Search

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 signature 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 regulates 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 → 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, during PLA decrease lever and increase food cup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from a dopamine sensor, GRAB DA (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. SIGNIFICANCE STATEMENT Substance use disorder (SUD) is a chronically relapsing psychological disorder that affects a subset of individuals who engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences before drug experience that predict SUD and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug-motivated behaviors., (Copyright © 2023 the authors.)

The detection of nutrients in the gut influences ongoing and future feeding behavior as well as the development of food preferences. In addition to nutrient sensing in the intestine, the hepatic portal vein plays a considerable role in detecting ingested nutrients and conveying this information to brain nuclei involved in metabolism, learning, and reward. Here, we review mechanisms underlying hepatic portal vein sensing of nutrients, particularly glucose, and how this is relayed to the brain to influence feeding behavior and reward. We additionally highlight several gaps where future research can provide new insights into the effects of portal nutrients on neural activity in the brain and feeding behavior., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Individual differences in Pavlovian approach predict differences in devaluation sensitivity. Recent studies indicate goal-tracking (GT) rats are sensitive to outcome devaluation while sign-tracking (ST) rats are not. With extended training in Pavlovian lever autoshaping (PLA), GT rats display more lever-directed behavior, typical of ST rats, suggesting they may become insensitive to devaluation with more Pavlovian training experience. Here, we use a within-subject satiety-induced outcome devaluation procedure to test devaluation sensitivity after limited and extended PLA training in GT and ST rats. We trained rats in PLA to determine GT and ST groups. Then, we sated rats on either the training pellets (devalued condition) or homecage chow (valued condition) prior to brief non-reinforced test sessions after limited (sessions 5/6) and extended (sessions 17/18) PLA training. GT rats decreased conditioned responding under devalued relative to valued conditions after both limited and extended training, demonstrating they are sensitive to satiety devaluation regardless of the amount of PLA training. While ST rats were insensitive to satiety devaluation after limited training, their lever directed behavior became devaluation sensitive after extended training. To determine whether sign-tracking rats also displayed sensitivity to illness-induced outcome devaluation after extended training, we trained a separate cohort of rats in extended PLA and devalued the outcome with lithium chloride injections after pellet consumption in the homecage. ST rats failed to decrease conditioned responding after illness-induced outcome devaluation, while Non-ST rats (GT and intermediates) were sensitive to illness-induced outcome devaluation after extended training. Together, our results confirm devaluation sensitivity is stable in GT rats across training and devaluation approaches. Extended training unmasks devaluation sensitivity in ST rats after satiety, but not illness-induced devaluation, suggesting ST rats respond appropriately by decreasing responding to cues during state-dependent but not inference-based devaluation. The differences in behavioral flexibility across tracking groups and devaluation paradigms have translational relevance for the understanding state- vs. inference-based reward devaluation as it pertains to drug addiction vulnerability., (Copyright © 2020 Keefer, Bacharach, Kochli, Chabot and Calu.)

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., Competing Interests: The authors have declared that no competing interests exist.

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.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

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.