in fact decreased reward function.
To support this hypothesis, a holistic view of alcoholism will be presented with the following arguments. A negative emotional state is a common presentation in most alcoholics during withdrawal and protracted abstinence. Compulsivity observed in alcoholism has an important negative reinforcement component that perpetuates alcoholism. Such negative emotional states become sensitized over time and set up an allostatic state that perpetuates dependence. Negative emotional states set up a powerful motivational state for relapse. Finally, the neurobiological substrates underlying the motivation to seek alcohol will be reviewed, and an argument will be presented that it is loss of reward function and gain of brain stress function that mediate the negative emotional state outlined as key to alcoholism.
Drug addiction has generally been conceptualized as a disorder that involves elements of both impulsivity and compulsivity, in which impulsivity
can be defined behaviorally as “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others” (Moeller et al. 2001
). Impulsivity is measured in two domains: the choice of a smaller, immediate reward over a larger, delayed reward (Rachlin and Green 1972
) or the inability to inhibit behavior by changing the course of action or to stop a response once it is initiated (Logan et al. 1997
). Impulsivity is a core deficit in substance abuse disorders (Allen et al. 1998
) and neuropsychiatric disorders such as attention deficit hyperactivity disorder. Operationally, delay-to-gratification tasks (delayed discounting tasks; impulsive choice) and the stop-signal or go/no-go task (behavioral impulsivity) have been used as measures of impulsivity (Fillmore and Rush 2002
; Green et al. 1994
can be defined as elements of behavior that result in perseveration of responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations (e.g., operationally, responding for a drug or alcohol in the face of adverse consequences (Wolffgramm and Heyne 1995
) or responding for a drug or alcohol on a progressive-ratio schedule of reinforcement (Walker et al. 2008
)). Compulsivity is analogous to the symptoms of Substance Dependence outlined by the American Psychiatric Association: continued substance use despite knowledge of having had a persistent or recurrent physical or psychological problem and a great deal of time spent in activities necessary to obtain the substance (American Psychiatric Association 2000
Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle comprising three stages—preoccupation/anticipation, binge/intoxication,
and withdrawal/negative affect
—in which impulsivity often dominates at the early stages and compulsivity dominates at terminal stages (). As an individual moves from impulsivity to compulsivity, a shift occurs from positive reinforcement driving the motivated behavior to negative reinforcement driving the motivated behavior (Koob 2004
). Negative reinforcement can be defined as the process by which removal of an aversive stimulus (e.g., negative emotional state of drug withdrawal) increases the probability of a response (e.g., dependence-induced drug intake to relieve the negative emotional state). Note that negative reinforcement is not punishment, although both involve an aversive stimulus. In punishment, the aversive stimulus suppresses behavior, including drug taking (e.g., disulfiram [Antabuse]). Negative reinforcement can be perhaps described in lay terms as reward via relief (i.e., relief reward), such as removal of pain or in the case of alcoholism removal of the negative emotional state of acute withdrawal or protracted abstinence. The three stages are conceptualized as interacting with each other, becoming more intense, and ultimately leading to the pathological state known as addiction (Koob and Le Moal 1997
Fig. 1 (Top left) Diagram showing the stages of impulse control disorder and compulsive disorder cycles related to the sources of reinforcement. In impulse control disorders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratification, (more ...)
In alcohol addiction, or alcoholism, a pattern of oral drug taking evolves that is often characterized by binges of alcohol intake that can be daily episodes or prolonged days of heavy drinking and is characterized by a severe emotional and somatic withdrawal syndrome. Many alcoholics continue with such a binge/withdrawal pattern for extended periods of time, but some individuals can evolve into an opioid-like situation in which they must have alcohol available at all times to avoid the negative consequences of abstinence. Here, intense preoccupation with obtaining alcohol (craving) develops that is linked not only to stimuli associated with obtaining the drug but also to stimuli associated with withdrawal and the aversive motivational state. A pattern develops in which the drug must be obtained to avoid the severe dysphoria and discomfort of abstinence.
The pattern of alcohol addiction, related to reward dysfunction, can be amply illustrated by excerpts from two case histories from Knapp (1996)
and Goodwin (1981)
. In the first representative case history, an individual progresses from the state where they stated, “I drank when I was happy and I drank when I was anxious and I drank when I was bored and I drank when I was depressed, which was often,” to, “I loved the way drink made me feel, and I loved its special power of deflection, its ability to shift my focus away from my own awareness of self and onto something else, something less painful than my own feelings,” and, “There’s a sense of deep need, and the response is a grabbiness, a compulsion to latch on to something outside yourself in order to assuage some deep discomfort” (Knapp 1996
). Similarly, in a second representative case history, “Alcohol seemed to satisfy some specific need I had, which I can’t describe,” and, “There were always reasons to drink. I was low, tense, tired, mad, happy,” and, “The goal, always, was to maintain a glow, not enough, I hoped, that people would notice, but a glow,” and, “By now I was hooked and knew it, but desperately did not want others to know it. I had been sneaking drinks for years—slipping out to the kitchen during parties and such—but now I began hiding alcohol, in my desk, bedroom, car glove compartment, so it would never be far away, ever. I grew panicky even thinking I might not have alcohol when I needed it, which was just about always, “ and, “ I loathed myself. I was waking early and thinking what a mess I was, how I had hurt so many others and myself. The words ‘guilty’ and ‘depression’ sound superficial in trying to describe how I felt. The loathing was almost physical—a dead weight that could be lifted in only one way, and that was by having a drink” (Goodwin 1981
; see Koob and Le Moal 2006
, Appendix, for full quotations).
These case histories illustrate numerous key points regarding the present treatise, but the main point to be further discussed below is the transition from drinking to feel good to drinking to avoid feeling bad. To some extent, this transition is facilitated by personality differences, presumably shaped not only by genetics but also by developmental and even social factors. As Khantzian (1997)
cogently argued, addiction can be considered a type of chronic emotional distress syndrome that varies with the individual from physical and emotional pain to chronic dysphoria to stress and anxiety to interpersonal difficulties for which drugs can be argued to be sources of self-medication for such negative emotional states. Additionally, he argued that self-medication may be drug-specific—patients may have a preferential use of drugs that fits with the nature of the painful feeling states that they are self-medicating (e.g., opiates to counter intense anger and rage, stimulants as augmenting agents for high-energy individuals, energizing agents for low-energy individuals, and depressants [e.g., alcohol] for individuals who are tense and anxious). The common element argued by Khantzian is that each class of drugs serves as antidotes or correctives to dysphoric states and acts as a “replacement for a defect in the psychological structure” (Kohut 1971
, p. 46) of such individuals (Khantzian 2003
1.1 Theoretical Framework: Motivation, Withdrawal, and Opponent Process
Motivation is a state that can be defined as a “tendency of the whole animal to produce organized activity” (Hebb 1972
), and such motivational states are not constant but rather vary over time. Early work by Wikler stressed the role of changes in drive states associated with dependence. Subjects described changes in withdrawal as a “hunger” or primary need and the effects of morphine on such a state as “satiation” or gratification of the primary need (Wikler 1952
). Although Wikler argued that positive reinforcement was retained even in heavily dependent subjects (thrill of the intravenous opioid injection), dependence produced a new source of gratification, that of negative reinforcement (see above).
The concept of motivation in addiction was inextricably linked with hedonic, affective, or emotional states in the context of temporal dynamics by Solomon’s opponent process theory of motivation. Solomon and Corbit (1974)
postulated that hedonic, affective, or emotional states, once initiated by drugs, are automatically modulated by the central nervous system with mechanisms that reduce the intensity of hedonic feelings. The a-process
includes affective or hedonic habituation (or tolerance), and the b-process
includes affective or hedonic withdrawal (abstinence). The a-process
in drug use consists of positive hedonic responses, occurs shortly after presentation of a stimulus, correlates closely with the intensity, quality, and duration of the reinforcer, and shows tolerance. In contrast, the b-process
in drug use appears after the a-process
has terminated, consists of negative hedonic responses, and is sluggish in onset, slow to build up to an asymptote, slow to decay, and gets larger with repeated exposure. The thesis here is that opponent processes begin early in drug taking, reflect changes in the brain reward and stress systems, and later form one of the major motivations for compulsivity in drug taking.
Thus, dependence or manifestation of a withdrawal syndrome after removal of chronic drug administration is defined in terms of motivational
aspects of dependence, such as emergence of a negative emotional state (e.g., dysphoria, anxiety and irritability) when access to the drug is prevented (Koob and Le Moal 2001
), rather than on the physical
, signs of dependence. Indeed, some have argued that the development of such a negative affective state can define dependence as it relates to addiction:
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 (Russell 1976
Alcoholics show dramatic evidence of dysphoric states during acute withdrawal that persist into protracted abstinence. Alcohol withdrawal in humans produces well documented physical (somatic) symptoms, such as tremor, autonomic hyperactivity, nausea, vomiting, and seizures, but more importantly produces significant affective symptoms of anxiety, dysphoria, and depression-like symptoms. Acute withdrawal (i.e., the first week post-alcohol) is characterized by Beck Depression Inventory scores of approximately 20, which is categorized within the range of moderate depression (Potokar et al. 21997
; 15–30), and Hamilton Depression Scores of 18, which is close to 20 (the cutoff for antidepressant medication in affective disorder; Brown and Schuckit 1988
). Depression scores decline during subsequent weeks of treatment but remain at close to 10 for Hamilton Depression Scores for up to 4 weeks of an inpatient treatment program (Brown and Schuckit 1988
). In another study of inpatient alcoholics during withdrawal, the Beck Depression Inventory score was at 15 at withdrawal and remained at 12.8 two days into withdrawal and at 9.4 two weeks post-withdrawal (de Timary et al. 2008
). Similar results were obtained for anxiety measures (Potokar et al. 1997
; de Timary et al. 2008
). In another study with a long-term follow-up of 6 months after a 4-week inpatient detoxification. Beck Depression Inventory scores remained at approximately 6, and trait anxiety scores (STAI-X2) remained above 33 even in subjects without comorbid anxiety or depression (Driessen et al. 2001
). Independent of comorbidity status, individuals who relapsed had higher trait anxiety scores than those who abstained (Driessen et al. 2001
). Thus, although alcoholics show significant decreases in measures of depression and anxiety during withdrawal, there is a measurable level of depression-like symptoms that persist long after acute withdrawal into protracted abstinence that may be clinically (treatment) relevant.
More compelling for the present thesis, during a 2-week inpatient withdrawal study, alexithymia (defined as a state of deficiency in understanding, processing, or describing emotions: from the Greek a
for “lack.” lexis
for “word,” and thymos
for “emotion”; Sifneos 1973
; Taylor and Bagby 2000
), which results in poor emotional regulation and stress management abilities, remained high and stable during the 2-week period (de Timary et al. 2008
). Alexithymia scores did not decline between the 0 and 2 day time-points but remained high at a score of 57 and declined only to 53 at the 3-week time-point (de Timary et al. 2008
). The authors argued that alexithymia is a stable personality trait in alcoholics rather than a state-dependent phenomenon, providing support for the self-medication hypothesis outlined above.
Animal models can also be used to test the hypothesis that there are opponent process-like motivational changes associated with the development of alcohol dependence. Electrical brain stimulation reward or intracranial self-stimulation has a long history as a measure of activity of the brain reward system and of the acute reinforcing effects of drugs of abuse. All drugs of abuse, when administered acutely, decrease brain stimulation reward thresholds (Kornetsky and Esposito 1979
) and when administered chronically increase reward thresholds during withdrawal (see above). Brain stimulation reward involves widespread neurocircuitry in the brain, but the most sensitive sites defined by the lowest thresholds involve the trajectory of the medial forebrain bundle that connects the ventral tegmental area with the basal forebrain (Olds and Milner 1954
; Koob et al. 1977
). Although much emphasis was focussed initially on the role of the ascending monoamine systems in the medial forebrain bundle in brain stimulation reward, other nondopaminergic systems in the medial forebrain bundle clearly play a key role (Hernandez et al. 2006
Rats made dependent using chronic ethanol vapor exposure at blood alcohol levels sufficient to drive excessive drinking showed an increase in brain reward thresholds during withdrawal that lasted up to 3 days post-withdrawal (Schulteis et al. 1995
). However, data suggest that, similar to other drugs of abuse, such opponent-like processes can begin with a single dosing ().
Fig. 2 a Withdrawal from a single boul of acute ethanol intoxication (week 1) resulted in a significant but transient increase in brain reward threshold only with the highest dose of ethanol tested (2.0 g/kg: aP < 0.05, compared with vehicle controls (more ...)
An acute elevation in brain reward thresholds was observed during repeated acute withdrawal from ethanol, bearing a striking resemblance to human subjective reports (Schulteis and Liu 2006
) (). These results demonstrate that the elevation in brain reward thresholds following prolonged access to alcohol may fail to return to baseline levels between repeated and prolonged exposure to alcohol self-administration (i.e., a residual reward deficit), thus creating the greater elevation in reward thresholds observed during withdrawal from chronic ethanol. Rapid acute tolerance and opponent process-like effects in response to the hedonic effects of alcohol have been reported in human studies using the alcohol clamp procedure (Morzorati et al. 2002
). These data provide compelling evidence for brain reward dysfunction with chronic alcohol, which provides strong support for a hedonic allostasis model of alcoholism (Koob 2003
The dysregulation of brain reward function associated with withdrawal from chronic administration of drugs of abuse is a common element of all drugs of abuse. Withdrawal from chronic cocaine (Markou and Koob 1991
), amphetamine (Paterson et al. 2000
), opioids (Schulteis et al. 1994
), cannabinoids (Gardner and Vorel 1998
), nicotine (Epping-Jordan et al. 1998
), and ethanol (Schulteis et al. 1995
) leads to increases in reward thresholds during acute abstinence, and some of these elevations in threshold can last for up to 1 week. These observations lend credence to the hypothesis that opponent processes can set the stage for one aspect of compulsivity in which negative reinforcement mechanisms are engaged.
More recently, the opponent process theory has been expanded into the domains of the neurobiology of drug addiction from a neurocircuitry perspective. An allostatic model of the brain motivational systems has been proposed to explain the persistent changes in motivation that are associated with dependence in addiction (Koob and Le Moal 2001
). In this formulation, addiction is conceptualized as a cycle of increasing dysregulation of brain reward/anti-reward mechanisms that results in a negative emotional state contributing to the compulsive use of drugs. Counteradaptive processes that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range. These counteradaptive processes are hypothesized to be mediated by two mechanisms: within-system neuroadaptations and between-system neuroadaptations (Koob and Bloom 1988
In a within-system neuroadaptation. “the primary cellular response element to the drug would itself adapt to neutralize the drug’s effects: persistence of the opposing effects after the drug disappears would produce the withdrawal response” (Koob and Bloom 1988
). Thus, a within-system neuroadaptation is a molecular or cellular change within a given reward circuit to accommodate overactivity of hedonic processing associated with addiction resulting in a decrease in reward function.
The emotional dysregulation associated with the withdrawal/negative affect
stage may also involve between-system neuroadaptations in which neurochemical systems other than those involved in the positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation of the reward system. “In the between-systems opposing process, a different cellular system and separable molecular apparatus would be triggered by the changes in the primary drug response neurons and would produce the adaptation and tolerance” (Koob and Bloom 1988
). Thus, a between-system neuroadaptation is a circuitry change in which another different circuit (anti-reward circuit) is activated by the reward circuit and has opposing actions, again limiting reward function. The remainder of this review explores the neuroadaptational changes that occur in the brain emotional systems to account for the neurocircuitry changes that produce opponent processes and are hypothesized to play a key role in the compulsivity of addiction.