Effects of psychedelic, DOI, on nucleus accumbens dopamine signaling to predictable rewards and cues in rats.

Psychedelics produce lasting therapeutic responses in neuropsychiatric diseases suggesting they may disrupt entrenched associations and catalyze learning. Here, we examine psychedelic 5-HT agonist, DOI, effects on dopamine signaling in the nucleus accumbens (NAc) core, a region extensively linked to reward learning, motivation, and drug-seeking. We measure phasic dopamine transients following acute DOI administration in rats during well learned Pavlovian tasks in which sequential cues predict rewards.

Dorsomedial Striatum CB1R signaling is required for Pavlovian outcome devaluation in male Long Evans rats and reduces inhibitory synaptic transmission in both sexes.

Cannabinoid-1 receptor (CB1R) signaling in the dorsal striatum regulates the shift from flexible to habitual behavior in instrumental outcome devaluation. Based on prior work establishing individual, sex, and experience-dependent differences in Pavlovian behaviors, we predicted a role for dorsomedial striatum CB1R signaling in driving rigid responding in Pavlovian autoshaping and outcome devaluation. We trained male and female Long Evans rats in Pavlovian Lever Autoshaping (PLA).

Decreased Ventral Tegmental Area CB1R Signaling Reduces Sign Tracking and Shifts Cue-Outcome Dynamics in Rat Nucleus Accumbens.

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.

Reward-Mediated, Model-Free Reinforcement-Learning Mechanisms in Pavlovian and Instrumental Tasks Are Related.

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 goal-tracking behaviors, are also governed by variations in model-free and model-based value representations that guide behavior.

Inactivation of the Basolateral Amygdala to Insular Cortex Pathway Makes Sign-Tracking Sensitive to Outcome Devaluation.

Goal-tracking (GT) rats are sensitive to Pavlovian outcome devaluation while sign-tracking (ST) rats are devaluation insensitive. During outcome devaluation, GT rats flexibly modify responding to cues based on the current value of the associated outcome. However, ST rats rigidly respond to cues regardless of the current outcome value.

Investigating discriminative stimulus modulation of opioid seeking after conflict-induced abstinence in sign- and goal-tracking rats.

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.

Corrigendum: Role of BNST CRFR1 Receptors in Incubation of Fentanyl Seeking.

[This corrects the article DOI: 10.3389/fnbeh.2020.

Choose your path: Divergent basolateral amygdala efferents differentially mediate incentive motivation, flexibility and decision-making.

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.

Basolateral Amygdala to Nucleus Accumbens Communication Differentially Mediates Devaluation Sensitivity of Sign- and Goal-Tracking Rats.

Rats rely on communication between the basolateral amygdala (BLA) and nucleus accumbens (NAc) to express lever directed approach in a Pavlovian lever autoshaping (PLA) task that distinguishes sign- and goal-tracking rats. During PLA, sign-tracking rats preferentially approach an insertable lever cue, while goal-tracking rats approach a foodcup where rewards are delivered. While sign-tracking rats inflexibly respond to cues even after the associated reward is devalued, goal-tracking rats flexibly reduce responding to cues during outcome devaluation.

Role of BNST CRFR1 Receptors in Incubation of Fentanyl Seeking.

The time-dependent increase in cue-triggered opioid seeking, termed "incubation of opioid craving," is modeled in rodents by examining responding for opioid-associated cues after a period of forced abstinence. With opioid drugs, withdrawal symptoms may heighten cue reactivity by recruiting brain systems involved in both reward seeking and stress responses. Corticotropin releasing factor (CRF) in the bed nucleus of the stria terminalis (BNST) is a critical driver of stress-induced relapse to drug seeking.

Effects of 5-HT receptor stimulation on economic demand for fentanyl after intermittent and continuous access self-administration in male rats.

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-HT 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.

Effects of Limited and Extended Pavlovian Training on Devaluation Sensitivity of Sign- and Goal-Tracking Rats.

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.

Stability of individual differences in sucralose taste preference.

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.

Manipulating the revision of reward value during the intertrial interval increases sign tracking and dopamine release.

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.

Cannabinoid receptor-1 signaling contributions to sign-tracking and conditioned reinforcement in rats.

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.

Disconnection of basolateral amygdala and insular cortex disrupts conditioned approach in Pavlovian lever autoshaping.

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.

The Dopamine Prediction Error: Contributions to Associative Models of Reward Learning.

Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto's (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. This is argued to endow the reward-predictive cue with the value inherent in the reward, motivating behavior toward cues signaling the presence of reward.

Individual variability in behavioral flexibility predicts sign-tracking tendency.

Sign-tracking rats show heightened sensitivity to food- and drug-associated cues, which serve as strong incentives for driving reward seeking. We hypothesized that this enhanced incentive drive is accompanied by an inflexibility when incentive value changes. To examine this we tested rats in Pavlovian outcome devaluation or second-order conditioning prior to the assessment of sign-tracking tendency.

Intrinsic plasticity: an emerging player in addiction.

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.

Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history.

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.

Effect of cafeteria diet history on cue-, pellet-priming-, and stress-induced reinstatement of food seeking in female rats.

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.

The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research.

Background And Rationale: Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding.

The use of the reinstatement model to study relapse to palatable food seeking during dieting.

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.

Optogenetic inhibition of dorsal medial prefrontal cortex attenuates stress-induced reinstatement of palatable food seeking in female rats.

Relapse to maladaptive eating habits during dieting is often provoked by stress. Recently, we identified a role of dorsal medial prefrontal cortex (mPFC) neurons in stress-induced reinstatement of palatable food seeking in male rats. It is unknown whether endogenous neural activity in dorsal mPFC drives stress-induced reinstatement in female rats.