Large-scale brain correlates of sweet versus cocaine reward in rats.

Cocaine induces many supranormal changes in neuronal activity in the brain, notably in learning- and reward-related regions, in comparison with nondrug rewards-a difference that is thought to contribute to its relatively high addictive potential. However, when facing a choice between cocaine and a nondrug reward (e.g., water sweetened with saccharin), most rats do not choose cocaine, as one would expect from the extent and magnitude of its global activation of the brain, but instead choose the nondrug option. We recently showed that cocaine, though larger in magnitude, is also an inherently more delayed reward than sweet water, thereby explaining why it has less value during choice and why rats opt for the more immediate nondrug option. Here, we used a large-scale Fos brain mapping approach to measure brain responses to each option in saccharin-preferring rats, with the hope to identify brain regions whose activity may explain the preference for the nondrug option. In total, Fos expression was measured in 142 brain levels corresponding to 52 brain subregions and composing 5 brain macrosystems. Overall, our findings confirm in rats with a preference for saccharin that cocaine induces more global brain activation than the preferred nondrug option does. Only very few brain regions were uniquely activated by saccharin. They included regions involved in taste processing (i.e., anterior gustatory cortex) and also regions involved in processing reward delay and intertemporal choice (i.e., some components of the septohippocampal system and its connections with the lateral habenula).

Preference for Cocaine is Represented in the Orbitofrontal Cortex by an Increased Proportion of Cocaine Use-Coding Neurons.

Cocaine addiction is a harmful preference for drug use over and at the expense of other nondrug-related activities. Here we identify in the rat orbitofrontal cortex (OFC) a mechanism that explains individual preferences between cocaine use and an alternative, nondrug action. OFC neuronal activity was recorded while rats performed each of these 2 actions separately or while they chose between them. First, we found that these actions are encoded by 2 nonoverlapping neuronal populations and that the relative size of the cocaine population represented individual preferences. A larger relative size was only observed in cocaine-preferring individuals. Second, OFC neurons encoding a given individual's preferred action progressively fired more than other action-coding neurons few seconds before the preferred action was actually chosen, suggesting a prechoice neuronal competition for action selection. In cocaine-preferring rats, this manifested by a prechoice ramping-up activity in favor of the cocaine population. Finally, pharmacological manipulation of prechoice activity in favor of the cocaine population caused nondrug-preferring rats to shift their choice to cocaine. Overall, this study suggests that an individual preference for cocaine is represented in the OFC by a population size bias that systematically advantages cocaine use-coding neurons during prechoice competition for action selection.

Neuronal representation of individual heroin choices in the orbitofrontal cortex.

Drug addiction is a harmful preference for drug use over and at the expense of other non-drug-related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non-drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non-drug reward separately or while they chose between the two. First, we found that heroin-rewarded and sweet water-rewarded actions were encoded by two non-overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action-which was the non-drug action in the large majority of individuals-progressively fired more than non-preferred action-coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre-choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug-specific differences in OFC encoding activity. Notably, the proportion of neurons that non-selectively encode both the drug and the non-drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice.

Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats.

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking.

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues.

Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.

Bidirectional relationship between attentional deficits and escalation of nicotine intake in male rats.

RATIONALE: People with tobacco addiction have deficits in cognition, in particular deficits in attention. It is not clear however, whether deficits are a cause or a consequence, or both, of chronic nicotine use. Here we set out a series of experiments in rats to address this question and, more specifically, to assess the effects of exposure to and withdrawal from chronic nicotine self-administration on attentional performance. METHODS: Animals were trained in a 5-choice serial reaction time task to probe individual attentional performance and, then, were given access to a fixed versus increasing dose of intravenous nicotine for self-administration, a differential dose procedure known to induce two between-session patterns of nicotine intake: a stable versus escalation pattern. Attentional performance was measured daily before, during and also 24-h after chronic access to the differential dose procedure of nicotine self-administration. CONCLUSIONS: We found that pre-existing individual variation in attentional performance predicts individual vulnerability to develop escalation of nicotine intake. Moreover, while chronic nicotine self-administration increases attention, withdrawal from nicotine intake escalation induces attentional deficits, a withdrawal effect that is dose-dependently reversed by acute nicotine. Together, these results suggest that pre-existing individual variation in attentional performance predicts individual vulnerability to develop escalation of nicotine intake, and that part of the motivation for using nicotine during escalation might be to alleviate withdrawal-induced attentional deficits.

Knowledge by omission: the significance of omissions in the 5-choice serial reaction time task.

RATIONALE: The 5-choice serial reaction time task (5-CSRTT) is commonly used to assess attention in rodents. Manipulation of this task by decreasing the light stimulus duration is often used to probe attentional capacity and causes a decrease in accuracy and an increase in omissions. However, although a decrease in response accuracy is commonly interpreted as a decrease in attention, it is more difficult to interpret an increase in omissions in terms of attentional performance. METHODS: Here we present a series of experiments in rats that seeks to investigate the origins of these key behavioral measures of attention in the 5-CSRTT. After an initial training in the 5-CSRTT, rats were tested in a variable stimulus duration procedure to increase task difficulty and probe visual attentional capacity under several specific controlled conditions. CONCLUSIONS: We found that response accuracy reflects visuospatial sustained attentional processing, as commonly interpreted, while response omission reflects rats' ignorance about the stimulus location, presumably due to failure to pay attention to the curved wall during its presentation. Moreover, when rats lack of relevant information, they choose not to respond instead of responding randomly. Finally, pretreatment with nicotine selectively decreased response omissions, without affecting response accuracy, particularly when the attentional demand was high. Overall, our results indicate that response accuracy and response omission thus correspond to two distinct attentional states.

Sugar addiction: pushing the drug-sugar analogy to the limit.

PURPOSE OF REVIEW: To review research that tests the validity of the analogy between addictive drugs, like cocaine, and hyperpalatable foods, notably those high in added sugar (i.e., sucrose). RECENT FINDINGS: Available evidence in humans shows that sugar and sweetness can induce reward and craving that are comparable in magnitude to those induced by addictive drugs. Although this evidence is limited by the inherent difficulty of comparing different types of rewards and psychological experiences in humans, it is nevertheless supported by recent experimental research on sugar and sweet reward in laboratory rats. Overall, this research has revealed that sugar and sweet reward can not only substitute to addictive drugs, like cocaine, but can even be more rewarding and attractive. At the neurobiological level, the neural substrates of sugar and sweet reward appear to be more robust than those of cocaine (i.e., more resistant to functional failures), possibly reflecting past selective evolutionary pressures for seeking and taking foods high in sugar and calories. SUMMARY: The biological robustness in the neural substrates of sugar and sweet reward may be sufficient to explain why many people can have difficultly to control the consumption of foods high in sugar when continuously exposed to them.

Altered neuronal activity in the ventromedial prefrontal cortex drives nicotine intake escalation.

Nicotine addiction develops after prolonged drug use and escalation of drug intake. However, because of difficulties in demonstrating escalation of nicotine use in rats, its underlying neuroadaptations still remain poorly understood. Here we report that access to unusually high doses of nicotine (i.e., from 30 µg to 240 µg/kg/injection) for self-administration precipitated a rapid and robust escalation of nicotine intake and increased the motivation for the drug in rats. This nicotine intake escalation also induced long-lasting changes in vmPFC neuronal activity both before and during nicotine self-administration. Specifically, after escalation of nicotine intake, basal vmPFC neuronal activity increased above pre-escalation and control activity levels, while ongoing nicotine self-administration restored these neuronal changes. Finally, simulation of the restoring effects of nicotine with in vivo optogenetic inhibition of vmPFC neurons caused a selective de-escalation of nicotine self-administration.

fMRI response in the medial prefrontal cortex predicts cocaine but not sucrose self-administration history.

Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self-administration (SA). Since natural rewards also activate the mesolimbic reward system in a partially overlapping fashion as cocaine, our design also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed-ratio one, long-access schedule (6 h/day for 20 days). A third group of naïve, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with functional magnetic resonance imaging (fMRI) following an intravenous cocaine injection challenge. A strong positive fMRI response, as measured by fractional cerebral blood volume changes relative to baseline (CBV%), was seen in the sedentary control group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. Given that the two SA groups had identical histories of operant training and handling, this region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals.

Progressive and lasting amplification of accumbal nicotine-seeking neural signals.

Although neuroadaptations in the nucleus accumbens (NAc) are thought to contribute to nicotine addiction, little is known about the chronic effects of nicotine on NAc neuronal activity. In the present experiment, rats were exposed to a 23 d period of nicotine self-administration (SA), a 30 d abstinence period, and a 7 d period of reexposure to SA. Chronic electrophysiological procedures were used to record the activity of individual NAc neurons on the 3rd and 23rd days of initial SA and on the 1st, 3rd, and 7th days of reexposure. Between-session comparisons showed that NAc neurons exhibit two patterns of plasticity under the present experimental conditions. First, phasic-increase firing patterns time-locked to the nicotine-reinforced lever press do not change during initial SA, but then show increases in prevalence and amplitude after abstinence, which persist during reexposure. Second, for neurons that show no phasic response time-locked to the nicotine-reinforced lever press, average baseline and SA firing rates decrease during initial SA, return to normal during abstinence, and decrease again during reexposure. As a combined consequence of the two types of neurophysiological plasticity, average firing rate of NAc neurons at the time of nicotine-directed behavior undergoes a progressive and persistent net amplification, across the successive stages of SA, abstinence, and reexposure. This net increase in NAc firing at the time of nicotine-directed behavior occurs in association with an increase in animals' motivation to seek nicotine. The adaptations that occur in nicotine-exposed animals do not occur in animals exposed to sucrose. The NAc neurophysiological plasticity potentially contributes to compulsive tobacco use.

Probing the decision-making mechanisms underlying choice between drug and nondrug rewards in rats.

Delineating the decision-making mechanisms underlying choice between drug and nondrug rewards remains a challenge. This study adopts an original approach to probe these mechanisms by comparing response latencies during sampling versus choice trials. While lengthening of latencies during choice is predicted in a deliberative choice model (DCM), the race-like response competition mechanism postulated by the Sequential choice model (SCM) predicts a shortening of latencies during choice compared to sampling. Here, we tested these predictions by conducting a retrospective analysis of cocaine-versus-saccharin choice experiments conducted in our laboratory. We found that rats engage deliberative decision-making mechanisms after limited training, but adopt a SCM-like response selection mechanism after more extended training, while their behavior is presumably habitual. Thus, the DCM and SCM may not be general models of choice, as initially formulated, but could be dynamically engaged to control choice behavior across early and extended training.

Voluntary nicotine consumption triggers in vivo potentiation of cortical excitatory drives to midbrain dopaminergic neurons.

Active response to either natural or pharmacological reward causes synaptic modifications to excitatory synapses on dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we examine these modifications using nicotine, the main addictive component of tobacco, which is a potent regulator of VTA DA neurons. Using an in vivo electrophysiological technique, we investigated the role of key components of the limbic circuit, the infralimbic cortex (ILCx) and the bed nucleus of the stria terminalis (BNST), in operant behaviors related to nicotine reward. Our results indicated that nicotine self-administration in rats, but not passive delivery, triggers hyperactivity of VTA DA neurons. The data suggest that potentiation of the ILCx-BNST excitatory pathway is involved in these modifications in VTA DA neurons. Thus, recruitment of these specific excitatory inputs to VTA DA neurons may be a neural correlate for the learned association between active responding and the reward experience.

Orbitofrontal and insular cortex: neural responses to cocaine-associated cues and cocaine self-administration.

Based on neuro-imaging studies in cocaine-addicted humans, it is hypothesized that increases in neural activity within several regions of the prefrontal cortex contribute to cue-induced cocaine seeking and cocaine-induced compulsive drug self-administration. However, electrophysiological tests of these hypotheses are lacking. In the present study, animals were trained to self-administer cocaine (0.75 mg/kg) for 14 days. On the 14th day, we conducted electrophysiological recordings of lateral orbitofrontal (LO) and ventral anterior insula (AIV) neurons. A subset of the combined population of recorded neurons showed a change in firing rate in association with one or more of the following discrete events: (1) presentation of a discriminative stimulus that signaled the onset of the self-administration session, (2) occurrence of the first cocaine-directed operant response, (3) occurrence of a cocaine-reinforced press, and (4) presentation of cues normally paired with delivery of the cocaine reinforcer. The majority of the stimulus- and response-related changes in firing involved a brief increase in firing during the stimulus and response event, respectively. In addition to these event-specific responses, approximately half of the recorded neurons exhibited a sustained change in average firing (i.e., discharges per 30-s bin) during the cocaine self-administration session, relative to average firing during a presession, drug-free period (referred to as session changes). The prevalence of session-increases and decreases were not significantly different. These and other findings are discussed in relation to hypotheses about cue-evoked and cocaine-maintained cocaine-directed behavior.

Varenicline effects on cocaine self administration and reinstatement behavior.

This study tested the effects of the nicotine addiction treatment varenicline on cocaine self administration (SA) and reinstatement. In one SA experiment, rats were trained to self-administer cocaine (0.75 mg/kg/infusion). Thereafter, daily SA sessions continued as before except that every fourth session was preceded by a presession injection of varenicline (0.0, 0.3, 1.0 and 2.0 mg/kg, SC, 50-min presession). In three reinstatement experiments, animals were exposed sequentially to SA training, extinction training, and several reinstatement test sessions. In two of the reinstatement experiments, cocaine-seeking was reinstated by presentation of cocaine-predictive cues at the onset of the test session (cue reinstatement). In a third reinstatement experiment, cocaine-seeking was reinstated by a presession injection of cocaine (drug reinstatement). Each reinstatement session was preceded by an injection of either vehicle or varenicline (dose range of 0.1-2.0 mg/kg). The SA and reinstatement experiments showed that low-dose varenicline decreases reinstatement behavior, without significantly affecting cocaine SA. In contrast, high-dose varenicline increases reinstatement of cocaine-directed behavior and decreases cocaine SA. A control study showed that sucrose-directed behavior is unaltered by varenicline. On the basis of these findings, low-varenicline doses might decrease relapse in cocaine-addicted individuals, but high doses of varenicline might have the opposite effect.

Reorganization of theta phase-locking in the orbitofrontal cortex drives cocaine choice under the influence.

Cortical theta oscillations of neuronal activity are a fundamental mechanism driving goal-directed behavior. We previously identified in the rat orbitofrontal cortex (OFC) a neuronal correlate of individual preferences between cocaine use and an alternative nondrug reward (i.e. saccharin). Whether theta oscillations are also associated with choice behavior between a drug and a nondrug reward remains unknown. Here we investigated the temporal structure between single unit activity and theta band oscillations (4-12 Hz) in the OFC of rats choosing between cocaine and saccharin. First, we found that the relative amplitude of theta oscillations is associated with subjective value and preference between two rewards. Second, OFC phase-locked neurons fired on opposite phase of the theta oscillation during saccharin and cocaine rewards, suggesting the existence of two separable neuronal assemblies. Finally, the pharmacological influence of cocaine at the moment of choice altered both theta band power and theta phase-locking in the OFC. That is, this drug influence shifted spike-phase relative to theta cycle and decreased the synchronization of OFC neurons relative to the theta oscillation. Overall, this study indicates that the reorganization of theta phase-locking under the influence of cocaine biases OFC neuronal assemblies in favor of cocaine choice and at the expense of a normally preferred alternative, a neuronal change that may contribute to drug preference in cocaine addiction.

Habitual Preference for the Nondrug Reward in a Drug Choice Setting.

For adaptive and efficient decision making, it must be possible to select between habitual alternative courses of action. However, research in rodents suggests that, even in the context of simple decision-making, choice behavior remains goal-directed. In contrast, we recently found that during discrete trial choice between cocaine and water, water-restricted rats preferred water and this preference was habitual and inflexible (i.e., resistant to water devaluation by satiation). Here we sought to test the reproducibility and generality of this surprising finding by assessing habitual control of preference for saccharin over cocaine in non-restricted rats. Specifically, after the acquisition of preference for saccharin, saccharin was devalued and concurrent responding for both options was measured under extinction. As expected, rats responded more for saccharin than for cocaine during extinction, but this difference was unaffected by saccharin devaluation. Together with our previous research, this result indicates that preference for nondrug alternatives over cocaine is under habitual control, even under conditions that normally support goal-directed control of choice between nondrug options. The possible reasons for this difference are discussed.

A neuronal population code for resemblance between drug and nondrug reward outcomes in the orbitofrontal cortex.

The orbitofrontal cortex (OFC) is implicated in choice and decision-making in both human and non-human animals. We previously identified in the rat OFC a mechanism that influences individual drug choices and preferences between a drug and a nondrug (i.e., sweet) outcome that is common across different types of drugs (cocaine and heroin). Importantly, this research also revealed some intriguing drug-specific differences. Notably, the size of non-selective OFC neurons that indiscriminately encode both the drug and the sweet outcomes varies as a function of the drug outcome available (cocaine or heroin). Here we tested the hypothesis that the relative size of the non-selective OFC population somehow represents the degree of resemblance between the drug and nondrug reward outcomes. We recorded OFC neuronal activity in vivo in the same individual rats while they were choosing between two outcomes with varying degrees of resemblance: high (two concentrations of sweet), intermediate (sweet versus heroin) and low (sweet versus cocaine). We found that the percentage of non-selective OFC neurons dramatically increased with the degree of resemblance between choice outcomes, from 26 to 62%. Overall, these findings reveal the existence of a neuronal population code for resemblance between different kinds of choice outcomes in the OFC.

Relapse to cocaine use persists following extinction of drug-primed craving.

Craving often precedes relapse into cocaine addiction. This explains why considerable research effort is being expended to try to develop anti-craving strategies for relapse prevention. Recently, we discovered using the classic reinstatement model of cocaine craving that the reinstating or priming effect of cocaine can be extinguished with repeated priming in rats - a phenomenon dubbed extinction of cocaine priming because it is thought to involve extinction of the conditioned interoceptive cues of the drug. Here we measured the effect of this extinction strategy on subsequent relapse-like behavior in rats (i.e., return to the pre-extinction pattern of cocaine self-administration once the drug is made again available after extinction). We found that extensive extinction of the conditioned priming effects of cocaine had no major impact on relapse-like behavior. This lack of effect occurred despite evidence for post-extinction loss of neuronal responses to cocaine priming in brain regions causally involved in cocaine reinstatement (i.e., the dorsomedial prefrontal cortex and the core of the nucleus accumbens). These findings suggest that the conditioned priming effects of cocaine can be dissociated from and are thus not essential for relapse-like behavior, and that extinction of these effects is unlikely to represent a viable approach to relapse prevention. Overall, these findings are in general agreement with previous neurobiological dissociation studies and with research on extinction of exteroceptive drug cues.

Incubation of Accumbal Neuronal Reactivity to Cocaine Cues During Abstinence Predicts Individual Vulnerability to Relapse.

An important goal for the treatment of cocaine addiction is to identify neuromarkers that can predict individual vulnerability to relapse after abstinence. There is some evidence that individual reactivity to cue-induced craving may predict subsequent relapse after a period of abstinence. Here we sought to identify the neuronal correlates of this predictive relationship in rats. Rats were trained to self-administer cocaine (6 h) for 16 days to induce escalation of cocaine intake. Then rats underwent a 1-month period of forced abstinence after which they were re-exposed to cocaine self-administration (6 h) for 8 additional days to induce re-escalation of cocaine intake. We recorded nucleus accumbens (NAc) neuronal responses to drug conditioned stimuli (CS) 1 day before and after 1 month of abstinence from cocaine intake escalation. Rats were ranked according to their individual percentage of CS responsive neurons recorded during the last day of abstinence and split by the median into two groups. We found evidence for a robust, incubation-like increase in NAc reactivity to cocaine cues after abstinence only in a subset of individuals (High CS rats). Importantly, compared with other rats that did not present an incubation of NAc reactivity to cocaine cues (Low CS rats), High CS rats were faster to re-escalate their intake of cocaine after abstinence. In addition, after re-escalation, they worked harder and were less sensitive to risk of punishment than Low CS rats, indicating a strengthened motivation to seek and/or take the drug in that group of rats. Overall, these findings indicate that incubation of NAc neuronal reactivity to cocaine cues during abstinence may constitute a predictive neuromarker for individual vulnerability to relapse.