Drug addiction is a chronically relapsing disorder characterized by (i
) compulsion to seek and take the drug, (ii
) loss of control in limiting intake, and (iii
) emergence of a negative emotional state (e.g., dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented (defined here as dependence) (Koob and Le Moal, 1997
is assumed to be identical to the syndrome of Substance Dependence
(as currently defined by the Diagnostic and Statistical Manual of Mental Disorders
; American Psychiatric Association, 1994). Clinically and in animal models, the occasional but limited use of a drug with the potential
for abuse or dependence is distinct from escalated drug intake and the emergence of a chronic drug-dependent state.
Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity, where 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 in 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 in responding in the face of adverse consequences or perseveration in the face of incorrect responses in choice situations. These elements are analogous to the symptoms of Substance Dependence as 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 comprised of three stages—preoccupation/anticipation
, and withdrawal/negative affect
—where 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). These 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
) (). The present review will focus on the role of an animal model of compulsivity that derives from the negative emotional state of the withdrawal/negative affect
stage of the addiction cycle.
Stages of the addiction cycle.
Different drugs produce different patterns of addiction with emphasis on different components of the addiction cycle. Opioids can be considered classic drugs of addiction because subjects meet most of the criteria classically associated with addiction, including dramatic tolerance and withdrawal. A pattern of intravenous or smoked drug-taking evolves, including intense intoxication, the development of tolerance, escalation in intake, and profound dysphoria, physical discomfort, and somatic withdrawal signs during abstinence. Intense preoccupation with obtaining opioids (craving) develops that often precedes the somatic signs of withdrawal and 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 where the drug must be obtained to avoid the severe dysphoria and discomfort of abstinence. Other drugs of abuse follow a similar pattern but may involve more the binge/intoxication stage (psychostimulants and alcohol) or less binge/intoxication and more withdrawal/negative affect and preoccupation/anticipation stages (nicotine and cannabinoids).
Alcohol addiction, or alcoholism, can follow a similar trajectory, but the pattern of oral drug taking 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, 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. Tobacco addiction contrasts with the above patterns—the binge/intoxication stage forms a minor component of nicotine dependence. The pattern of nicotine intake is one of highly titrated intake of the drug except during periods of sleep. However, during abstinence, users experience negative emotional states, including dysphoria, irritability, and intense craving. Marijuana Dependence follows a pattern similar to opioids and tobacco, with a significant intoxication stage, but as chronic use continues, subjects begin to show a pattern of use manifest by chronic intoxication during waking hours and withdrawal characterized by dysphoria, irritability, and sleep disturbances. Psychostimulants, such as cocaine and amphetamines, show a pattern focused on the binge/intoxication stage in which binges can be hours or days in duration and often are followed by a withdrawal (“crash”) characterized by extreme dysphoria and inactivity.
1.1. 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 withdrawal changes 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 was linked inextricably with hedonic, affective, or emotional states in addiction 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, 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, 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
Rapid acute tolerance and opponent process-like effects in response to the hedonic effects of cocaine have been reported in human studies of smoked coca paste (Van Dyke and Byck, 1982
) (). After a single smoking session, the onset and intensity of the “high” are very rapid via the smoked route of administration, and a rapid tolerance is manifest. The “high” decreases rapidly despite significant blood levels of cocaine. Even more intriguing is that human subjects also actually report a subsequent “dysphoria,” again despite high blood levels of cocaine. Intravenous cocaine produced similar patterns of a rapid “rush” followed by an increased “low” in human laboratory studies (Breiter et al., 1997
) (). With intravenous cocaine self-administration in animal models, such elevations in reward threshold begin rapidly and can be observed within a single session of self-administration (Kenny et al., 2003
) (), bearing a striking resemblance to human subjective reports. These results demonstrate that the elevation in brain reward thresholds following prolonged access to cocaine failed to return to baseline levels between repeated, prolonged exposure to cocaine self-administration (i.e., residual hysteresis), thus creating a greater and greater elevation in “baseline” ICSS thresholds. These data provide compelling evidence for brain reward dysfunction in escalated cocaine self-administration that provide strong support for a hedonic allostasis model of drug addiction.
Figure 1 (A) Dysphoric feelings followed the initial euphoria in experimental subjects who smoked cocaine paste, even though the concentration of cocaine in the plasma of the blood remained relatively high. The dysphoria is characterized by anxiety, depression, (more ...)
Figure 2 Rats (n = 11) were allowed to self-administer 10, 20, 40, and 80 injections of cocaine (0.25 mg per injection), and intracranial self-stimulation reward thresholds were measured 15 min and 2, 24, and 48 h after the end of each intravenous cocaine self-administration (more ...)
Similar results have been observed showing dysphoria-like responses accompanying acute opioid and ethanol withdrawal (Liu and Schulteis, 2004
; Schulteis and Liu, 2006). Here, naloxone administration following single injections of morphine increased reward thresholds, measured by ICSS, and increased thresholds with repeated morphine and naloxone-induced withdrawal experience (Liu and Schulteis, 2004
). Similar results were observed during repeated acute withdrawal from ethanol (Schulteis and Liu, 2006).
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 threshold during acute abstinence, and some of these elevations in threshold can last for up to one week (). These observations lend credence to the hypothesis that opponent processes can set the stage for one aspect of compulsivity where negative reinforcement mechanisms are engaged.
Figure 3 (A) Effects of ethanol withdrawal on CRF-like immunoreactivity (CRF-L-IR) in the rat amygdala determined by microdialysis. Dialysate was collected over four 2 h periods regularly alternated with nonsampling 2 h periods. The four sampling periods corresponded (more ...)
More recently, 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 also may 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 (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 purpose of this review is to explore the neuroadaptational changes that occur in the brain emotional systems to account for the neurocircuitry changes that produce opponent processes and are hypothesized to have a key role in the compulsivity of addiction.
1.2. Animal models of compulsivity in addiction measured by negative emotional-like states: Place aversion, animal models of anxiety, and reward thresholds
Animal models of the withdrawal/negative affect
stage include measures of conditioned place aversion (rather than preference) to precipitated withdrawal or spontaneous withdrawal from chronic administration of a drug, increases in reward thresholds using brain stimulation reward (Markou and Koob, 1991
; Schulteis et al., 1994
; Epping-Jordan et al., 1998
; Gardner and Vorel, 1998
; Paterson et al., 2000
), and increases in anxiety-like responses (for review, see Shippenberg and Koob, 2002
; Sanchis-Segura and Spanagel, 2006
1.3. Animal models of compulsivity in addiction as defined by increased drug taking: Escalation in drug self-administration with prolonged access
A progressive increase in the frequency and intensity of drug use is one of the major behavioral phenomena characterizing the development of addiction and has face validity with the criteria of the Diagnostic and Statistical Manual of Mental Disorders: “The substance is often taken in larger amounts and over a longer period than was intended” (American Psychological Association, 1994). A framework with which to model the transition from drug use to drug addiction can be found in recent animal models of prolonged access to intravenous cocaine self-administration. Historically, animal models of cocaine self-administration involved the establishment of stable behavior from day to day to allow the reliable interpretation of data provided by within-subject designs aimed at exploring the neuropharmacological and neurobiological bases of the reinforcing effects of acute cocaine. Up until 1998, after acquisition of self-administration, rats typically were allowed access to cocaine for 3 h or less per day to establish highly stable levels of intake and patterns of responding between daily sessions. This was a useful paradigm for exploring the neurobiological substrates for the acute reinforcing effects of drugs of abuse.
However, in an effort to explore the possibility that differential access to intravenous cocaine self-administration in rats may produce different patterns of drug intake, rats were allowed access to intravenously self-administration cocaine for 1 or 6 h per day (Ahmed and Koob, 1998
). One hour access (short access or ShA) to intravenous cocaine per session produced low and stable intake as observed previously. In contrast, 6 h access (long access or LgA) to cocaine produced drug intake that gradually escalated over days (). Increased intake was observed in the extended access group during the first hour of the session, with sustained intake over the entire session and an upward shift in the dose-effect function, suggesting an increase in hedonic set point. When animals were allowed access to different doses of cocaine, both the LgA and ShA animals titrated their cocaine intake, but the LgA rats consistently self-administered almost twice as much cocaine at any dose tested, further suggesting an upward shift in the set point for cocaine reward in the escalated animals (Ahmed and Koob, 1999
; Deroche-Gamonet et al., 2004
; Mantsch et al., 2004
). Escalation also is associated with an increase in break point for cocaine in a progressive-ratio schedule of reinforcement, suggesting an enhanced motivation to seek cocaine or an enhanced efficacy of cocaine reward (Paterson and Markou, 2003
; Wee et al., 2008
). Such increased self-administration in dependent animals has now been observed with cocaine, methamphetamine, nicotine, heroin, and alcohol (Ahmed et al., 2000
; Ahmed and Koob, 1998
; Kitamura et al., 2006
; O’Dell et al., 2004
; George et al., 2007
) (). This model is a key element for evaluating the motivational significance of opponent process changes in the brain reward and stress systems in addiction that lead to compulsivity in addiction. Similar changes in the reinforcing and incentive effects of cocaine as drug intake have been observed following extended access and include increased cocaine-induced reinstatement after extinction and a decreased latency to goal time in a runway model for cocaine reward (Deroche et al., 1999
). Altogether, these results suggest that drug taking with extended access changes the motivation to seek the drug. Whether this enhanced drug taking reflects a sensitization of reward or a reward deficit state remains under discussion (Vezina, 2004
), but the brain reward and neuropharmacological studies outlined below argue for a reward deficit state driving the increased drug taking during extended access.
Figure 4 (A) Effect of drug availability on cocaine intake (mean ± SEM). In 6 h long-access (LgA) rats (n = 12) but not in 1 h short-access (ShA) rats (n = 12), mean total cocaine intake started to increase significantly from session 5 (p < 0.05; (more ...)
The hypothesis that compulsive cocaine use is accompanied by a chronic perturbation in brain reward homeostasis has been tested in an animal model of escalation in drug intake with prolonged access combined with measures of brain stimulation reward thresholds. Animals implanted with intravenous catheters and allowed differential access to intravenous self-administration of cocaine showed increases in cocaine self-administration from day to day in the long-access group (6 h; LgA) but not in the short-access group (1 h; ShA). The differential exposure to cocaine self-administration had dramatic effects on reward thresholds that progressively increased in LgA rats but not in ShA or control rats across successive self-administration sessions (Ahmed et al., 2002
). Elevation in baseline reward thresholds temporally preceded and was highly correlated with escalation in cocaine intake (). Post-session elevations in reward thresholds failed to return to baseline levels before the onset of each subsequent self-administration session, thereby deviating more and more from control levels. The progressive elevation in reward thresholds was associated with the dramatic escalation in cocaine consumption that was observed previously. After escalation had occurred, an acute cocaine challenge facilitated brain reward responsiveness to the same degree as before but resulted in higher absolute brain reward thresholds in LgA compared with ShA rats (Ahmed et al., 2002
). Similar results have been observed with extended access to heroin (Kenny et al., 2006
). Rats allowed 23 h access to heroin also showed a time-dependent increase in reward thresholds that paralleled the increases in heroin intake ().
Figure 5 (A) Relationship between elevation in intracranial self-stimulation reward thresholds and cocaine intake escalation. (Left) Percentage change from baseline ICSS thresholds. (Right) Number of cocaine injections earned during the first hour of each session. (more ...)