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Outbred rats display variable preferences for bittersweet solutions, expressed as preference or avoidance of high concentrations of artificial sweeteners over water. This may reflect individual differences in appetitive/aversive conflict processing that may have predictive validity for disorders of motivation. Here we use a homecage two-bottle choice procedure to examine the test/retest stability and between-tastant consistency in sucralose preference to determine the reliability of bittersweet taste preference. Sucralose is a non-caloric artificial sweetener that is preferred by some rats and avoided by others. We sought to determine whether sucralose preference is consistent with preference of sucrose/quinine solutions that have known sweet and bitter taste qualities, respectively. We give fluid restricted rats 45-minutes homecage access to water and ascending concentrations of sucralose (SUCRA; 0.0025-10mM) or a compound solution of sucrose (116mM) + quinine (0.002-2mM) (SQ). We use a within-subject counterbalanced design (SUCRA or SQ testing) to determine preference of each bittersweet solution relative to water. We observed individual variability in preference for SUCRA and SQ, such that some rats preferred bittersweet solutions over water (preferring) while other rats preferred water over bittersweet solutions (avoiding). Within tastant, this preference remained stable across repeated testing. Between solutions, SUCRA preference scores correlated with SQ scores, suggesting consistent taste conflict processing for both bittersweet solutions. Population level analyses confirmed that preference generalizes across bittersweet solutions, and that rats’ preferences for bittersweet solutions relative to water are stable over time. The test/retest and between-tastant reliability of this taste conflict screening procedure support the potential utility of this model for exploring individual variability in appetitive/aversive conflict processes mediating motivated behavior. [ABSTRACT FROM AUTHOR]

Exposure to drugs of abuse, such as cocaine, leads to plastic changes in the activity of brain circuits, and a prevailing view is that these changes play a part in drug addiction. Notably, there has been intense focus on drug-induced changes in synaptic excitability and much less attention on intrinsic excitability factors (that is, excitability factors that are remote from the synapse). Accumulating evidence now suggests that intrinsic factors such as K+ channels are not only altered by cocaine but may also contribute to the shaping of the addiction phenotype. [ABSTRACT FROM AUTHOR]

Excessive consumption of unhealthy foods is a major public health problem. While many people attempt to control their food intake through dieting, many relapse to unhealthy eating habits within a few months. We have begun to study this clinical condition in rats by adapting the reinstatement model, which has been used extensively to study relapse to drug seeking. In our adaptation of the relapse model, reinstatement of palatable food seeking by exposure to food-pellet priming, food-associated cues, or stress is assessed in food-restricted (to mimic dieting) rats after operant food-pellet self-administration training and subsequent extinction of the food-reinforced responding. In this review, we first outline the clinical problem and discuss a recent study in which we assessed the predictive validity of the reinstatement model for studying relapse to food seeking during dieting by using the anorexigenic drug fenfluramine. Next, we summarize results from our initial studies on the role of several stress- and feeding-related peptides (corticotropin-releasing factor, hypocretin, melanin-concentrating hormone, peptide YY3-36) in reinstatement of palatable food seeking. We then present results from our studies on the role of dopamine and medial prefrontal cortex in stress-induced reinstatement of food seeking. We conclude by discussing potential clinical implications. We offer two main conclusions: (1) the food reinstatement model is a simple, reliable, and valid model to study mechanisms of relapse to palatable food seeking during dieting, and to identify medications to prevent this relapse; (2) mechanisms of relapse to food seeking are often dissociable from mechanisms of ongoing food intake. This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’. [ABSTRACT FROM AUTHOR]

Abstract: Excessive consumption of unhealthy foods is a major public health problem. While many people attempt to control their food intake through dieting, many relapse to unhealthy eating habits within a few months. We have begun to study this clinical condition in rats by adapting the reinstatement model, which has been used extensively to study relapse to drug seeking. In our adaptation of the relapse model, reinstatement of palatable food seeking by exposure to food-pellet priming, food-associated cues, or stress is assessed in food-restricted (to mimic dieting) rats after operant food-pellet self-administration training and subsequent extinction of the food-reinforced responding. In this review, we first outline the clinical problem and discuss a recent study in which we assessed the predictive validity of the reinstatement model for studying relapse to food seeking during dieting by using the anorexigenic drug fenfluramine. Next, we summarize results from our initial studies on the role of several stress- and feeding-related peptides (corticotropin-releasing factor, hypocretin, melanin-concentrating hormone, peptide YY3-36) in reinstatement of palatable food seeking. We then present results from our studies on the role of dopamine and medial prefrontal cortex in stress-induced reinstatement of food seeking. We conclude by discussing potential clinical implications. We offer two main conclusions: (1) the food reinstatement model is a simple, reliable, and valid model to study mechanisms of relapse to palatable food seeking during dieting, and to identify medications to prevent this relapse; (2) mechanisms of relapse to food seeking are often dissociable from mechanisms of ongoing food intake. This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’. [Copyright &y& Elsevier]

Summary: Attention or variations in event processing help drive learning. Lesion studies have implicated the central nucleus of the amygdala (CeA) in this process, particularly when expected rewards are omitted. However, lesion studies cannot specify how information processing in CeA supports such learning. To address these questions, we recorded CeA neurons in rats performing a task in which rewards were delivered or omitted unexpectedly. We found that activity in CeA neurons increased selectively at the time of omission and declined again with learning. Increased firing correlated with CeA-inactivation sensitive measures of attention. Notably CeA neurons did not fire to the cues or in response to unexpected rewards. These results indicate that CeA contributes to learning in response to reward omission due to a specific role in signaling actual omission rather than a more general involvement in signaling expectancies, errors, or reward value. [ABSTRACT FROM AUTHOR]

The amygdala is critical for associating predictive cues with primary rewarding and aversive outcomes. This is particularly evident in tasks in which information about expected outcomes is required for normal responding. Here we used a pavlovian overexpectation task to test whether outcome signaling by amygdala might also be necessary for changing those representations in the face of unexpected outcomes. Rats were trained to associate several different cues with a food reward. After learning, two of the cues were presented together, in compound, followed by the same reward. Before each compound training session, rats received infusions of 2,3-dioxo-6-nitro-1,2,3,4- tetrahydrobenzo[f]quinoxaline-7-sulfonamide or saline into either the basolateral (ABL) or central nucleus (CeN) of amygdala.Wefound that infusions into CeN abolished the normal decline in responding to the compounded cue in a later probe test, whereas infusions into ABL had no effect. These results are inconsistent with the proposal that signaling of information about expected outcomes by ABL contributes to learning, at least in this setting, and instead implicate the CeN in this process, perhaps attributable to the hypothesized involvement of this area in attention and variations in stimulus processing. [ABSTRACT FROM AUTHOR]

The discovery that dopamine neurons signal errors in reward prediction has demonstrated that concepts empirically derived from the study of animal behavior can be used to understand the neural implementation of reward learning. Yet the learning theory models linked to phasic dopamine activity treat attention to events such as cues and rewards as static quantities; other models, such as Pearce-Hall, propose that learning might be influenced by variations in processing of these events. A key feature of these accounts is that event processing is modulated by unsigned rather than signed reward prediction errors. Here we tested whether neural activity in rat basolateral amygdala conforms to this pattern by recording single units in a behavioral task in which rewards were unexpectedly delivered or omitted. We report that neural activity at the time of reward is providing an unsigned error signal with characteristics consistent with those postulated by these models. This neural signal increased immediately after a change in reward, and stronger firing was evident whether the value of the reward increased or decreased. Further, as predicted by these models, the change in firing developed over several trials as expectations for reward were repeatedly violated. This neural signal was correlated with faster orienting to predictive cues after changes in reward, and abolition of the signal by inactivation of basolateral amygdala disrupted this change in orienting and retarded learning in response to changes in reward. These results suggest that basolateral amygdala serves a critical function in attention for learning. [ABSTRACT FROM AUTHOR]

The dopamine system is thought to be involved in making decisions about reward. Here we recorded from the ventral tegmental area in rats learning to choose between differently delayed and sized rewards. As expected, the activity of many putative dopamine neurons reflected reward prediction errors, changing when the value of the reward increased or decreased unexpectedly. During learning, neural responses to reward in these neurons waned and responses to cues that predicted reward emerged. Notably, this cue-evoked activity varied with size and delay. Moreover, when rats were given a choice between two differently valued outcomes, the activity of the neurons initially reflected the more valuable option, even when it was not subsequently selected. [ABSTRACT FROM AUTHOR]

Animals prefer a small, immediate reward over a larger delayed reward (time discounting). Lesions of the orbitofrontal cortex (OFC) can either increase or decrease the breakpoint at which animals abandon the large delayed reward for the more immediate reward as the delay becomes longer. Here we argue that the varied effects of OFC lesions on delayed discounting reflect two different patterns of activity in OFC; one that bridges the gap between a response and an outcome and another that discounts delayed reward. These signals appear to reflect the spatial location of the reward and/or the action taken to obtain it, and are encoded independently from representations of absolute value. We suggest a dual role for output from OFC in both discounting delayed reward, while at the same time supporting new learning for them. [ABSTRACT FROM AUTHOR]

Rationale: Discriminative stimuli (DS) are cues that predict reward availability. DS are resistant to extinction and motivate drug seeking even after long periods of abstinence. Previous studies have demonstrated that sign-tracking (ST) and goal-tracking (GT) differences in Pavlovian approach predict distinct cue-modulated vulnerabilities to cocaine reinstatement. GT rats show heightened reinstatement to contextual and DS, while ST rats show heightened reinstatement to discrete stimuli. Here we examine whether DS modulate reinstatement after electric barrier-induced abstinence and whether tracking-related relapse vulnerabilities generalize to opioid relapse. Objectives: We examine whether DS-modulated reinstatement to fentanyl seeking persists in the presence of reduced adverse consequences after electric barrier-induced abstinence. We also examine whether tracking differences predict the magnitude of DS-modulated reinstatement of fentanyl seeking after electric barrier-induced abstinence. Methods: We used Pavlovian lever autoshaping (PLA) training to determine sign-, goal-, and intermediate tracking groups in male and female Sprague Dawley rats. We then trained rats in a DS model of intermittent fentanyl self-administration, and extinguished drug seeking by imposing an electric barrier of increasing intensity. We then measured the level of DS-modulated reinstatement in the presence of a reduced electric barrier intensity. Results: We report that DS strongly modulate fentanyl seeking after electric barrier-induced abstinence. DS–modulation of fentanyl acquisition, electric barrier-induced abstinence, and reinstatement was similar for sign- and goal-tracking groups. Conclusions: Discriminative stimuli powerfully motivate opioid seeking, despite continued aversive consequences. Pavlovian approach differences do not predict the level of DS-modulated reinstatement to fentanyl seeking after conflict-induced abstinence. [ABSTRACT FROM AUTHOR]

The relative value of and motivation for abused drugs often increases with drug experience and differs based on drug availability. Here, we determined how different intake patterns of fentanyl, a μ-opioid agonist, alter economic demand for fentanyl and how 5-HT2A receptor stimulation affects economic demand for fentanyl. We used a within-session demand threshold procedure to characterize changes in economic demand for fentanyl before and after intermittent or continuous access schedules. We subsequently tested the acute effects of 5-HT2A receptor stimulation with psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) on economic demand for fentanyl. Extended fentanyl experience with both intermittent and continuous schedules increased fentanyl consumption at low cost (Q0 ), increased total fentanyl consumption, and decreased demand elasticity (α), indicating both schedules elevated motivation to self-administer fentanyl. Overall, the two schedules produced similar alterations in economic demand for fentanyl, although low-cost consumption (Q0 ) increased more in the continuous access group. Systemic injections of DOI (0.0-0.4 mg/kg, i.p.) dose-dependently produced economic demand changes in the opposite direction produced by fentanyl experience. DOI decreased motivation (increased "α"), decreased Q0 , and decreased total fentanyl consumption. The selective 5-HT2A antagonist, M100907 (0.3 mg/kg, i.p.), blocked the effects of DOI, indicating that DOI is acting through 5-HT2A receptors to alter economic demand for fentanyl. In an economic food demand experiment, DOI (0.4 mg/kg) also increased demand elasticity and reduced food consumption. These results demonstrate that both intermittent and continuous fentanyl experience raise the economic demand for fentanyl, and acute 5-HT2A receptor activation reduces economic demand for fentanyl and food. [ABSTRACT FROM AUTHOR]

The article explores the role of glial cell line-derived neurotrophic factor (GDNF) in the reversal of withdrawal-induced decreases in nucleus accumbens dopamine and attenuation of alcohol reward. Dopamine-depletion hypothesis and related opponent process theories are being referred. It is concluded that further research is necessary to determine the mechanistic connection between GDNF and alcohol reward.

Sign-tracking (ST) rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug seeking compared with goal-tracking or intermediate rats. Cue-evoked dopamine in the nucleus accumbens (NAc) is a neurobiological signa)ture of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system, endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the ventral tegmental area (VTA) to control cue-evoked striatal dopamine levels. We use cell type)specific optogenetics, intra-VTA pharmacology, and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regu)lates NAc dopamine levels to control sign tracking. We trained male and female rats in a Pavlovian lever autoshaping (PLA) task to determine their tracking groups before testing the effect of VTA fi NAc dopamine inhibition. We found that this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, dur)ing PLA decrease lever and increase food cup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from a dopamine sensor, GRABDA (AAV9-hSyn-DA2m), we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping in female rats. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases in NAc shell, but not core, dopamine levels during reward delivery [unconditioned stimulus (US)]. Our results suggest that CB1R signaling in the VTA influences the balance between the conditioned stimulus-evoked and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats. [ABSTRACT FROM AUTHOR]

Model-free and model-based computations are argued to distinctly update action values that guide decision-making processes. It is not known, however, if these model-free and model-based reinforcement learning mechanisms recruited in operationally based instrumental tasks parallel those engaged by pavlovian-based behavioral procedures. Recently, computational work has suggested that individual differences in the attribution of incentive salience to reward predictive cues, that is, sign- and goaltracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior. Moreover, it is not appreciated if these systems that are characterized computationally using model-free and model-based algorithms are conserved across tasks for individual animals. In the current study, we used a within-subject design to assess sign-tracking and goal-tracking behaviors using a pavlovian conditioned approach task and then characterized behavior using an instrumental multistage decision-making (MSDM) task in male rats. We hypothesized that both pavlovian and instrumental learning processes may be driven by common reinforcement-learning mechanisms. Our data confirm that sign-tracking behavior was associated with greater reward-mediated, model-free reinforcement learning and that it was also linked to model-free reinforcement learning in the MSDM task. Computational analyses revealed that pavlovian model-free updating was correlated with model-free reinforcement learning in the MSDM task. These data provide key insights into the computational mechanisms mediating associative learning that could have important implications for normal and abnormal states. [ABSTRACT FROM AUTHOR]

Aversive states are proposed to drive addiction. Here, Wheeler and colleagues show that drug-associated cues come to activate neural representations of aversive information in nucleus accumbens and that this activation predicts subsequent drug use. These remarkable data identify a potential neural substrate through which aversive affective representations may motivate drug use. [Copyright &y& Elsevier]

Addiction is characterized by compulsive or inflexible behavior, observed both in the context of drug-seeking and in contexts unrelated to drugs. One possible contributor to these inflexible behaviors may be drug-induced dysfunction within circuits that support behavioral flexibility, including the basolateral amygdala (ABL) and the orbitofrontal cortex (OFC). Here we describe data demonstrating that chronic cocaine exposure causes long-lasting changes in encoding properties in the ABL and the OFC during learning and reversal in an odor-guided task. In particular, these data suggest that inflexible encoding in ABL neurons may be the proximal cause of cocaine-induced behavioral inflexibility, and that a loss of outcome-expectant encoding in OFC neurons could be a more distal contributor to this impairment. A similar mechanism of drug-induced orbitofrontal–amygdalar dysfunction may cause inflexible behavior when animals and addicts are exposed to drug-associated cues and contexts. [ABSTRACT FROM AUTHOR]

To survive in a complex environment, individuals form associations between environmental stimuli and rewards to organize and optimize reward seeking behaviors. The basolateral amygdala (BLA) uses these learned associations to inform decision-making processes. In this review, we describe functional projections between BLA and its cortical and striatal targets that promote learning and motivational processes central to decision-making. Specifically, we compare and contrast divergent projections from the BLA to the orbitofrontal (OFC) and to the nucleus accumbens (NAc) and examine the roles of these pathways in associative learning, value-guided decision-making, choice behaviors, as well as cue and context-driven drug seeking. Finally, we consider how these projections are involved in disorders of motivation, with a focus on Substance Use Disorder. [ABSTRACT FROM AUTHOR]

Rationale: Endocannabinoids (eCBs) are critical gatekeepers of dopaminergic signaling, and disrupting cannabinoid receptor-1 (CB1) signaling alters DA dynamics to attenuate cue-motivated behaviors. Prior studies suggest that dopamine (DA) release plays a critical role in driving sign-tracking.Objectives: Here, we determine whether systemic injections of rimonabant, a CB1 receptor inverse agonist, during Pavlovian lever autoshaping impair the expression of sign-tracking. We next examine whether rimonabant blocks the reinforcing properties of the Pavlovian lever cue in a conditioned reinforcement test.Methods: In Exp. 1, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1, 3 mg/kg) during early and late Pavlovian lever autoshaping sessions. In Exp. 2, we trained rats in Pavlovian lever autoshaping prior to systemic rimonabant injections (0, 1 mg/kg) during a conditioned reinforcement test.Results: Rimonabant dose-dependently decreased lever contact and probability, and increased sign-tracker’s latency to approach the lever cue early in Pavlovian training. With extended training, many previously goal-tracking and intermediate rats shifted to lever approach, which remained dose-dependently sensitive to rimonabant. Rimonabant attenuated cue-evoked food cup approach early, but not late, in conditioning, and did not affect pellet retrieval or consumption. The inserted lever cue served as a robust conditioned reinforcer after Pavlovian lever autoshaping, and 1 mg/kg rimonabant blocked conditioned reinforcement.Conclusions: Together, our results suggest that CB1 signaling mediates two critical properties of incentive stimuli; their ability to attract (Exp. 1) and their ability to reinforce (Exp. 2) behavior. [ABSTRACT FROM AUTHOR]

Recent computational models of sign tracking (ST) and goal tracking (GT) have accounted for observations that dopamine (DA) is not necessary for all forms of learning and have provided a set of predictions to further their validity. Among these, a central prediction is that manipulating the intertrial interval (ITI) during autoshaping should change the relative ST-GT proportion as well as DA phasic responses. Here, we tested these predictions and found that lengthening the ITI increased ST, i.e., behavioral engagement with conditioned stimuli (CS) and cue-induced phasic DA release. Importantly, DA release was also present at the time of reward delivery, even after learning, and DA release was correlated with time spent in the food cup during the ITI. During conditioning with shorter ITIs, GT was prominent (i.e., engagement with food cup), and DA release responded to the CS while being absent at the time of reward delivery after learning. Hence, shorter ITIs restored the classical DA reward prediction error (RPE) pattern. These results validate the computational hypotheses, opening new perspectives on the understanding of individual differences in Pavlovian conditioning and DA signaling. [ABSTRACT FROM AUTHOR]

Previously established individual differences in appetitive approach and devaluation sensitivity observed in goal- and sign-trackers may be attributed to differences in the acquisition, modification, or use of associative information in basolateral amygdala (BLA) pathways. Here, we sought to determine the extent to which communication of associative information between BLA and anterior portions of insular cortex (IC) supports ongoing Pavlovian conditioned approach behaviors in sign- and goal-tracking rats, in the absence of manipulations to outcome value. We hypothesized that the BLA mediates goal-, but not sign- tracking approach through interactions with the IC, a brain region involved in supporting flexible behavior. We first trained rats in Pavlovian lever autoshaping to determine their sign- or goal-tracking tendency. During alternating test sessions, we gave unilateral intracranial injections of vehicle or a cocktail of gamma -aminobutyric acid (GABA) receptor agonists, baclofen and muscimol, unilaterally into the BLA and contralaterally or ipsilaterally into the IC prior to reinforced lever autoshaping sessions. Consistent with our hypothesis we found that contralateral inactivation of BLA and IC increased the latency to approach the food cup and decreased the number of food cup contacts in goal-trackers. While contralateral inactivation of BLA and IC did not affect the total number of lever contacts in sign-trackers, this manipulation increased the latency to approach the lever. Ipsilateral inactivation of BLA and IC did not impact approach behaviors in Pavlovian lever autoshaping. These findings, contrary to our hypothesis, suggest that communication between BLA and IC maintains a representation of initially learned appetitive associations that commonly support the initiation of Pavlovian conditioned approach behavior regardless of whether it is directed at the cue or the location of reward delivery. [ABSTRACT FROM AUTHOR]

Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here, we addressed two fundamental questions regarding yohimbine's effect on reinstatement of reward seeking: (1) whether the drug's effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine's effect on dopamine levels in nucleus accumbens ( NAc) and medial prefrontal cortex ( mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine's effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine. [ABSTRACT FROM AUTHOR]

Background: Relapse to unhealthy eating habits is a major problem in human dietary treatment. The individuals most commonly seeking dietary treatment are overweight or obese women, yet the commonly used rat reinstatement model to study relapse to palatable food seeking during dieting primarily uses normal-weight male rats. To increase the clinical relevance of the relapse to palatable food seeking model, here we pre-expose female rats to a calorically-dense cafeteria diet in the home-cage to make them overweight prior to examining the effect of this diet history on cue-, pellet-priming- and footshock-induced reinstatement of food seeking. Methods: Post-natal day 32 female Long-Evans rats had seven weeks of home-cage access to either chow only or daily or intermittent cafeteria diet alongside chow. Next, they were trained to self-administer normally preferred 45 mg food pellets accompanied by a tone-light cue. After extinction, all rats were tested for reinstatement induced by discrete cue, pellet-priming, and intermittent footshock under extinction conditions. Results: Access to daily cafeteria diet and to a lesser degree access to intermittent cafeteria diet decreased food pellet self-administration compared to chow-only. Prior history of these cafeteria diets also reduced extinction responding, cue- and pellet-priming-induced reinstatement. In contrast, modest stress-induced reinstatement was only observed in rats with a history of daily cafeteria diet. Conclusion: A history of cafeteria diet does not increase the propensity for cue- and pellet-priming-induced relapse in the rat reinstatement model but does appear to make rats more susceptible to footshock stress-induced reinstatement. [ABSTRACT FROM AUTHOR]

Relapse to maladaptive eating habits during dieting is often provoked by stress and there is evidence for a role of ovarian hormones in stress responses and feeding. We studied the role of these hormones in stress-induced reinstatement of food seeking and medial prefrontal cortex (mPFC) neuronal activation in c-fos-GFP transgenic female rats, which express GFP in strongly activated neurons. Food-restricted ovariectomized or sham-operated c-fos-GFP rats were trained to lever-press for palatable food pellets. Subsequently, lever-pressing was extinguished and reinstatement of food seeking and mPFC neuronal activation was assessed after injections of the pharmacological stressor yohimbine (0.5-2 mg/kg) or pellet priming (1- 4 noncontingent pellets). Estrous cycle effects on reinstatement were also assessed in wild-type rats. Yohimbine- and pellet-priming-induced reinstatement was associated with Fos and GFP induction in mPFC; both reinstatement and neuronal activation were minimally affected by ovarian hormones in both c-fos-GFP and wild-type rats. c-fos-GFP transgenic rats were then used to assess glutamatergic synaptic alterations within activated GFP-positive and nonactivated GFP-negative mPFC neurons following yohimbine-induced reinstatement of food seeking. This reinstatement was associated with reduced AMPA receptor/NMDA receptor current ratios and increased paired-pulse facilitation in activated GFP-positive but not GFP-negative neurons. While ovarian hormones do not appear to play a role in stress-induced relapse of food seeking in our rat model, this reinstatement was associated with unique synaptic alterations in strongly activated mPFC neurons. Our paper introduces the c-fos-GFP transgenic rat as a new tool to study unique synaptic changes in activated neurons during behavior. [ABSTRACT FROM AUTHOR]

Summary: Humans and other animals change their behavior in response to unexpected outcomes. The orbitofrontal cortex (OFC) is implicated in such adaptive responding, based on evidence from reversal tasks. Yet these tasks confound using information about expected outcomes with learning when those expectations are violated. OFC is critical for the former function; here we show it is also critical for the latter. In a Pavlovian overexpectation task, inactivation of OFC prevented learning driven by unexpected outcomes, even when performance was assessed later. We propose this reflects a critical contribution of outcome signaling by OFC to encoding of reward prediction errors elsewhere. In accord with this proposal, we report that signaling of reward predictions by OFC neurons was related to signaling of prediction errors by dopamine neurons in ventral tegmental area (VTA). Furthermore, bilateral inactivation of VTA or contralateral inactivation of VTA and OFC disrupted learning driven by unexpected outcomes. [Copyright &y& Elsevier]

Addicts and drug-experienced animals have decision-making deficits in reversal-learning tasks and more complex 'gambling' variants. Here we show evidence that these deficits are mediated by persistent encoding of outdated associative information in the basolateral amygdala. Cue-selective neurons in the basolateral amygdala, recorded in cocaine-treated rats, failed to change cue preference during reversal learning. Further, the presence of these neurons was critical to the expression of the reversal-learning deficit in the cocaine-treated rats. [ABSTRACT FROM AUTHOR]