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International audience; Identifying vulnerable individuals before they transition to a compulsive pattern of drug seeking and taking is a key challenge in addiction to develop efficient prevention strategies. Oscillatory activity within the subthalamic nucleus (STN) has been associated with compulsive-related disorders. To study compulsive cocaine-seeking behavior, a core component of drug addiction, we have used a rat model in which cocaine seeking despite a foot-shock contingency only emerges in some vulnerable individuals having escalated their cocaine intake. We show that abnormal oscillatory activity within the alpha/theta and low-beta bands during the escalation of cocaine intake phase predicts the subsequent emergence of compulsive-like seeking behavior. In fact, mimicking STN pathological activity in noncompulsive rats during cocaine escalation turns them into compulsive ones. We also find that 30 Hz, but not 130 Hz, STN deep brain stimulation (DBS) reduces pathological cocaine seeking in compulsive individuals. Our results identify an early electrical signature of future compulsive-like cocaine-seeking behavior and further advocates the use of frequency-dependent STN DBS for the treatment of addiction.

Although deep brain stimulation (DBS) is now a widely used therapeutic strategy, its precise mechanism remains largely unclear. Since this approach is progressively extended to treat non-motor disorders such as depression, obsessive-compulsive disorders, the comprehension of its effects on motivated behaviors appears of the upmost importance for a possible application for addiction. In intact rats, we used inhibition and high frequency optogenetic activation of subthalamic nucleus (STN) neurons to test whether or not we could reproduce the effects of electric deep brain stimulation on rats’ motivation for sweet food and cocaine. Rats’ motivation was assessed using fixed-ratio 5 and progressive ratio schedules of reinforcement for both rewards and illumination was applied during behavioral testing. Efficiency of optogenetic manipulations has been validated using in-vitro electrophysiological recordings. Optogenetic inhibition of STN increased motivation for food and reduced motivation for cocaine. In contrast, optogenetic high frequency stimulation reduced the motivation for food without impacting motivation for cocaine. Optical inhibition mimics the effect of electric deep brain stimulation on food and cocaine motivation, confirming that the effects observed under electric DBS result from a specific inactivation of the STN. In contrast, optogenetic high frequency stimulation induces opposite effects to those of electric one, suggesting a stimulation of the STN that only seems to affect food motivation.; Although deep brain stimulation (DBS) is now a widely used therapeutic strategy, its precise mechanism remains largely unclear. Since this approach is progressively extended to treat non-motor disorders such as depression, obsessive-compulsive disorders, the comprehension of its effects on motivated behaviors appears of the upmost importance for a possible application for addiction. In intact rats, we used inhibition and high frequency optogenetic activation of subthalamic nucleus (STN) neurons to test whether or not we could reproduce the effects of electric deep brain stimulation on rats’ motivation for sweet food and cocaine. Rats’ motivation was assessed using fixed-ratio 5 and progressive ratio schedules of reinforcement for both rewards and illumination was applied during behavioral testing. Efficiency of optogenetic manipulations has been validated using in-vitro electrophysiological recordings. Optogenetic inhibition of STN increased motivation for food and reduced motivation for cocaine. In contrast, optogenetic high frequency stimulation reduced the motivation for food without impacting motivation for cocaine. Optical inhibition mimics the effect of electric deep brain stimulation on food and cocaine motivation, confirming that the effects observed under electric DBS result from a specific inactivation of the STN. In contrast, optogenetic high frequency stimulation induces opposite effects to those of electric one, suggesting a stimulation of the STN that only seems to affect food motivation.

International audience; Drug intake is known to be under the influence of social context. We have recently shown that presence of a peer influences drug intake in both rats and humans. Whether or not social acoustic communications between the peers play a role during cocaine or sucrose self-administration (SA) was investigated here, using playback of ultrasonic vocalizations (USV) at 50- and 22-kHz, conveying respectively positive and negative internal affective states in adult rats. To assess the neurobiological substrate of a potential USV influence on drug and food intake, we tested the effects of subthalamic nucleus (STN) lesions, given its role in emotional and motivational processes. In sham-control rats, playback of USV associated with positive affective states induced long-term decreased cocaine consumption, while USV associated with negative affective states induced short-term increase. Interestingly, no effect of USV playback was observed on sucrose intake, whatever the frequency. STN lesions abolished the influence of USV on cocaine intake, highlighting the influence of STN in emotional processes induced by USV emitted by a peer. These results show how acoustic social communication is important to regulate drug intake in rats and how STN modulation could interfere with addiction processes.

One of the key features of addiction is the escalated drug intake. The neural mechanisms involved in the transition to addiction remain to be elucidated. Since abnormal neuronal activity within the subthalamic nucleus (STN) stands as potential general neuromarker common to impulse control spectrum deficits, as observed in obsessive–compulsive disorders, the present study recorded and manipulated STN neuronal activity during the initial transition to addiction (i.e., escalation) and post-abstinence relapse (i.e., re-escalation) in rats with extended drug access. We found that low-frequency (theta and beta bands) neuronal oscillations in the STN increase with escalation of cocaine intake and that either lesion or high-frequency stimulation prevents the escalation of cocaine intake. STN–HFS also reduces re-escalation after prolonged, but not short, protracted abstinence, suggesting that STN–HFS is an effective prevention for relapse when baseline rates of self-administration have been re-established. Thus, STN dysfunctions may represent an underlying mechanism for cocaine addiction and therefore a promising target for the treatment of addiction.

Addicted individual compulsively use drug despite its negative consequences. This often originates from exacerbated motivation for the drug and impaired behavioral control over its use. Although they share commonalities, these two processes can involve various cerebral structures. To date, the emphasis has been made on the exacerbated motivation for the drug and therefore most studies from animal models to human studies have been focused on the reward circuit. The present chapter will not only review the various surgical interventions that have been carried out in the structures of the classical circuit but will also propose a more recent view of this circuit that includes the subthalamic nucleus (STN), a cerebral structure involved in both motivation and inhibitory control. We will thus also review the various results obtained after manipulation of the STN on motivational processes and addiction-related behaviors. The surgical strategy raises several issues, but in extreme cases when no treatment has proven efficacy, as for certain forms of addiction, surgery can be the best option. We will however also review here the noninvasive strategies developed in the recent years.

Cocaine seeking despite a foot-shock contingency is used to model compulsive drug seeking, a core component of drug addiction, in rodents. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficient on other addiction criteria models and we show here that 30-Hz STN stimulation reduces pathological cocaine seeking in compulsive-like rats. This confirms STN DBS as a potential strategy to treat addiction. We also observed that only ‘compulsive-like’ rats displayed a progressive increase in STN low frequency oscillations, especially in the alpha/theta band (6-13 Hz), during cocaine escalation. Conversely, applying 8-Hz STN DBS to mimic alpha/theta oscillations in ‘non-compulsive’ animals changed them into ‘compulsive’ ones. We have thus identified a predictive neuronal biomarker of compulsivity. Since one critical challenge in addiction research is to identify vulnerable individuals before they transition to harmful drug consumption pattern, our results could lead to new diagnostic tools and prevention strategies.; Cocaine seeking despite a foot-shock contingency is used to model compulsive drug seeking, a core component of drug addiction, in rodents. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is efficient on other addiction criteria models and we show here that 30-Hz STN stimulation reduces pathological cocaine seeking in compulsive-like rats. This confirms STN DBS as a potential strategy to treat addiction. We also observed that only ‘compulsive-like’ rats displayed a progressive increase in STN low frequency oscillations, especially in the alpha/theta band (6-13 Hz), during cocaine escalation. Conversely, applying 8-Hz STN DBS to mimic alpha/theta oscillations in ‘non-compulsive’ animals changed them into ‘compulsive’ ones. We have thus identified a predictive neuronal biomarker of compulsivity. Since one critical challenge in addiction research is to identify vulnerable individuals before they transition to harmful drug consumption pattern, our results could lead to new diagnostic tools and prevention strategies.

Drug intake is known to be under the influence of social context. We have recently shown that presence of a peer influences drug intake in both rats and humans. Whether or not social acoustic communications between the peers play a role during cocaine or sucrose self-administration (SA) was investigated here, using playback of ultrasonic vocalizations (USV) at 50- and 22-kHz, conveying respectively positive and negative internal affective states in adult rats. To assess the neurobiological substrate of a potential USV influence on drug and food intake, we tested the effects of subthalamic nucleus (STN) lesions, given its role in emotional and motivational processes. In sham-control rats, playback of USV associated with positive affective states induced long-term decreased cocaine consumption, while USV associated with negative affective states induced short-term increase. Interestingly, no effect of USV playback was observed on sucrose intake, whatever the frequency. STN lesions abolished the influence of USV on cocaine intake, highlighting the influence of STN in emotional processes induced by USV emitted by a peer. These results show how acoustic social communication is important to regulate drug intake in rats and how STN modulation could interfere with addiction processes.

Drug addiction is defined as a recurring cycle of intoxication, abstinence and relapse. The behavioural trait of novelty seeking is frequently observed in alcohol abusers. Moreover, converging evidence indicates that anxious individuals are also predisposed to alcohol abuse. We have analyzed the respective implication of those two behavioural factors on vulnerability to ethanol intake on rats in situations designed to reflect drug intoxication and relapse phases in humans. In a general population of Wistar rats, animals were tested in both the light/dark box and the novelty preference tests. Ethanol consumption was measured in a two-bottle free-choice procedure across three successive procedures. Animals were first exposed to increasing concentrations of ethanol (2, 4, 6, 8, 10, 12 % for 8 days at each concentration). Then, the concentration of the solution was diminished from 12 to 6 %. Finally, all rats were re-exposed to 6 % ethanol after 12 days of ethanol deprivation. Novelty preference predicted the amount of ethanol consumed across all phases. In contrast, anxiety was associated with a quicker recovery of ethanol consumption after the concentration drop and a greater increase in ethanol consumption after deprivation. Novelty seeking and anxiety are both but differentially implicated in predisposition to ethanol abuse. Whereas novelty seeking is related to the amount of ethanol consumed, anxiety is associated to higher ethanol consumption when ethanol concentration is decreased or after ethanol deprivation.

Background Development of maladaptive drug-seeking habits occurs in conjunction with a ventral-to-dorsal striatal shift in dopaminergic control over behavior. Although these habits readily develop as drug use continues, high impulsivity predicts loss of control over drug seeking and taking. However, whether impulsivity facilitates the transition to dorsolateral striatum (DLS) dopamine-dependent cocaine-seeking habits or whether impulsivity and cocaine-induced intrastriatal shifts are additive processes is unknown. Methods High- and low-impulsive rats identified in the five-choice serial reaction-time task were trained to self-administer cocaine (.25 mg/infusion) with infusions occurring in the presence of a cue-light conditioned stimulus. Dopamine transmission was blocked in the DLS after three stages of training: early, transition, and late-stage, by bilateral intracranial infusions of α-flupenthixol (0, 5, 10, or 15 μg/side) during 15-min cocaine-seeking test sessions in which each response was reinforced by a cocaine-associated conditioned stimulus presentation. Results In early-stage tests, neither group was affected by DLS dopamine receptor blockade. In transition-stage tests, low-impulsive rats showed a significant dose-dependent reduction in cocaine seeking, whereas high-impulsive rats were still unaffected by α-flupenthixol infusions. In the final, late-stage seeking test, both groups showed dose-dependent sensitivity to dopamine receptor blockade. Conclusions The results demonstrate that high impulsivity is associated with a delayed transition to DLS-dopamine-dependent control over cocaine seeking. This suggests that, if impulsivity confers an increased propensity to addiction, it is not simply through a more rapid development of habits but instead through interacting corticostriatal and striato-striatal processes that result ultimately in maladaptive drug-seeking habits.

Compulsive drug use and a persistent vulnerability to relapse are key features of addiction. Imaging studies have suggested that these features may result from deficits in prefrontal cortical structure and function, and thereby impaired top-down inhibitory control over limbic–striatal mechanisms of drug-seeking behaviour. We tested the hypothesis that selective damage to distinct subregions of the prefrontal cortex, or to the amygdala, after a short history of cocaine taking would: (i) result in compulsive cocaine seeking at a time when it would not usually be displayed; or (ii) facilitate relapse to drug seeking after abstinence. Rats with selective, bilateral excitotoxic lesions of the basolateral amygdala or anterior cingulate, prelimbic, infralimbic, orbitofrontal or anterior insular cortices were trained to self-administer cocaine under a seeking–taking chained schedule. Intermittent mild footshock punishment of the cocaine-seeking response was then introduced. No prefrontal cortical lesion affected the ability of rats to withhold their seeking responses. However, rats with lesions to the basolateral amygdala increased their cocaine-seeking responses under punishment and were impaired in their acquisition of conditioned fear. Following a 7-day abstinence period, rats were re-exposed to the drug-seeking environment for assessment of relapse in the absence of punishment or cocaine. Rats with prelimbic cortex lesions showed decreased seeking responses during relapse, whereas those with anterior insular cortex lesions showed an increase. Combined, these results show that acute impairment of prefrontal cortical function does not result in compulsive cocaine seeking after a short history of self-administering cocaine, but further implicates subregions of the prefrontal cortex in relapse.

Continued instrumental drug seeking despite contingent punishment is a core phenotype of drug addiction. Although the neuroanatomical basis of punished drug seeking is unclear, we hypothesize that the sensorimotor striatum, a structure that mediates habitual drug seeking, also mediates punished cocaine seeking. Forelimb sensorimotor projections into the striatum of the rat extend from the dorsolateral to midlateral striatum. Here, we selectively inactivated the dorsolateral and midlateral striatum in rats responding for cocaine in a seeking–taking task. We inactivated both regions after the acquisition of cocaine seeking, after extended cocaine self-administration and finally after the introduction of intermittent, seeking-contingent foot shock. The results show that inactivation of the dorsolateral striatum selectively disrupted punished drug seeking but did not affect unpunished drug seeking, even after extended training. Inactivation of the midlateral striatum, on the other hand, disrupted drug seeking at all stages of training. The effect of inactivating the dorsolateral striatum under punishment conditions was present before delivery of the first shock in the session, and responding reverted to baseline the next day. Thus, inactivation of the dorsolateral striatum seems to enhance the influence of recalled threat of negative consequences of cocaine seeking. The proportional reduction in responding after inactivation of the dorsolateral striatum did not vary with the individual level of compulsivity. Together, these results suggest a novel differentiation of function in the sensorimotor striatum, where the dorsolateral striatum selectively mediates the rigidity of responding after overtraining, while the midlateral striatum mediates responding itself at all stages of training.

Although high anxiety is commonly associated with drug addiction, its causal role in this disorder is unclear. In light of strong evidence for dissociable neural mechanisms underlying heroin and cocaine addiction, the present study investigated whether high anxiety predicts the propensity of rats to lose control over intravenous cocaine or heroin self-administration. Sixty-four rats were assessed for anxiety in the elevated plus-maze, prior to extended access to intravenous cocaine or heroin self-administration. High-anxious rats, identified in the lower quartile of the population, showed a greater escalation of cocaine, but not heroin, self-administration compared with low-anxious rats selected in the upper quartile of the population. Anxiety scores were also positively correlated with the extent of escalation of cocaine self-administration. The present data suggest that high anxiety predisposes rats to lose control over cocaine—but not heroin—intake. High anxiety may therefore be a vulnerability trait for the escalation of stimulant but not opiate self-administration.

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D 2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.

In this chapter, we review evidence implicating the orbitofrontal cortex (OFC) in drug addiction. We show that the orbital cortex is involved in conditioned reinforcement and is thereby important for the acquisition of cocaine-seeking behavior studied in a way that provides an animal experimental homologue of orbital cortex activation and craving upon exposure of addicts to drug-associated stimuli. We discuss the evidence indicating orbital prefrontal cortex dysfunction in human drug addicts, reviewing both neuropsychological and neuroimaging studies. Finally, we consider animal experimental evidence suggesting that addictive drugs may cause orbital cortex dysfunction and thereby contribute to the transition to drug addiction. Reconciling the observations that even brief periods of drug exposure can lead to long-lasting functional and structural deficits associated with the OFC together with those suggesting interactions between a vulnerable phenotype and chronic drug-self-administration will be an important topic of future research.

International audience; The subthalamic nucleus (STN) belongs to the basal ganglia and is the current target for the surgical treatment of neurological and psychiatric disorders such as Parkinson's Disease (PD) and obsessive compulsive disorders (OCD), but also a proposed site for the treatment of addiction. It is therefore very important to understand its functions in order to anticipate and prevent possible side-effects in the patients. Although the involvement of the STN is well documented in motor, cognitive and motivational processes, less is known regarding emotional processes. Here we have investigated the direct consequences of STN inactivation by excitotoxic lesions on emotional processing and reinforcement in the rat. We have used various behavioral procedures to assess affect for neutral, positive and negative reinforcers in STN lesioned rats. STN lesions reduced affective responses for positive (sweet solutions) and negative (electric foot shock, Lithium Chloride-induced sickness) reinforcers while they had no effect on responses for a more neutral reinforcer (novelty induced place preference (NIPP)). Furthermore, when given the choice between saccharine, a sweet but non caloric solution, and glucose, a more bland but caloric solution, in contrast to sham animals that preferred saccharine, STN lesioned animals preferred glucose over saccharine. Taken altogether these results reveal that STN plays a critical role in emotional processing. These results, in line with some clinical observations in PD patients subjected to STN surgery, suggest possible emotional side-effects of treatments targeting the STN. They also suggest that the increased motivation for sucrose previously reported cannot be due to increased pleasure, but could be responsible for the decreased motivation for cocaine reported after STN inactivation.

Surgical treatment for psychiatric disorders has been revitalized for the past ten years after deep brain stimulation (DBS) had shown its efficacy for the treatment of neurological disorders such as Parkinson's disease. In the field of psychiatric disorders, DBS has been first used for obsessive compulsive disorder and treatment-resistant depression. Only recently it has been proposed for the treatment of addiction. Whatever the disease, the selected target is a constant question. In this review, we present theoretical, empirical and technical arguments in favor of targeting the subthalamic nucleus as the best candidate over other areas for DBS in the treatment of drug addiction.

Compulsive drug seeking, which is characterized by continued instrumental effort despite contingent punishment, has been shown to emerge after extended drug self-administration. Exactly what aspect of drug self-administration drives the appearance of addictive behavior is unclear, but the mechanistic explanations that have been offered differ in one key respect. On one hand, it has been suggested that dysfunctional conditioning during self-administration drives unrealistic reward expectations, ultimately producing resistance to punishment. If this is indeed the pathological process that drives compulsive behavior, then compulsivity should be apparent only in the presence of the pavlovian and instrumental stimuli that underwent frequent pairing with the drug reward. On the other hand, it has also been suggested that extended drug intake produces general changes to reward and decision-making circuits that manifest as compulsive drug seeking. Unfortunately, conditioning history and drug intake are generally intrinsically intertwined. However, here we used an animal model of compulsive cocaine seeking to selectively manipulate drug intake and the degree of conditioning in the test context, to investigate which of the two is more important for the emergence of compulsive cocaine seeking. The results show that extended drug intake alone is sufficient, but extended conditioning in the test context is not necessary for the emergence of compulsive cocaine seeking, resolving a fundamental question in addiction research.

Background Relapse is a hallmark feature of cocaine addiction and a main challenge for treatment strategies. Human studies indicate a link between impulsivity and increased susceptibility to relapse. Methods Rats were screened for high (HI) and low impulsivity (LI) on the 5-choice serial reaction time task. The HI and LI rats were trained to self-administer cocaine under a seeking-taking chained schedule: responses on the seeking lever resulted in presentation of the taking lever, responding upon which resulted in cocaine reinforcement. After the establishment of stable responding, an intermittent punishment schedule was introduced: completion of the seeking link resulted in the random presentation of either the taking lever or a mild footshock. This resulted in a progressive decrease in cocaine-seeking approaching abstinence. Relapse was assessed 7 days after punishment, during which responding on the seeking lever resulted in the presentation of the cocaine-associated stimuli (i.e., in the absence of cocaine or footshock). Results The HI and LI animals significantly reinstated the cocaine-seeking response after a single phase of seeking punishment. However, after a second punishment phase only the HI rats reinitiated suppressed seeking responses and relapsed, an effect that was facilitated by prior extended cocaine access. In a preliminary study we found that the selective noradrenaline reuptake inhibitor, atomoxetine, a drug known to reduce impulsivity, prevented the reinstatement of cocaine-seeking. Conclusions Impulsivity pre-dating drug abuse increases the susceptibility to relapse after abstinence. Medications targeting impulsivity might have utility as treatment interventions for relapse prevention and the promotion of abstinence.

Some clinical studies have shown that anxiety disorders are often associated with drug dependence, although it remains unclear whether these disorders are primary or secondary to drug abuse. We have investigated whether anxiety may be a factor that predisposes to cocaine use. From an outbred Wistar strain, we have selected male rats regarded as anxious or non-anxious on the basis of their scores on two behavioural tests of unconditioned anxiety, the elevated plus-maze and the light/dark box test. They were also screened for their locomotor activity in an inescapable novel environment and for their preference for novelty presented in a free-choice. Rewarding effects of cocaine (2.5-20 mg/kg; i.p.) were then determined in the conditioned place preference paradigm (CPP). Anxious and non-anxious rats showed no difference in their responsiveness to inescapable novelty or their preference for novelty in a free-choice procedure. Only anxious rats developed a CPP induced by increasing doses of cocaine, the magnitude of CPP induced by the 10 mg/kg dose of cocaine being significantly higher than that observed in anxious rats conditioned with saline. These results suggest that anxiety affects the sensitivity to aversive/anxiogenic effects of cocaine. Thus, anxious rats which were highly responsive to positive effects of cocaine may be more prone to develop cocaine addiction than non-anxious rats.

The subthalamic nucleus (STN) has only recently been added into the reward circuit. It has been shown to encode information regarding rewards (4% sucrose, 32% cocaine). To investigate the encoding of negative value, STN neurons were recorded in rats performing a task using discriminative stimuli predicting various rewards and especially during the replacement of a positive reinforcer (4% sucrose) by an aversive reinforcer (quinine). The results show that STN neurons encode information relative to both positive and aversive reinforcers via specialized subpopulations. The specialization is reset when the context is modified (change from a favorable context (4% vs 32% sucrose) to an unfavorable context (quinine vs 32% sucrose). An excitatory response to the cue light predicting the reward seems to be associated with the preferred situation, suggesting that STN plays a role in encoding the relative value of rewards. STN also seems to play a critical role in the encoding of execution error. Indeed, various subpopulations of neurons responding exclusively at early (i.e., “oops neurons”) or at correct lever release were identified. The oops neurons respond mostly when the preferred reward (32% sucrose) is missed. Furthermore, STN neurons respond to reward omission, suggesting a role in reward prediction error. These properties of STN neurons strengthen its position in the reward circuit as a key cerebral structure through which reward-related processes are mediated. It is particularly important given the fact that STN is the target of surgical treatment for Parkinson’s disease and obsessive compulsive disorders, and has been suggested for the treatment of addiction as well.

Sensation/novelty seeking is frequently observed in drug abusers. Rats with high locomotor activity in response to inescapable novelty may be more prone to drug addiction. However, it is not clear whether this response to novelty represents reactivity to the novelty-induced stress or seeking for novelty. We have compared the influence of the response to novelty—presented in a forced stressful or in a free choice non-stressful manner—on vulnerability to addictive properties of amphetamine. Wistar rats were selected according to their (i) reactivity to inescapable novelty and (ii) novelty preference. For this purpose, animals were exposed during two 30-min sessions, 24 h apart, to the same compartment; their motor activity during the first session was used as an index of reactivity. On the third day, they were allowed to choose between this "familiar" environment and a novel one. Rewarding properties of amphetamine (0.2–3.2 mg/kg, s.c.) were determined by place conditioning. Amphetamine oral consumption (10–50 mg/l) in a free-choice paradigm was measured over a period of 32 days. Reactivity to novelty and novelty preference were not correlated. Reactivity to inescapable novelty predicted place conditioning induced by the lowest dose of amphetamine, whereas preference for novelty did not. High responders to inescapable novelty consumed less amphetamine than low responders. Novelty preference was positively correlated to amphetamine oral consumption only at the lowest concentration. Reactivity to inescapable novelty and novelty preference represent different behavioural components, which are related differentially with amphetamine place conditioning and its oral consumption.