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Introduction: A Model of What?

In behavioral pathology and comparative psychiatry a precondition for an animal model is to be informed about what will be modeled. The poor awareness of the complexity of such human conditions is the origin of misunderstanding between clinicians and neurobiolo-gists. This is particularly true in the field of drug abuse. Drug ► addiction, also known as substance dependence, is characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and

(3) emergence of a negative emotional state (e.g., dyspho-ria, anxiety, irritability) when access to the drug is prevented (Koob and Le Moal 1997). The terms addiction and substance dependence (as currently defined by the American Psychiatric Association (1994)) are used interchangeably and refer to a final stage of a misusage process that moves from drug use to a chronic relapsing disorder. This point is critical. It is referred here to a brain pathology from which a recovery is questionable. In other words, the occasional but limited or controlled use of a drug with a potential for abuse or dependence is distinct from the emergence of a chronic drug-dependent state. An important goal of current neurobiological research is to understand the molecular and neuropharmacological neuroadaptations within specific neurocircuits that mediate the transition from occasional, controlled drug use to the loss of behavioral control over drug seeking and drug taking. A key element of the addiction process is the underactivation of natural motivational systems such that the reward system becomes compromised and that an antireward system becomes recruited to provide the powerful motivation for drug seeking associated with compulsive use (Koob and Le Moal 2008).

The process of drug addiction involves elements of both ► impulsivity and compulsivity (Fig. 1), where im-pulsivity can be defined by an increasing sense of tension or arousal before committing an impulsive act and by a sense of pleasure, gratification, or relief at the time of t Craving it Craving t Craving it Craving

Positive reinforcement Negative reinforecemt

Addictive Disorder: Animal Models. Fig. 1. ''The addiction cycle.'' Diagram describing the addiction cycle that is conceptualized as having three major components: preoccupation/anticipation (''craving''), binge/intoxication, and withdrawal/ negative affect. Note that as the individual moves from the impulsivity stage to the compulsivity stage, there is a shift from positive reinforcement associated with the binge/intoxication component to negative reinforcement associated with the withdrawal/ negative affect component. Craving is hypothesized to increase in the compulsivity stage because of an increase in the need state for the drug that is driven not only by loss of the positive reinforcing effects of the drugs (tolerance), but also by generation of an antireward state that supports negative reinforcement. (Reproduced with permission from Koob and Le Moal 2008.)

committing the act. Compulsivity can be defined by anxiety and stress before committing a compulsive repetitive behavior and relief from the stress by performing the compulsive behavior. Collapsing the cycles of impulsivity and compulsivity yields a composite addiction cycle comprised of three stages: preoccupation/anticipation, binge/ intoxication, and withdrawal/negative effect, where impul-sivity 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. These three stages interact with each other, becoming more intense, and ultimately leading to the final pathological state: addiction. Here it is important to realize that the main symptoms correspond to different structural-functional entities including large systems in the brain.

Classic Validation of Animal Models of Drug Addiction

• General typology of animal models

Animal models are critical for understanding the neu-ropharmacological mechanisms involved in the development of addiction. While there are no complete animal models of addiction, animal models may exist for elements of the syndrome. An animal model can be viewed as an experimental preparation developed for studying a given phenomenon found in humans (McKinney 1988; Geyer and Markou 2002). The most relevant conceptualization of validity for animal models of addiction is the concept of construct validity. Construct validity refers to the inter-pretability, "meaningfulness," or explanatory power of each animal model and incorporates most other measures of validity where multiple measures or dimensions are associated with conditions known to affect the construct. An alternative conceptualization of construct validity is the requirement that models meet the construct of functional equivalence, defined as assessing how controlling variables influence outcome in the model and the target disorders and the most efficient process for evaluating functional equivalence has been argued to be through common experimental manipulations, which should have similar effects in the animal model and the target disorder (Katz and Higgins 2003). This process is very similar to the broad use of the construct of predictive validity. Face validity often is the starting point in animal models where animal syndromes are produced, which resemble those found in humans in order to study selected parts of the human syndrome but is limited by necessity. Reliability refers to the stability and consistency with which the variable of interest can be measured and is achieved when, following objective repeated measurement of the variable, small within- and between-subject variability is noted, and the phenomenon is readily reproduced under similar circumstances. The construct of predictive validity refers to the model's ability to lead to accurate predictions about the human phenomenon based on the response of the model system. Predictive validity is used most often in the narrow sense in animal models of psychiatric disorders to refer to the ability of the model to identify pharmacological agents with potential therapeutic value in humans. However, when predictive validity is more broadly extended to understanding the physiological mechanism of action of psychiatric disorders, it incorporates other types of validity (i.e., etiologi-cal, convergent or concurrent, discriminant) considered important for animal models, and approaches the concept of construct validity. Some animal models have been shown to be reliable and to have construct validity for various stages of the addictive process will be described.

• Animal models and the stages of the addiction cycle

Table 1 summarizes the models used in most laboratories according to the stages of the addiction cycle.

1. Animals models for the Binge/Intoxication Stage

According to the evolution of the process defined above (Fig. 1), the individual moves from impulsivity to compulsivity with the development of preoccupation-anticipation and when he or she is in abstinence, negative effect and withdrawal symptoms progressively appear as signature of addiction. The procedures used have proven reliability and to have predictive validity in their ability to understand the neurobiological basis of the acute reinforcing effects of drugs. If one could reasonably argue that drug addiction mainly involves counteradaptive mechanisms that go far beyond the acute reinforcing actions of drugs, understanding the neurobiological mechanisms for positive reinforcing actions of drugs of abuse also provides a framework for understanding the motivational effects of counteradaptive mechanisms. Many of the operant measures used as models for the reinforcing effects of drugs of abuse lend themselves to within-subjects designs, limiting the number of subjects required. Indeed, once an animal is trained, full dose-effect functions can be generated for different drugs, and the animal can be tested for weeks and months. Pharmacological manipulations can be conducted with standard reference compounds to validate any effect. In addition, a rich literature on the experimental analysis of behavior is available for exploring the

Addictive Disorder: Animal Models. Table 1. Stages of the addiction cycle and models.

Stage

Source of reinforcement

Animal models

Binge/ intoxication

Positive reinforcement

Conditioned place preference

Drug self-administration

Decreased reward thresholds

Intracranial self-stimulation

Withdrawal/ negative affect

Negative reinforcement

Conditioned place aversion

Increased self-administration in dependence

Increased reward thresholds

Intracranial self-stimulation

Preoccupation/ anticipation

Conditioned positive and negative reinforcement

Drug-induced reinstatement

Cue-induced reinstatement

Stress-induced reinstatement

Protracted abstinence

hypothetical constructs of drug action as well as for modifying drug reinforcement by changing the history and contingencies of reinforcement. The advantage of the intracranial self-stimulation (ICSS) paradigm as a model of drug effects on motivation and reward is that the behavioral threshold measure provided by ICSS is easily quantifiable. ICSS threshold estimates are very stable over periods of several months. Another considerable advantage of the ICSS technique is the high reliability with which it predicts the abuse liability of drugs. For example, there has never been a false positive with the classic discrete trials threshold technique. The advantages of place conditioning as a model for evaluating drugs of abuse include its high sensitivity to low doses of drugs, its potential utility in studying both positive and negative reinforcing events, the fact that testing for drug reward is done under drug-free conditions, and its allowance for precise control over the interaction of environmental cues with drug administration.

2. Animal Models for the Preoccupation/Anticipation

Stage

Each of the models outlined above has face validity to the human condition and ideally heuristic value for understanding the neurobiological bases for different aspects of the craving stage of the addiction cycle. The DSM-IV criteria that apply to the craving stage and loss of control over drug intake include any unsuccessful effort or persistent desire to cut down or control substance use. The extinction paradigm has predictive validity, and with the reinstatement procedure, it can be a reliable indicator of the ability of conditioned stimuli to reinitiate drug-seeking behavior. The conditioned-reinforcement paradigm has the advantage of assessing the motivational value of a drug infusion in the absence of acute effects of the self-administered drug that could influence performance or other processes that interfere with motivational functions. For example, nonspecific effects of manipulations administered before the stimulus drug pairings, do not directly affect the assessment of the motivational value of the stimuli because the critical test can be conducted several days after the stimulus drug pairings. Also, the paradigm contains a built-in control for nonspecific motor effects of a manipulation by its assessment of the number of responses on an inactive lever.

The animal models for the conditioned negative reinforcing effects of drugs are reliable measures and have good face validity. Work in this area, however, has largely been restricted to the opiate field where competitive antagonists precipitate a withdrawal syndrome. There is consensus that the animal reinstatement models have face validity. However, predictive validity remains to be established. To date, there is some predictive validity for the stimuli that elicit reinstatement in the animal models, but little evidence of predictive validity from studies of the pharmacological treatments for drug relapse. Very few clinical trials have tested medications that are effective in the reinstatement model, and very few anti-relapse medications have been tested in the animal models of reinstatement. From the perspective of functional equivalence or construct validity there is some evidence of functional commonalities. For example, drug re-exposure or priming, stressors, and cues paired with drugs all produce reinstatement in animal models and promote relapse in humans.

3. Animal Models for the Withdrawal/Negative Affect

Stage

It has been proposed by some authors that the motivational measures of drug withdrawal have much the same value for the study of the neurobiological mechanisms of addiction as procedures used to study the positive reinforcing effects of drugs. ICSS threshold procedures have high predictive validity for changes in reward valence. The disruption of operant responding during drug abstinence is very sensitive. Place aversion is hypothesized to reflect an aversive unconditioned stimulus. Drug discrimination allows a powerful and sensitive comparison to other drug states. The use of multiple dependent variables for the study of the motivational effects of withdrawal may provide a powerful means of assessing overlapping neurobiological substrates and to lay a heuristic framework for the counteradaptive mechanisms hypothesized to drive addiction.

Individual differences, the concept of vulnerabilities and animal models

(a) Individual differences: a central problem in addiction medicine

For all the paradigms presented above and in consequence for these animal models used, all the subjects (rodents) are equal. The data are presented by means with their standard errors. In clinical practice, huge individual differences exist for the proneness to take drugs, for their perceived reinforcing effects and above all for the propensity to continue to misuse them and enter in a spiral of addiction. In other words, one of the most important problems in drug addiction today is to understand why an enormous amount of people take drugs according to the various circumstances of social life whereas only a small percentage of them will become addicted. Some individuals can stop their misusage without noticeable withdrawal syndrome. It is also reported that some get hooked with the first usage. Some individuals are vulnerable, other not. Vulnerability refers to a construct that covers all the fields of medicine. After a period devoted to the description of symptoms and diagnostic, then to identify the pathophysiological bases of the disease, then to find the causes, then to cure, predictive medicine will be the next step, i.e., to discover markers and prodromic states of vulnerabilities. Some vulnerabilities are specific for a given class of diseases, other are, in the state of knowledge, nonspecific. It is a strange phenomenon that while the problem of vulnerability in addiction medicine is abundantly discussed in clinical literature, it is almost completely absent in experimental and animal research.

Needless to say, drugs also have their own pharmacological effects that depend on intrinsic and differential dangerousness of the products. However, a drug is addictive because a specific individual in a given social environment uses it. Moreover, a vulnerable phenotype and vulnerability are revealed a-posteriori.

The origins of vulnerability are numerous and interacting: genetic, environmental, aversive life events and stress, age and gender. All these factors have left traces in the organism. Vulnerability participates to psychopatho-logical syndromes and to comorbid factors diagnosed in most of the psychiatric disorders. Each individual has his own history that participates in a unique way to the entrance in addiction process. These factors, each or associated, contribute to psychobiological traits. However, such a view, based on clinical observations and studies is at variance with most of the experimental investigations and raised methodological considerations about animal and biological models and the neuroscience of addiction in general.

(b) Vulnerability and transition to addiction: two opposite views

The first one, adaptive or individual-centered, places the subject with his own characteristics at the center of research and interest. The adaptive perspective (Fig. 2) is based on a predisposition, on the fact that explains why subjects are at risk and why their intrinsic predisposed state determines the neuroplasticity induced by drugs.

To detect the sources of vulnerability would lead to predictive medicine and toward psychosocial interventions. A translation from the real world and from clinical psychiatry to the laboratory must discover and develop models that will present (1) gradual individual differences from the resilient to the most vulnerable phenotypes, (2) a transition from use to misuse for some animals prone to enter in the disease spiral and, (3) the main symptoms of the disease as defined by the DSM IV at the end of the process. An individual-centered approach is basically a historic approach. Patients and animals are considered different and more or less vulnerable because of their past, of developmental characteristics or genetic background. The sequences of the process are represented in Fig. 3.

This paradigm opposes classic pharmacological approaches, i.e., drug-centered, or exposure model, based on drug-induced neuroplasticity and on acquired vulnerability. Here, drug abuse is a iatrogenic disorder and both research and therapeutics are oriented toward understanding drug pharmacological properties and toxicological actions on brain substrates, and toward counteracting these effects by other pharmacological means. This paradigm is largely dominant in laboratory research; animals are considered not in relation with their past (a-historic models) but with the amount of drug taken (Fig. 4).

Addictive Disorder: Animal Models. Fig. 2. "An individual-centered research paradigm (a) for an historic-individual animal model (b).'' Individuals are considered as different from the point of view of their past life events, developmental characteristics, and genetic background. Individual comparisons require nonparametric statistics. (Reproduced with permission from Le Moal (2009) Drug abuse: vulnerability and transition to addiction. Pharmacopsychiatry 42:S42-S55, © Georg Thieme Verlag Stuttgart, New York.)

Individual differences are hidden under statistical standard errors or considered as protocol artifacts.

These two different research interests and practices have their own logic and necessities and are sometimes complementary. It is important to discover the neurotoxic damages and neuroplasticities induced by drugs. These neurobiological changes explain the transition from impulsive to compulsive behaviors and loss of control. Drugs of abuse have different addictive properties. It is a trivial observation that frequent usage of a drug, or the repetition of specific behaviors, combined with the intrinsic dangerous state of each drug (gambling, eating, sex...) are dangerous by themselves and lead progressively to loss of control.

(c) Two recent models: drug-centered versus individual centered

A conceptual framework upon which animal models can be directly related to the compulsive behavior and loss of control over intake, that is the hallmark of addiction, is to specifically relate a given animal model to a specific symptom of the DSM-IV criteria for addiction. Recent studies have emphasized animal models that contribute to specific elements of the DSM-IV criteria with strong face validity, and at the same time may represent specific endophenotypes of the compulsive nature of the addiction process.

1. Ahistoric model: escalation in drug self-administration with prolonged access

A progressive increase in the frequency and intensity of drug use is a behavioral phenomena often characterizing the development of addiction and has face validity with the DSM-IV criteria. A framework with which to model the transition from drug use to drug addiction is found in a recent animal model 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 neuropharmacolo-gical and neurobiological bases of the reinforcing effects

Addictive Disorder: Animal Models. Fig. 3. "Vulnerability to addiction process.'' A given drug or behavior (e.g., eating, gambling, sex) is "addictive" because of its exposure to a vulnerable individual (1) who will be prone to repeat the drug use (2). Drug use then will induce neuropharmacological and neurotoxicological effects and profound neuronal changes (3) and then addiction (4). A, B, C, D: Process sequence. (Reproduced with permission from Le Moal (2009) Drug abuse: vulnerability and transition to addiction. Pharmacopsychiatry 42:S42-S55, © Georg Thieme Verlag Stuttgart, New York.)

Addictive Disorder: Animal Models. Fig. 4. "A drug-centered research paradigm (a) for a ahistoric animal model (b).'' Group comparisons require parametric statistics. The subjects are not considered from their individual characteristics - they are considered equal or similar. (Reproduced with permission from Le Moal (2009) Drug abuse: vulnerability and transition to addiction. Pharmacopsychiatry 42:S42-S55, © Georg Thieme Verlag Stuttgart, New York.)

of acute cocaine. Typically, after the acquisition of self-administration, rats allowed access to cocaine for 3 h or less per day establish highly stable levels of intake and patterns of responding between daily sessions. These models do not fit with the concept of addiction.

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 the intravenous self-administration of cocaine for 1 or 6 h per day. One hour access (short access or ShA) to intravenous cocaine per session produced low and stable intake as observed previously. In contrast, with 6 h access (long access or LgA) to cocaine, drug intake gradually escalated over days (Ahmed and Koob 1998). It is observed in the escalation group, there was increased intake during the first hour of the session as well as 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. Escalation also is associated with an increase in break point for cocaine in a progressive-ratio schedule, suggesting an enhanced motivation to seek cocaine or an enhanced efficacy of cocaine reward.

This model fits with the drug-centered paradigm. It is a-historic: the subjects are not considered from their individual characteristics but considered at the beginning of the experiment equal or similar. Only the drug parameters (amount taken) change.

2. Historic model: differential vulnerability for a transition to addiction

A second model considers that each individual has different characteristics and vulnerabilities to the pharmacological aspects of drugs. Such differential vulnerabilities had been demonstrated for the propensity to like drugs. A first paper published demonstrated that it was possible to evidence in rats (1) marked individual differences in the development of psychostimulant self administration; (2) that a differential propensity to drug taking was predicted by individual reactivity to novelty, a robust permanent trait; (3) a significant positive correlation between the magnitude of the reactivity and the amount of the drug self-administered during an acquisition session (Piazza et al. 1989). In a recent study explored further the behavioral effects of drug-taking in animals with access to cocaine for 3 months and a number of behavioral tests were administered that were hypothesized to capture DSM-IV criteria of addiction (Deroche-Gamonet et al. 2004). Unsuccessful effort or a persistent desire to cut down or control substance use was linked to the persistence of cocaine seeking during a period of signaled non-availability. A great deal of time spent in activities necessary to obtain the substance was linked to performance on a progressive-ratio schedule, and continued substance use despite knowledge of having a persistent physical or psychological problem was linked to the persistence in responding for drug by animals when drug delivery was associated with punishment. Rats were trained to self-administer cocaine intravenously and then separated by groups based on a test for reinstatement to small doses of cocaine administered after 5 days of extinction. The animals with the high tendency to show reinstatement showed progressively increased responding during signaled nondrug periods, higher break points on the progressive-ratio test, and higher responding after punishment (Deroche-Gamonet et al. 2004). Further study of rats subjected to all three tests above revealed that the animals that met all three positive criteria represented 17% of the entire population, a percentage noted by the authors to be similar to the number of human cocaine users meeting the DSM-IV criteria for addiction while 41% of the rats were resilient (0 criterion). This model highlights the importance of differential vulnerability to addiction. It demonstrates huge individual differences for the propensity to enter in the addiction cycle. It is typically anindividual-centered model and corresponds to what is met in addiction medicine.

Conclusion

Animal models for addiction have progressed from simple drug reinforcement models to sophisticated models with solid face validity. Escalation in drug intake with extended access has been observed in numerous laboratories with all the drugs of abuse. This drug-centered model do not discriminate animals according to potential previous vulnerabilities; here the transition to addiction is linked to compulsivity. More recently, animal models for criteria of addiction that reflect the channeling toward drug seeking at the expense of other environmental contingencies (Deroche-Gamonet et al. 2004; Vanderschuren and Everitt 2004) have been developed and linked to the compulsive loss of control over intake. The model described above may prove particularly sensitive to the transition to addiction in otherwise vulnerable individuals.

Acknowledgments

I thank Lisa Romero for her expert assistance with word processing and graphic presentations. This work is supported by the Institut National de la Sante et de la Recherche Medicale (INSERM) and University Victor Segalen-Bordeaux 2.

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