This section is not an extensive review of the literature but a description of several pertinent examples that support the existence of three concatenated, independent steps in the transition to addiction. For this reason, we apologize in advance to our colleagues who have produced very important work that is not cited here.
Psychobiological basis of recreational, sporadic drug use
Activation of the brain substrate of natural reinforcers mediates the learning of drug use
The first phase of addiction is a learning process based on drugs of abuse activating the same brain substrates that mediate the positive reinforcing effects of natural reinforcers. The study and discovery of this fundamental basic mechanism was the focus of the early days of the addiction research field. Thus, for the most part, our neurobiological knowledge derives from studies using limited-access and behavioral procedures, such as conditioned place preference. As a consequence, most knowledge we have today concerns “normal” recreational drug use rather than pathological drug use. However, many important contributions have been made in this context, in particular, identification of the crucial role of activation of the mesocorticolimbic dopamine system.
Briefly, the general idea that was progressively put forward and is still largely believed is that drugs of abuse increases dopamine release in the nucleus accumbens and, in particular, in the shell of this nucleus, and that this biological change mediates their appetitive effects. Using complementary approaches, the work of the Di Chiara group (Di Chiara and Imperato 1988), the Concordia group (Wise 1978, 1984, 1987; Kalivas and Stewart 1991; Wise 1994), and of the Koob and Le Moal groups (Le Moal et al. 1979; Koob et al. 1989) are fundamental in proving this concept. Later on, the dopamine-activated downstream intracellular signals, such as adenylate cyclase (Self and Nestler 1995), and the mitogen-activated protein kinase (MAPK) pathways (Valjent et al. 2004) have been discovered and characterized.
An important role of dopamine and of its downstream intracellular mechanisms was also extended to conditioned stimuli associated with drug delivery. Such stimuli become important discriminative stimuli of drug availability and, under some training conditions, secondary reinforcers. The idea here is that the increase in dopamine is backward-shifted and is now activated by discriminative stimuli that predict drug availability more than by the drug itself (Wanat et al. 2009). It is noteworthy that exactly the same phenomenon happens with natural reinforcers, showing that these neurobiological mechanisms activated by drugs are part of the normal learning sequence of the behaviors directed at acquiring any kind of appetitive stimulus (Schultz et al. 1997).
Liking drugs is the major substrate of drug use
As the majority of research in the first 30 years of the addiction research field was performed using models of recreational drug use and not of the later phase of transition of addiction, it is not surprising that one of the first interpretations of drug addiction was actually the explanation of why we take drugs recreationally, or in other words, why drugs can act as positive reinforcers. This initial theory can be summarized by saying that we become addicted because we strongly like (Wise and Bozarth 1982) or want (Robinson and Berridge 1993) drugs, and we like or want drugs because they, or cues associated with them (Stewart et al. 1984), activate mesolimbic dopamine. We believe that this theory cannot explain the entire process of transition to addiction. In contrast, we think that this is a sound explanation of why we use drugs recreationally. Certainly, the primary reinforcing effects of the drugs and the perception of positive effects are the major reasons we learn to use drugs of abuse.
Overactivation of dopamine transmission is why drugs are extremely likeable and wanted stimuli
Despite the fact that learning to obtain drugs and food is mediated by identical brain substrates, drugs of abuse are described by most users as more salient and appetitive than natural reinforcers. Why is that? Two reasons can be advanced: (1) increase in dopamine induced by most drugs is significantly higher than that induced by natural reinforcers; (2) increase in dopamine induced by natural reinforcers rapidly habituates; however, this does not occur, or at least occurs more slowly, in response to drugs of abuse (Bassareo and Di Chiara 1997; Di Chiara 1998).
How dopamine makes us like or want drugs is still unclear, and the initial idea that dopamine is the neurotransmitter of pleasure seems increasingly implausible today. In particular, pleasure is defined as the sensation we perceive during the consummatory phase of a primary reinforcer: tasting the food, reaching the climax. However, in our pleasurable relationship with positive reinforcers, the ultimate consummatory phase is just a small component of the entire behavioral sequence leading to them. What we also strongly respond to is the sight of the stimulus and to its predictors. Salience of the stimuli or how attractive they look is then a very important hedonic dimension of our lives. It is fundamental in controlling and motivating behavior even more than the sensation we receive from the final consummatory phase. We believe that this is the role of an increase in dopamine: to light up stimuli, to increase their salience, and to make them strongly pleasant and irresistibly appetitive without the need to actually consume them (Schultz et al. 1997; Robinson and Berridge 2000). This is a tremendous power that justifies why the dopaminergic response to natural reinforcers and their predictors is moderate and habituates quickly and explains why, when this does not happen—as for drugs of abuse—the stimuli stand out and are perceived as strongly appetitive.
Is there a role of individual differences in recreational drug use?
Given the large number of humans that use drugs recreationally, and the observation that most animals learn to self-administer drugs (approximately 90 % of the population in both cases), we believe that the question should be turned around to ask whether there is a psychobiological “resistance” to using a drug recreationally. The answer is probably yes, since, as we said before, there are few laboratory animals that do not learn to self-administer drugs and few humans that do not take any type of drug. One possible explanation for this behavior is that drugs are aversive and not appetitive in these few individuals. This is a likely possibility, because drugs of abuse, particularly cocaine, are complex stimuli that possess both aversive and appetitive properties, with their final effects resulting from the algebraic summation of the two (Ettenberg 2004). Thus, if in some individuals the aversive effects of drugs outweigh their rewarding effects, then they will avoid drugs of abuse (Schechter 1992). Although this seems a likely hypothesis, to our knowledge, the mechanisms of resistance to recreational drug use have not been directly studied. Although recent investigations start elucidating why drugs, and in particular psychostimulants, can be aversive (Wenzel et al. 2011; O’Neill et al. 2013; Jhou et al. 2013), this hypothesis remains mainly speculative and needs direct validation.
Psychobiological basis of intensified, sustained, escalated drug use
For transition from physiology (drug use) to pathophysiology (sustained drug use and loss of control), we must go from independent to relevants variables
Knowledge of many neurobiological substrates involved in addiction that the research field, including ourselves, has identified so far is based on data collected after few weeks of exposure to drugs or from data obtained from noncontingent, limited drug exposure in locomotor sensitization studies (Piazza et al. 1996; Deroche-Gamonet et al. 2003; Kalivas and Volkow 2005; Nestler 2005; Hyman et al. 2006; Koob and Le Moal 2008a, b; Robbins et al. 2008b; Robinson and Berridge 2008; Ambroggi et al. 2009). This time frame is too short to allow the development of addiction-like behavior. As a consequence, most of these neurobiological changes more likely concern the mechanisms of the transition from recreational to sustained drug use than the substrate of loss of control and full addiction.
For some of these studies, a central issue is then to understand which of the proposed drug-induced modifications mediate sustained drug use. Drugs of abuse have a large number of biological effects, but very few of those effects are abuse related. Just comparing drug-treated animals with drug-naive animals does not allow distinguishing abuse-related from abuse-unrelated effects. In addition, most of these studies were done using a small number of rats or mice and without taking into account individual differences. As a limited number of individuals develop sustained drug use and finally addiction, it is possible that the observed changes reflect what happens in the brain of individuals resistant to drugs, which represent the majority of individuals within a population. As a consequence, some of the proposed putative mechanisms of addiction could be either completely unrelated to it or, alternatively, mechanisms of resistance to transition to addiction.
What approach will allow us to identify with a good degree of confidence the biological basis of transition to drug abuse and then to addiction? The answer to this question is simple: we should stop using approaches that are valid for physiological studies and start using approaches that are adapted to pathophysiological investigations. Physiology is discovering what the biological mechanisms (independent variables) are of a given bodily function (dependent variable). In this context, practically all biological factors for which manipulations modifies the target function can be safely defined as a necessary or sufficient condition of that function and is therefore part of its physiology.
Pathophysiological studies go one step further and attempt to identify the variables that induce pathology in a physiological function rather than attempting to identify all independent variables. In real life, pathological states do not develop by a random modification of all variables involved in the physiology of the diseased system. They result from deregulation of a precise subset of independent variables along a precise cascade of events. This specific selection of a subset of independent variables in the development of a disease is probably because pathology is often the result of the failure of an organ or biological system to adapt to a bodily or environmental constraint, i.e., the etiological factor of the disease. Adaptation or failure to do so depends on the adaptive capacity of the system and from what is called its “functional reserve,” i.e., how much that system can be impaired before the function it subserves is disrupted (Harrison 2011). It is then likely that the subsets of independent variables involved in a specific pathological process are the ones with the smaller functional reserve. Alternatively, they could also be the independent variables that play multifunctional roles. Thus, adaptation that protects one function can be disruptive for another. Clearly, these are not exhaustive examples of how a pathological state can occur. They are just few examples aimed at clarifying why the pathophysiology of a disease selects a subset of the variables involved in the physiology of the target system. We propose naming these independent, disease-specific variables “relevant variables” to differentiate them from the more generic independent variables involved in physiology.
How do we go, then, from studying independent variables to identifying relevant ones? The answer was outlined many years ago by Claude Bernard in his book on fundaments of experimental medicine (Bernard 1865). A biological factor or a biological chain of events can be considered a physiopathological mechanism; i.e., an independent variable can be considered a relevant variable when: (1) changes in its activity can be correlated with the predisposition of vulnerable individuals and/or with the appearance of the disease; (2) known etiological or predisposing external conditions modify the activity of such a factor; (3) opposite manipulations of such a factor can induce and reverse the disease.
In other words, to go from physiology to pathophysiology, we need models that allow either identification of spontaneously vulnerable and resistant individuals, or models that use known etiological factors to induce the disease in a subgroup of individuals. This is particularly important when, as in the case of transition to addiction, only a small percentage of individuals exposed to the pathogen (the drug) develop the disease. It is only by comparing individuals exposed to drugs who do or do not develop sustained drug use followed by loss of control that we can distinguish the three major families of variables that can be modified by drug exposure: (1) variables unrelated to transition to addiction, which will be modified in all individuals; (2) variables that protect against developing sustained drug use and loss of control, which will be modified in individuals who do not develop addiction; (3) variables involved in sustained drug use and loss of control, which will be modified in individuals who will develop these pathological behaviors.
For these reasons, in the following paragraph, we discuss only some of the data that we believe can be specifically related to the pathophysiology of transition to sustained drug use and not all psychobiological modifications induced by repeated exposure to drugs.
Sensitized dopamine: a pathophysiological mechanism of transition to intensified drug use
Sensitization has become a complicated word to use in the drug-abuse research field because many different meanings have been attached to it. Originally, sensitization is the opposite of tolerance. Tolerance refers to a decrease in a drug effect over repeated exposure to the drug. Sensitization defines the converse phenomenon: an increase in drug effect over repeated drug exposure. By definition, the motivational effects of drugs increase, or sensitize, during transition to escalated and sustained drug use. If the motivational effects underwent tolerance, individuals would take increasingly less drug and not increasingly more. Although this seems logical, for a long time, the opposite was argued: individuals would take increased amounts of the drug because they felt their effects less. The debate between tolerance and sensitization has long animated the drug-abuse research field.
In the late 1980s and first half of the 1990s, we and others demonstrated that individuals who were vulnerable for esclation to drug use had a spontaneously sensitized dopaminergic system (Piazza et al. 1991b; Hooks et al. 1992) and a very high response to initial drug exposure (Hooks et al. 1991). Over the same period, we also showed that this sensitized response and the associated vulnerability to escalate to sustained drug use could be induced either by repeated stress or repeated drug exposure (Deroche et al. 1995; Piazza et al. 1996; Piazza and Le Moal 1996; Ambroggi et al. 2009). In particular, vulnerable rats had a higher stress-induced increase in dopaminergic transmission in the nucleus accumbens (Rougé-Pont et al. 1993). Later, we showed that over an intermediate period of drug intake, including at least the first stages of the intensified-use phase, the incentive and reinforcing properties of drugs were increased or “sensitized,” not decreased or “undergoing tolerance” (Deroche et al. 1999).
These and related data were used as the basis to the sensitization theory of drug addiction that proposed sensitization of the motivational systems—which makes the individual increasingly want drugs—as a comprehensive explanation of addiction (Robinson and Berridge 1993, 2001). Available data certainly show that sensitization of dopaminergic transmission is an important element in transition to addiction. However, these data more particularly point to an important role for sensitized dopamine in triggering the ISuE use phase, inducing an escalation in drug intake. Later on, an increase in dopamine seems to play a less important role (Ahmed et al. 2003), and other factors contribute to maintaining the ISuE phase and to the final transition to the LoC phase and true addiction. Thus, dopamine sensitization is not an exhaustive explanation of transition to addiction but probably a crucial factor specific for the first step of this process.
Clearly, a sensitized dopamine response is not the only possible mechanism mediating escalated intensified drug use, but it serves as an example to show that the different phases of transition to addiction have distinct biological bases. For example, another well documented mechanism that we believe could play an important role in the ISuE phase is an impairment of the prefrontal cortex, and we refer readers to several good reviews on the subject (Jentsch and Taylor 1999; Kalivas et al. 2005; Volkow et al. 2011).
How the accumbens dopaminergic system get sensitized
Several independent variables can increase activity (sensitize) of the dopaminergic projections to the nucleus accumbens. We describe here variables that have been identified as relevant and can consequently be advocated as part of the pathophysiological mechanism leading to transition to addiction.
One mechanism of transition to intensified drug use that has been rather extensively studied as a pathophysiological mechanism is the interaction between glucocorticoid hormones and the dopaminergic system [for review see Piazza et al. (1996); Piazza and Le Moal (1996, 1997); Marinelli and Piazza (2002)]. In a series of publications, we showed that glucocorticoid tone is one of the most crucial regulators of dopaminergic transmission activity in the accumbens and that these hormones are involved in the pathophysiological mechanisms that induce transition from recreational drug use to escalated sustained drug use (Deroche et al. 1997). Thus, HR rats have a higher production of glucocorticoids (Piazza et al. 1991a), and these hormones were a crucial factor in determining their vulnerability to drug abuse (Rougé-Pont et al. 1998; Deroche-Gamonet et al. 2003). Glucocorticoid hormones increase the activity of the dopaminergic system by acting on one of the two brain receptors, more specifically, the glucocorticoid receptor (GR) expressed by striatal medium spiny neurons that project back to the ventral tegmental area (VTA). Suppressing the GR specifically in these neurons dramatically reduced the activity of the dopaminergic projection to the accumbens and induced a behavioral phenotype identical to the one of abuse-resistant rats; the LR (Ambroggi et al. 2009). On the contrary, administering glucocorticoids repeatedly increases vulnerability to drug self-administration (Deroche et al. 1992).
The pathophysiological role of glucocorticoids was confirmed by another series of studies showing that stress-induced sensitization of dopaminergic transmission (Rougé-Pont et al. 1995) and the subsequent vulnerability to escalate to the ISuE phase is dependent on stress-induced glucocorticoid production (Deroche et al. 1995; Marinelli and Piazza 2002). Thus, it was enough to block glucocorticoid secretion to completely suppress the effects of stress on vulnerability to drug self-administration. Similarly, suppressing the GR in accumbens medium spiny neurons suppressed the sensitization induced by repeated exposure to drugs of abuse (Ambroggi et al. 2009).
In conclusion, an increase in GR activation seems a sufficient and necessary condition to the expression of increased vulnerability to drug abuse shown by certain individuals. It is probably because of this GR overactivation that some individuals increasingly want more of a drug and have a higher vulnerability to develop the ISuE phase.
Impulse and desire: two servants of one master
Desire or impulse? Do we escalate in drug abuse because we increasingly desire more of a drug or because we cannot refrain from taking it? This is basically the debate between supporters of motivational views of addiction (such as the incentive sensitization theory) and those who favor the role of impulse control and behavioral disinhibition (Jentsch and Taylor 1999; Volkow et al. 2011). We believe that available evidence suggests that both phenomena contribute to the shift from recreational to sustained drug use. At the behavioral level, rats vulnerable to escalated sustained drug use show signs of increased motivation to take drugs and a degree of impulsivity, in particular, intolerance for delayed reward (Anker et al. 2009; Marusich and Bardo 2009). Similarly, in human addicts, motivation to seek a drug is certainly increased and a higher incidence of impulsivity was found [for review see (de Wit 2009)]. At the neurobiological level, the increased activity of dopaminergic neurons in the nucleus accumbens is consistent with a higher “desire” to take drugs, whereas impairment of the prefrontal cortex was found in human addicts (Goldstein and Volkow 2011) with a higher impulsivity (Jentsch and Taylor 1999).
In conclusion, concerning the second phase of transition to addiction, pathological motivation and increased impulsivity seem to be two servants of the same master, i.e., transition from sporadic recreational drug use to ISuE drug use. What remain unclear is the relationship between impulsivity and vulnerability to full addiction. We and others found impulsivity to be associated with sustained escalated drug use but not with the propensity to lose control and become fully addicted (Deroche-Gamonet et al. 2004). In contrast, Belin et al. (2008) found that a certain measure of impulsivity predicted LoC. One possible reason for this discrepancy is that different components of impulsivity may be associated with different phases of transition to addiction. Impulsivity is a complex trait composed of multiple components, including behavioral disinhibition, intolerance for delayed reward, and impaired ability to consider the consequences of behaviors (Evenden 1999). Vulnerability to develop sustained drug use seems reliably associated with intolerance to delayed reward (Perry et al. 2005, 2008; Belin et al. 2008; Anker et al. 2009), which differs in HRs and LRs. In contrast, behavioral disinhibition seems to predict the development of LoC (Belin et al. 2008; Winstanley et al. 2010). This result seems quite difficult to reconcile with the finding that extinction (also a measure of behavioral disinhibition) and addiction-like behaviors are not correlated and load on orthogonal factors (Deroche-Gamonet et al. 2004). It is then possible that behavioral disinhibition predicts loss of control but does not mediate it, because it is no longer present when addiction-like behavior appears.
Allostasis: a pathophysiological mechanism that stabilizes sustained drug use
The establishment of an allostatic state has been proposed by Le Moal and Koob as the crucial phenomenon in the addiction process (Koob and Le Moal 1997, 2001, 2005). In this context, the idea that the word allostasis carries is that following extended drug use, reward systems adapt to the daily overexposure of the brain to drugs by shifting the homeostatic set point (allostasis) to adapt to this continuous overstimulation. Because of this shift, the drug state progressively becomes the normal state and the nondrug state is now perceived as a pathological, or at least, as an unpleasant state. In other words, drugs progressively shift from being strongly wanted to also strongly needed.
The major empirical evidence for this theoretical construct is modification of the hedonic set point observed in rats that develop drug abuse. In such rats, the reward system seems to become less sensitive and needs stronger stimulation to achieve the same level of reward, as assessed in the electrical brain-stimulation reward procedure (Ahmed et al. 2002). The fact that this modification is very short lasting after discontinuation of drug self-administration reinforces our idea that this process plays a major role specifically in stabilizing an ongoing state of sustained drug use.
What makes these data relevant in our opinion is that a valid experimental medicine approach was used to obtain them, i.e., comparison of short- and long-access animals, which differ in the development of signs of sustained drug use. Although this approach does not take into account individual differences but maximizes the influence of drug availability, it remains a valid experimental medicine approach. Koob and Le Moal, even before their close collaboration, were pioneers in seeing addiction for what it is: a pathological condition that should be explained by a pathophysiological process and not the use of a “normal” behavioral response to a nonnatural reward.
In addition to a shift in the hedonic set point, other neurobiological and molecular long-term adaptations to chronic drug intake (see for example Nestler 2005; Kalivas 2009; Self and Nestler 1995; Wolf 2010a), are potentially involved in the allostatic state. The only incertitude in this impressive body of work is to clarify which of the described drug-induced neuroadaptations are relevant variables for transition to addiction.
In conclusion, as we said earlier for other available theories of addiction, we do not think that the published evidence indicates that allostasis and a shift in the hedonic set point can explain the entire process of transition to addiction and, in particular, loss of control of drug intake. However, drug-induced psychological and physiological allostatic changes clearly play an important role in maintaining a pathological and sustained drug use.
Habitual behavior is an experimental psychology concept that describes how after long periods of training in operant tasks (e.g., pressing a lever for obtaining food) performed in perfectly standardized conditions, the behavior becomes automated in the sense that it is no longer initiated with reference to the goal. Two views of habit learning exist: behaviorist and ideomotor. According to the ideomotor view, although the behavior is automated (i.e., triggered by environmental cues), its remains controlled by its consequences (the value of the reinforcer). In contrast, according to the behaviorist view, the behavior is decreasingly controlled by its consequences (the delivery of the primary reinforcer) and increasingly by environmental contingencies (i.e., the light associated with drug delivery, the position of the lever in the chamber, the physical feature of the chamber, etc.). Because of this, when delivery of the primary reinforcer (food or drug) is interrupted or the primary reinforcer is devalued (by adulteration or punishment), individuals with a habit will keep responding, whereas changes in lever position or physical features of the operant chamber will more effectively disrupt the behavior. In the case of addiction, this implies that the drug becomes increasingly less necessary to sustain and control behavior, which becomes more strictly controlled by the conditions and context in which the drug is taken (drug paraphernalia, administration context, etc).
The potential role of associative learning and habitual behavior in addiction is well summarized in recent reviews by Hogarth et al. (2013). Importantly, the role of habit in addiction has been progressively revised (Everitt and Robbins 2005; Belin et al. 2009b, 2013). Indeed, it now seems unlikely that habit by itself can be responsible for loss of control of drug use (Robinson and Berridge 2003; Everitt and Robbins 2005). More recently, in its behaviorist conception, a role for habit even in earlier phases of transition to addiction has also been questioned (Hogarth et al. 2010).
Drawing the parallel between the behaviorist habit and full addiction was certainly tempting because both imply a form of loss of control. However, controllers and the controlled show opposite relationships between behaviorist habit and full addiction. In addiction, the individual loses control over the primary reinforcer, the drug. In habit, the reinforcer loses control over the behavior of the individual. In other words, during addiction, the drug gains increasing control over behavior, whereas during habit formation, the reinforcer/reward, i.e. the drug, progressively loses that control. The limited usefulness of placebo as a treatment for addiction is exemplary in this context. If drug addiction was a habit, by substituting the drug with a placebo, the addict should scarcely notice it for a reasonable amount of time. However, this is not the case, and even compounds that target the same receptor as the original abused drug but with different pharmacokinetics—as, for example, methadone—are not completely satisfactory in treating addiction. In addition, experimental data in human (Sheeran et al. 2005; Hogarth et al. 2010) and laboratory animals (Olmstead et al. 2001; Root et al. 2009) show that drug-seeking does not become independent of its consequences, as postulated by the behaviorist habit theory.
The first phase of the addiction process—recreational drug use—cannot be explained by a habit, as the behavior is sporadic and controlled by the appetitive effect of the drug (the primary reinforcer). Escalation to sustained drug use is also unlikely to be explained by the formation of habit. In this intermediate phase of addiction, the drug still plays an important role; the higher the impact of the primary reinforcer, the higher the chances of escalation to sustained drug use. When sustained drug intake is in place, a pathological habit can contribute to its stabilization. However, this can happen only in the very specific conditions of standardized and habitual patterns of drug consumption necessary for habit development. In the context of the ideomotor view of automated behavior (Aarts and Dijksterhuis 2000; Aarts et al. 2008), habit could contribute to the impulsive-like drug-seeking observed during sustained drug intake (Sheeran et al. 2005; Hogarth et al. 2010). Behaviorist habit could also play a role in stabilizing sustained drug intake. Thus, once sustained drug use is in place, the development of an allostatic state and the shift of the hedonic set point appear. Now the individual takes drugs not to feel high but to feel right. This implies a devaluation of the reinforcing effects of the drug despite intense use, which is consistent with habit behavior but also with an increased motivational drive created by the appearance of a discomfort when the drug is absent. In any case, habit behavior can influence intensified drug intake only if the pattern of drug use is standardized enough to allow for its development—a condition that is probably very infrequent in real-life addiction.
Conclusions: desire, impulse, and need—the three keys to transition to sustained drug use
In conclusion, development of sustained drug use (the ISuE phase) can be mediated by sensitized dopaminergic transmission in the accumbens (as described here) and by decreased functionality of the prefrontal cortex (Jentsch and Taylor 1999; Goldstein and Volkow 2011). These changes can be either spontaneously present or induced by stress and drug exposure. Sensitized dopamine transmission and impaired prefrontal cortex converge to make drugs highly appetitive and difficult to resist. In other words, these processes increase the desire and impulse for the drug and facilitate the development of an escalation in drug intake and sustained drug use. The establishment of sustained drug intake will then induce, as a form of additional adaptation, an allostatic state associated with a downregulated reward system that will progressively bring the nondrug state out of the comfort zone. The drug now is not only the object of strong impulses and desire but is also strongly needed–the transition to an escalated, sustained drug use is now complete. Finally, under certain conditions of highly standardized pattern of drug use, the establishment of habit behavior can also contribute to the maintenance of sustained drug intake.
Psychobiology of loss of control and full addiction
Impaired synaptic plasticity is associated with the development of loss of control and full addiction
Our knowledge concerning the pathophysiological mechanisms of the loss of control-prone phenotype is very limited. Indeed, the only biological modification yet specifically associated with loss of control of drug intake is a loss of synaptic plasticity (Kasanetz et al. 2010, 2012). It is important to emphasize here that the implication of synaptic plasticity to addiction was not proposed by us but by several of our colleagues who showed that, depending on the protocol and the conditions used, repeated drug intake would induce impaired synaptic plasticity (White and Kalivas 1998; Kalivas 2005; Kauer and Malenka 2007; Thomas et al. 2008; Russo et al. 2010; Lüscher and Malenka 2011). Our contribution was to show that impairment in long-term depression of synaptic transmission (LTD) in the brain is not just another drug-induced change but to date the only one specifically associated with cocaine-addiction-like behavior.
Briefly, we have shown that after a short period of self-administration (around 7 days), there are no impairments in synaptic plasticity (in the form of LTD) in the cortex or the nucleus accumbens. However, after 18 days, before the appearance of addiction-like behavior, a loss of N-mathyl-D-aspartate (NMDA)-dependent LTD appears in the accumbens of all individuals self-administering cocaine. On the contrary, no modifications of synaptic plasticity are observed in the prefrontal cortex. Later on, after 60 days of self-administration, a normal NMDA-dependent LTD is recovered in the accumbens of rats that maintain a controlled drug intake. In contrast, in rats that have developed addiction-like behavior, LTD in the accumbens appears to be permanently lost (at least up to 3 months). This stable impairment in accumbens LTD is accompanied by the appearance of an impaired metabotropic glutamate receptor 2/3-mediated LTD (mGluR2/3-LTD) that is observed selectively in the cortex of addicted rats.
In conclusion, rats that develop addiction-like behaviors have impaired NMDA and mGluR2/3-dependent LTD in the nucleus accumbens and prefrontal cortex, respectively, whereas both types of LTD are functional in nonaddicted rats. An exception is the endocannabinoid-mediated long-term synaptic depression (eCB-LTD) that after 60 days of self-administration is impaired both in addicted and nonaddicted rats. Thus, eCB-LTD is an example of drug-induced neuroadaptations that are unrelated to addiction that we previously discussed.
These data change the frame of reference in which vulnerability and resistance to addiction should be conceptualized. One way to view resistance and vulnerability to addiction is to say that some vulnerable individuals have a pathological response to addictive drugs, whereas resistant individuals are insensitive to the addiction-promoting effects of drugs of abuse. Our data show that this is not the case. Most drug-induced impairments in synaptic plasticity are initially observed in all individuals, but the majority of individuals, the resistant ones, are able to adapt and recover from most of them. Thus, resistance to drugs is not a passive immunity or insensitivity to the deleterious effects of drugs; this resistance is an active, biological, adaptive process—an active resilience. Conversely, the addict does not develop a response to drugs that is completely different from that of resistant individuals but is principally an individual who cannot adapt to the changes in the brain induced by the drug. As a consequence, vulnerability to addiction can be conceptualized as involving a degree of “anaplasticity,” the inability to recover a lost function, rather than a unique sensitivity to the drug’s deleterious effects.
Behavioral crystallization: a “missing” hypothesis of the psychological process underlying loss of control and full addiction
We propose here an evidence-based hypothesis of the psychological process underlying loss of control and full addiction. This hypothesis is based on the first and only neurobiological impairment specifically associated with loss of control in a rat model: i.e., a persistent loss of synaptic plasticity in the nucleus accumbens and medial prefontal cortex. We propose to the reader to follow two subsequent steps: (1) conceptualize what behavioral deficit could follow a loss in synaptic plasticity; (2) assess whether such a behavioral deficit could be consistent with the behavior observed in individuals showing the severe form of SUD characterized by loss of control of drug intake.
It is largely believed, and we agree with this hypothesis, that synaptic plasticity, as studied by long-term potentiation (LTP) and LTD, represents the ability of the brain to strengthen or depress neuronal circuits in order to maintain adaptive behavioral responses to changes in environmental contingencies (Goto et al. 2010; Neiman and Loewenstein 2013). In other words, one can say that the synapses of the brain circuit mediating a current behavioral sequence are “fully potentiated.” However, if an environmental event makes a current behavioral sequence maladaptive, your brain is able to depress the synaptic strength in that circuit and potentiate synaptic strength in a new circuit, thus mediating a new and more adaptive behavioral sequence. In other words, the balance between potentiation (LTP) and depression (LTD) can shift from one behavior to another and maintain a flexible and adaptive behavior.
Let us imagine that, as observed in rats showing addiction-like behaviors, the brain loses the ability to perform LTD, especially in regions such as the nucleus accumbens and prefrontal cortex, which are important in selecting appropriate goal-directed behaviors. The consequences would be quite catastrophic: behavior would remain crystallized around one behavioral goal and would not be able to shift to another. There would be great perseverance to achieve the crystallized goal no matter the costs or consequences. This would be externally manifested as a considerable loss of control of drug use that will become very difficult to change. However, this is not a state of compulsive pathological motivation for the drug but a “prison” from which the behavior, crystallized around one unique goal, taking drugs, is not very likely to escape.
There is a metaphoric example that we like to provide to students to explain the concept of behavioral crystallization. Imagine that the brain is a tank full of water and behavioral goals are cylinders of very different shapes. You behave in a certain way when one of the behavioral cylinders is immersed in the water tank. When the brain functions normally, you can easily remove a given cylinder, submerge a different one, and change behavior. However, if the water freezes, i.e., crystallizes (loss of synaptic plasticity), it will hold tight to the cylinder that was submerged at the time (taking drugs), and you will then be stuck in the prison of this behavioral goal. With some help, effort, and scraping (painful first period of any detoxification therapy), you will be able to extract the active cylinder from the crystallized water. However, it will be impossible to fill the remaining hole with any other behavioral cylinder. Your behavior is now crystallized, you can learn to live with this hole but it will be too strong a temptation, given the occasion, to fill it up again with the only cylinder that fits: taking drugs (quick relapse to drug addiction even after prolonged abstinence). Clearly, the water could melt again and the behavior regain plasticity. However, this seems to happen in a very restricted number of individuals; rather, addiction becomes a “frozen” chronic relapsing disease in 90 % of cases.
In conclusion, because of behavioral crystallization, drugs are not only wanted and needed but also irremediably missed when they are not present. The absence of drugs is felt as the irreplaceable loss of something very dear and precious, like a pathological mourning that cannot be overcome. When we start pathologically mourning the “missing” drug and can no longer escape from its embrace, there and then the transition to addiction is complete.
Changing places: from the VTA to the accumbens to the cortex—a likely road to full addiction
One interesting hypothesis put forward recently is that during transition to addiction, modifications in synaptic plasticity migrate following a ventrodorsal gradient (Lüscher and Malenka 2011). Changes in plasticity would occur quickly in the VTA, migrate then to the accumbens, and later on to the prefrontal cortex. This process of the transfer of learned information between structures of the brain is a well-known concept that has been described for motor learning (Salmon and Butters 1995; Karni et al. 1995; Jueptner et al. 1997; Wu et al. 2008) and for spatial or declarative memory processes in both rodents and humans (Bontempi et al. 1999; Frankland and Bontempi 2005; Winocur et al. 2010; Helie et al. 2010).
Regarding memory formation, it is recognized that spatial information about a given environment is acquired through the hippocampus and then moves to the cortex for long-term storage (Winocur et al. 2010). Rule-based categorization in humans appears to move from subcortical to cortical regions automatically (Helie et al. 2010). The classic view of motor learning postulates that novel behaviors are dependent on the cortex, whereas automatic behaviors are primarily mediated by subcortical structures, e.g., the striatum. Although this view is now questioned (Ashby et al. 2010) and the role of the striatum in automatic motor tasks (such as playing a well-learned musical piece) and habitual behavior has been challenged, it remains true that plasticity phenomena within (Karni et al. 1995) and between brain structures occur (Wu et al. 2008) when automatic behaviors develop.
In the case of addiction, evidence suggest that the regions controlling drug use progress from the VTA to the accumbens and finally to the cortex. Thus, the accumbens seems completely spared during the first week of self-administration, during which the VTA should be affected. Modifications in the accumbens appear only later on but before the appearance of addiction-like behaviors. The last region to show a change in synaptic plasticity (which appears only in addicted rats) is the prefrontal cortex (Kasanetz et al. 2010, 2012).
It has also been suggested, based on neurochemical and pharmacological evidence (Veeneman et al. 2012; Willuhn et al. 2012), that the response to drugs of abuse and cues associated with them moves from the nucleus accumbens to the dorsal striatum (Belin and Everitt 2008; Belin-Rauscent et al. 2012). In the original framework that describes addiction as a form of habit-like behavior (Tiffany 1990), this shift is seen as the fundamental trigger of a stimulus–response habit (Belin et al. 2013).
In conclusion, whatever the exact structures involved and the exact timing of progression, the observations summarized above indicate that depending on the phase of transition to addiction, different structures mediate responses to drugs. These data strongly support the idea posited by our theory that the process of addiction is mediated by independent but concatenated phases.