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Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

RationaleThe endocannabinoid system makes critical contributions to reward processing, motivation, and behavioral control. Repeated exposure to THC or other cannabinoid drugs can cause persistent adaptions in the endocannabinoid system and associated neural circuitry. It remains unclear how such treatments affect the way rewards are processed and pursued.Objective and methodsWe examined if repeated THC exposure (5 mg/kg/day for 14 days) during adolescence or adulthood led to long-term changes in rats' capacity to flexibly encode and use action-outcome associations for goal-directed decision making. Effects on hedonic feeding and progressive ratio responding were also assessed.ResultsTHC exposure had no effect on rats' ability to flexibly select actions following reward devaluation. However, instrumental contingency degradation learning, which involves avoiding an action that is unnecessary for reward delivery, was augmented in rats with a history of adult but not adolescent THC exposure. THC-exposed rats also displayed more vigorous instrumental behavior in this study, suggesting a motivational enhancement. A separate experiment found that while THC exposure had no effect on hedonic feeding behavior, it increased rats' willingness to work for food on a progressive ratio schedule, an effect that was more pronounced when THC was administered to adults. Adolescent and adult THC exposure had opposing effects on the CB1 receptor dependence of progressive ratio performance, decreasing and increasing sensitivity to rimonabant-induced behavioral suppression, respectively.ConclusionsOur findings reveal that exposure to a translationally relevant THC exposure regimen induces long-lasting, age-dependent alterations in cognitive and motivational processes that regulate the pursuit of rewards.

The Pavlovian-instrumental transfer (PIT) paradigm is widely used to assay the motivational influence of reward-predictive cues, reflected by their ability to invigorate instrumental behavior. Leading theories assume that a cues motivational properties are tied to predicted reward value. We outline an alternative view that recognizes that reward-predictive cues may suppress rather than motivate instrumental behavior under certain conditions, an effect termed positive conditioned suppression. We posit that cues signaling imminent reward delivery tend to inhibit instrumental behavior, which is exploratory by nature, in order to facilitate efficient retrieval of the expected reward. According to this view, the motivation to engage in instrumental behavior during a cue should be inversely related to the value of the predicted reward, since there is more to lose by failing to secure a high-value reward than a low-value reward. We tested this hypothesis in rats using a PIT protocol known to induce positive conditioned suppression. In Experiment 1, cues signaling different reward magnitudes elicited distinct response patterns. Whereas the one-pellet cue increased instrumental behavior, cues signaling three or nine pellets suppressed instrumental behavior and elicited high levels of food-port activity. Experiment 2 found that reward-predictive cues suppressed instrumental behavior and increased food-port activity in a flexible manner that was disrupted by post-training reward devaluation. Further analyses suggest that these findings were not driven by overt competition between the instrumental and food-port responses. We discuss how the PIT task may provide a useful tool for studying cognitive control over cue-motivated behavior in rodents. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The dorsomedial prefrontal cortex (dmPFC) is known to make important contributions to flexible, reward-motivated behavior. However, it remains unclear if the dmPFC is involved in regulating the expression of Pavlovian incentive motivation, the process through which reward-paired cues promote instrumental reward-seeking behavior, which is modeled in rats using the Pavlovian-instrumental transfer (PIT) task. The current study examined this question using a bidirectional chemogenetic strategy in which inhibitory (hM4Di) or excitatory (hM3Dq) designer G-protein coupled receptors were virally expressed in dmPFC neurons, allowing us to later stimulate or inhibit this region by administering CNO prior to PIT testing. We found that dmPFC inhibition did not alter the tendency for a reward-paired cue to instigate instrumental reward-seeking behavior, whereas dmPFC stimulation disrupted the expression of this motivational influence. Neither treatment altered cue-elicited anticipatory activity at the reward-delivery port, indicating that dmPFC stimulation did not lead to more widespread motor suppression. A reporter-only control experiment indicated that our CNO treatment did not have non-specific behavioral effects. Thus, the dmPFC does not mediate the expression of Pavlovian incentive motivation but instead has the capacity to exert pronounced inhibitory control over this process, suggesting that it is involved in adaptively regulating cue-motivated behavior.

Efficient foraging requires an ability to coordinate discrete reward-seeking and reward-retrieval behaviors. We used pathway-specific chemogenetic inhibition to investigate how rats' mesolimbic and mesocortical dopamine circuits contribute to the expression and modulation of reward seeking and retrieval. Inhibiting ventral tegmental area dopamine neurons disrupted the tendency for reward-paired cues to motivate reward seeking, but spared their ability to increase attempts to retrieve reward. Similar effects were produced by inhibiting dopamine inputs to nucleus accumbens, but not medial prefrontal cortex. Inhibiting dopamine neurons spared the suppressive effect of reward devaluation on reward seeking, an assay of goal-directed behavior. Attempts to retrieve reward persisted after devaluation, indicating they were habitually performed as part of a fixed action sequence. Our findings show that complete bouts of reward seeking and retrieval are behaviorally and neurally dissociable from bouts of reward seeking without retrieval. This dichotomy may prove useful for uncovering mechanisms of maladaptive behavior.

Abstract: Efficient foraging requires an ability to coordinate discrete reward-seeking and reward-retrieval behaviors. We used pathway-specific chemogenetic inhibition to investigate how mesolimbic and mesocortical dopamine circuits contribute to the expression and modulation of reward seeking and retrieval. Inhibiting ventral tegmental area dopamine neurons disrupted the tendency for reward-paired cues to motivate reward seeking, but spared their ability to increase attempts to retrieve reward. Similar effects were produced by inhibiting dopamine inputs to nucleus accumbens, but not medial prefrontal cortex. Inhibiting dopamine neurons spared the suppressive effect of reward devaluation on reward seeking, an assay of goal-directed behavior. Attempts to retrieve reward persisted after devaluation, indicating they were habitually performed as part of a fixed action sequence. Our findings show that complete bouts of reward seeking and retrieval are behaviorally and neurally dissociable from bouts of reward seeking without retrieval. This dichotomy may prove useful for uncovering mechanisms of maladaptive behavior.

Cues signaling the availability of palatable food acquire the ability to potentiate food seeking and consumption. The current study employed a combination of behavioral, pharmacological, and analytical techniques to probe the role of Pavlovian incentive motivation in cue-potentiated feeding. We show that a cue paired with sucrose solution (CS+) can transfer its control over feeding to stimulate sucrose consumption at a new receptacle, and that this effect depends on activation of D1 dopamine receptors, which is known to modulate other forms of cue-motivated behavior but not taste palatability. Microstructural analyses of sucrose-licking behavior revealed that the CS+ tended to increase the frequency with which rats engaged in active bouts of licking behavior without having a reliable effect on the duration of those licking bouts, a measure that was instead associated with sucrose palatability. Furthermore, we found that individual differences in CS+ elicited increases in bout frequency were associated with total sucrose intake at test, supporting the view that this process was related to meaningful dysregulation of eating behavior. The current study, therefore, (1) demonstrates that a dopamine-dependent Pavlovian incentive motivational process can mediate cue-potentiated feeding, and (2) lays out an experimental and analytical approach for parsing this aspect of behavior.

The dorsomedial prefrontal cortex (dmPFC) is known to make important contributions to flexible, reward-motivated behavior. However, it remains unclear if the dmPFC is involved in regulating the expression of Pavlovian incentive motivation, the process through which reward-paired cues promote instrumental reward-seeking behavior, which is modeled in rats using the Pavlovian-instrumental transfer (PIT) task. The current study examined this question using a bidirectional chemogenetic strategy in which inhibitory (hM4Di) or excitatory (hM3Dq) designer G-protein coupled receptors were virally expressed in dmPFC neurons, allowing us to later stimulate or inhibit this region by administering CNO prior to PIT testing. We found that dmPFC inhibition did not alter the tendency for a reward-paired cue to instigate instrumental reward-seeking behavior, whereas dmPFC stimulation disrupted the expression of this motivational influence. Neither treatment altered cue-elicited anticipatory activity at the reward-delivery port, indicating that dmPFC stimulation did not lead to more widespread motor suppression. A reporter-only control experiment indicated that our CNO treatment did not have non-specific behavioral effects. Thus, the dmPFC does not mediate the expression of Pavlovian incentive motivation but instead has the capacity to exert pronounced inhibitory control over this process, suggesting that it is involved in adaptively regulating cue-motivated behavior.

It has been proposed that compulsive drug seeking reflects an underlying dysregulation in adaptive behavior that favors habitual (automatic and inflexible) over goal-directed (deliberative and highly flexible) action selection. Rodent studies have established that repeated exposure to cocaine or amphetamine facilitates the development of habits, producing behavior that becomes unusually insensitive to a reduction in the value of its outcome. The current study more directly investigated the effects of cocaine pre-exposure on goal-directed learning and action selection using an approach that discourages habitual performance. After undergoing a 15-day series of cocaine (15 or 30 mg/kg, i.p.) or saline injections and a drug withdrawal period, rats were trained to perform two different lever-press actions for distinct reward options. During a subsequent outcome devaluation test, both cocaine- and saline-treated rats showed a robust bias in their choice between the two actions, preferring whichever action had been trained with the reward that retained its value. Thus, it appears that the tendency for repeated cocaine exposure to promote habit formation does not extend to a more complex behavioral scenario that encourages goal-directed control. To further explore this issue, we assessed how prior cocaine treatment would affect the rats' ability to learn about a selective reduction in the predictive relationship between one of the two actions and its outcome, which is another fundamental feature of goal-directed behavior. Interestingly, we found that cocaine-treated rats showed enhanced, rather than diminished, sensitivity to this action-outcome contingency degradation manipulation. Given their mutual dependence on striatal dopamine signaling, we suggest that cocaine's effects on habit formation and contingency learning may stem from a common adaptation in this neurochemical system.

Abstract Background With a survival rate of 6 to 11%, out-of-hospital cardiac arrest (OHCA) remains a healthcare challenge with room for improvement in morbidity and mortality. The guidelines emphasize the highest possible quality of cardiopulmonary resuscitation (CPR) and chest compressions (CC). It is essential to minimize CC interruptions, and therefore increase the chest compression fraction (CCF), as this is an independent factor for survival. Survival is significantly and positively correlated with the suitability of CCF targets, CC frequency, CC depth, and brief predefibrillation pause. CC guidance improves adherence to recommendations and allows closer alignment with the CC objectives. The possibility of improving CCF by lengthening the time between two CC relays and the effect of real-time feedback on the quality of the CC must be investigated. Methods Using a 2 × 2 factorial design in a multicenter randomized trial, two hypotheses will be tested simultaneously: (i) a 4-min relay rhythm improves the CCF (reducing the no-flow time) compared to the currently recommended 2-min relay rate, and (ii) a guiding tool improves the quality of CC. Primary outcomes (i) CCF and (ii) correct compression score will be recorded by a real-time feedback device. Five hundred adult nontraumatic OHCAs will be included over 2 years. Patients will be randomized in a 1:1:1:1 distribution receiving advanced CPR as follows: 2-min blind, 2 min with guidance, 4-min blind, or 4 min with guidance. Secondary outcomes are the depth, frequency, and release of CC; length (care, no-flow, and low-flow); rate of return of spontaneous circulation; characteristics of advanced CPR; survival at hospital admission; survival and neurological state on days 1 and 30 (or intensive care discharge); and dosage of neuron-specific enolase on days 1 and 3. Discussion This study will contribute to assessing the impact of real-time feedback on CC quality in practical conditions of OHCA resuscitation. It will also provide insight into the feasibility of extending the relay rhythm between two rescuers from the currently recommended 2 to 4 min. Trial registration ClinicalTrials.gov, NCT03817892 . Registered on 28 January 2019

Studies on the social behavior and cooperation decisions of individuals within and between different ethnic or cultural groups have gained increasing importance in economic sciences, especially in the field of behavioral economics. Axelrod and Hammond (2006) developed an agent-based simulation model to better understand the fundamentals of this phenomenon. Briefly, this model simulates a world with four different neighborhoods, based in a square toroidal lattice shape, where a cell can be inhabited or uninhabited by an agent. The simulation takes 3 stages, Interaction, Reproduction and Death and Placement and get as main result, an ethnocentric agents dominate population based on the path of the agents. The present study aims to broaden the model created by the authors by adding a process of inductive reasoning for the decision making of the agents from the perception of the actions of the others toward him. Our main result are that individuals who understand and interpret part of the environment that are inserted and react inductively to it tend to be more cooperative to the detriment of discriminatory and ethnocentric behavior found in the original model. We also analyze the importance of agent perception in the model and find that agents that perceive and interact with a larger number of other agents tend to be less ethnocentric.