Enhancement Of Reward Research Articles

Reward enhancement of item-location associative memory spreads to similar items within a category

ABSTRACT The experience of a reward appears to enhance memory for recent prior events, adaptively making that information more available to guide future decision-making. Here, we tested whether reward enhances memory for associative item-location information and also whether the effect of reward spreads to other categorically-related but unrewarded items. Participants earned either points (Experiment 1) or money (Experiment 2) through a time-estimation reward task, during which stimuli-location pairings around a 2D-ring were shown followed by either high-value or low-value rewards. All stimuli were then tested for location memory or recognition (yes/no), immediately and after a 24-hour delay. Across both experiments (combined analysis), there was a robust improvement in location memory following high-value rewards, even though evidence supporting this effect was reliable in Experiment 2 but not in Experiment 1. The memory-enhancing effect of reward was observed on both the immediate and delayed location-memory tests. Reward-enhanced memory for both directly rewarded stimuli and categorically related stimuli that were not directly rewarded. No reliable effect of reward value on yes/no recognition-memory performance was observed in either experiment. We hypothesise that reward enhances the consolidation of recent experience and conceptually related memories to make these more available for future decisions.

Energy-delay-aware VNF scheduling: a reinforcement learning approach with hierarchical reward enhancement

Energy-delay-aware VNF scheduling: a reinforcement learning approach with hierarchical reward enhancement

Mindfulness, mental health, and motives for eating tasty foods when not in metabolic need.

Habitual consumption of highly palatable foods when not in metabolic need (HPF eating) is linked to obesity. High HPF consumption is also linked to mental health disorder (MHD) symptoms. Mindfulness-based interventions are popular treatments for obesity and MHDs, but little is known about the relationship between trait mindfulness and motive-based HPF eating. Therefore, a total of 927 young adults completed a survey that included the Palatable Eating Motives Scale-7 (which identifies Coping-, Reward enhancement-, Social-, and Conformity-eating), the Mindful Attention Awareness Scale, the Perceived Stress Scale, and demographic and body mass index (BMI) questions. An MHD questionnaire allowed a comparison of HPF eating between participants with and without various MHDs. Regressions revealed that Coping-eating was independently associated with lower mindfulness and also greater perceived stress, higher BMI, and female sex. Of these variables, only lower mindfulness was independently associated with Reward-, Social-, and Conformity-eating. Coping- and Reward-eating were more frequent in participants with versus without an anxiety disorder, depression, ADD/ADHD, and PTSD. Coping-eating was also more frequent in participants with body dysmorphic disorder. These findings warrant investigations in participants with clinically validated diagnoses for DSM-specific MHDs. Results from such investigations and the uncovered nature of associations between motive-specific HPF eating and trait mindfulness could provide novel targets to improve mindfulness-based interventions for obesity and MHDs.

Varenicline but not cotinine increased the value of a visual stimulus reinforcer in rats: No evidence for synergy of the two compounds

Smoking is the leading cause of preventable death worldwide, with <7 % of smoking cessation attempts being met with success. Nicotine, the main addictive agent in cigarettes, enhances the reinforcing value of other environmental rewards. Under some circumstances, this reward enhancement maintains nicotine consumption. Varenicline (i.e., cessation aid Chantix™) also has reward-enhancement effects via nicotinic acetylcholine receptor agonism (nAChRs) – albeit less robust than nicotine. Cotinine is the major metabolite of nicotine. Recent studies suggest that cotinine is a positive allosteric modulator (PAM) and/or a weak agonist at nAChRs. Thus, cotinine may enhance the behavioral effects of nAChR compounds such as varenicline and/or exert some behavioral effects alone. We used 20 (10M, 10F) Sprague-Dawley rats to assess reward-enhancement within-subjects by examining responding maintained by a reinforcing visual stimulus on a Variable Ratio 2 schedule of reinforcement. To assess the reward-enhancing effects of cotinine, rats received one injection of cotinine (saline, 0.1, 0.3, 1.0, 3.0, 6.0 mg/kg) before each 1 h session. To assess cotinine and varenicline interactions, rats received an injection of cotinine (saline, 0.1, 1.0, or 6.0 mg/kg) and of varenicline (saline, 0.1, 0.3, 1.0, or 3.0 mg/kg) before the session. While we replicated prior work identifying reward-enhancement by 0.1, 0.3, and 1.0 mg/kg varenicline, cotinine alone did not produce reward-enhancement nor augment the reward-enhancing effects of varenicline. Future studies may consider examining the reward-enhancing effects of cotinine with other reinforcers or co-administered with other smoking cessation aids such as bupropion.

Motives and food craving: Associations with frequency of hyper-palatable food intake among college students

BackgroundCollege food environments provide wide access to hyper-palatable foods (HPF). Palatable eating motives and craving are individual factors that may impact HPF intake. Nevertheless, no study to date has examined the relationship between these factors and frequency of HPF intake in a dormitory all-you-can-eat-style cafeteria meal, a typical college food setting. MethodsCollege students (N = 218) self-reported frequency of HPF intake at a college cafeteria meal and their frequency of HPF intake in the overall diet. Quasipoisson and logistic regression models tested whether palatable eating motives (assessed via the Palatable Eating Motives Scale) and craving (assessed via the Food Craving Inventory) were associated with the rate of HPF intake during the cafeteria meal and excess frequency of HPF intake in the overall diet. ResultsCraving was associated with a 19% higher rate of HPF intake during the cafeteria meal (RR = 1.19; p = .015) and a >2-fold higher likelihood of excess frequency of HPF intake the overall diet (OR = 2.69; p < .001). Coping motive was associated with an 87% higher likelihood of excess frequency of HPF intake in the overall diet (OR = 1.87; p = .002), but not in the cafeteria meal. Reward enhancement, social and conformity motives were not significantly associated with the frequency of HPF intake in either setting. ConclusionsResults highlight the role of craving and coping motive in the frequency of HPF intake among college students. Prevention efforts may consider targeting craving and eating to cope to potentially address frequency of HPF intake among college students.

An Improved NSGA-III Algorithm Based on Deep Q-Networks for Cloud Storage Optimization of Blockchain

As the underlying technology of cryptocurrencies, blockchain has gained a lot of attention in recent years. However, the storage problem needs to be solved with the increasing number of blocks in the blockchain network. Cloud storage optimization is an effective way to solve the storage issue, which selects and stores parts of blocks to the cloud. Precisely, block selection can be described as a multiobjective optimization problem (MOP) and solved by evolutionary algorithms (EAs). To obtain well results of block selection, an improved NSGA-III algorithm based on deep Q-networks (DQN), termed NSGA-DQN, is proposed in this paper, which aims to maintain well convergence and diversity of the population. This way, a set of suitable solutions is obtained to determine the number of blocks stored to the cloud, and the storage problem can be solved effectively. To be specific, DQN creates a decision-making agent to maximize the expected reward by learning a policy that evaluates Q values of each action in each state. In the proposed selection mechanism, the reward values are set according to the convergence and diversity of the population, and the actions correspond to the individuals. This way, our method can determine a set of individuals that maximizes the convergence and diversity of the population. In addition, an adaptive maximum reward enhancement module (AMREM) is developed to further enhance the maximum expected reward by updating the new better reward and modifying the replay memory. We conduct the experimental study on block selection, and the results demonstrate that the proposed algorithm is superior to five state-of-the-art algorithms.

Determinantes de comportamentos alimentares desordenados: índice de massa corporal, alimentação emocional, restrição alimentar e motivos para comer alimentos palatáveis

ABSTRACT Objective: The study aimed to investigate the relationships between body mass index, reasons for consuming palatable foods, emotional eating, cognitive dietary restraint, and disordered eating behaviors in young adults. Methods: This study was conducted with 800 young adults, in Ankara, Türkiye. A questionnaire consisting of questions about socio-demographic characteristics, health status, and instruments including Eating Attitudes Test-26, Emotional Appetite Questionnaire, Palatable Eating Motives Scale, and The Three-Factor Eating Questionnaire were applied through face-to-face interviews. Results: According to the Eating Attitudes Test-26, 17.2% of males and 27.7% of females were at risk for disordered eating behaviors (χ2=9.750, p=0.002). The mean scores of the Three-Factor Eating Questionnaire-emotional eating, cognitive restraint subscales, and the positive and negative scores of the Emotional Appetite Questionnaire were higher in males than in females (p&lt;0.05). The mean scores of the Palatable Eating Motives Scale-coping and reward enhancement motives were higher in females, while the mean score for the conformity motives was significantly higher in males. Body mass index, Three-Factor Eating Questionnaire-cognitive restraint subscale, Emotional Appetite Questionnaire-negative, and PEMS-conformity motives were found for predictors for Eating Attitudes Test-26 (all p&lt;0.05). Conclusion: The results showed a high tendency for emotional eating, consumption of palatable foods, and cognitive dietary restraint in young adults, and these factors were considered determinants for eating disorders.

Value restructures the organization of free recall

A large body of research illustrates the prioritization of goal-relevant information in memory; however, it is unclear how reward-related memories are organized. Using a rewarded free recall paradigm, we investigated how reward motivation structures the organization of memory around temporal and higher-order contexts. To better understand these processes, we simulated our findings using a reward-modulated variant of the Context Maintenance and Retrieval Model (CMR; Polyn et al., 2009). In the first study, we found that reward did not influence temporal clustering, but instead shifted the organization of memory based on reward category. Further, we showed that a reward-modulated learning rate and source features of CMR most accurately depict reward's enhancement on memory and clustering by value. In a second study, we showed that reward-memory effects can exist in both extended periods of sustained motivation and frequent changes in motivation, by showing equivalent reward effects using mixed- and pure-list motivation manipulations. However, we showed that a reward-modulated learning rate in isolation can support reward's enhancement of memory in pure-list contexts. Overall, we conclude that reward-related memories are adaptively organized by higher-order value information, and contextual binding to value contexts may only be necessary when rewards are intermittent versus sustained.

Psychometric and cross-cultural generalizability outcomes of the Chinese version of the Kids-Palatable Eating Motives Scale (K-PEMS-C).

Overeating for non-homeostatic needs contributes to childhood obesity. However, validated measures or eating motives and cross-cultural comparisons are limited. This study aimed to validate the Kids-Palatable Eating Motives Scale (K-PEMS) and its association with body mass index z score (BMIz) in China, and further assess its generalization across Chinese and American youth. Data were from participants aged 8-18 years from Hangzhou, China (n = 426) and Birmingham, AL, U.S (n = 73). The K-PEMS had sound reliability and validation (Cronbach's α = 0.920 and all factor loadings >0.50) in the Chinese sample. Multi-group nested models CFAs showed that the ∆CFI of model comparisons of measurement weights and structural covariance, variance, and means were ⩽0.01, and ∆TLI of measurement intercepts ⩽0.05. Linear regressions revealed that frequency of consuming palatable foods and drinks for Coping, Reward Enhancement, and Conformity, but not Social motives, were positively associated with BMIz. The K-PEMS had good cross-cultural generalization and could be useful in treating obesity by identifying specific motives for consuming excessive calories.

Change in craving and frequency of consuming palatable foods for non-homeostatic motives after a gut-cued eating intervention

IntroductionLittle is known regarding consumption of palatable foods (PFs) for non-homeostatic reasons after weight-loss interventions and if baseline or change in frequency of this kind of eating can predict weight-loss outcomes. Little is also known of the relationship between PF eating for non-homeostatic motives and PF craving. Addressing these gaps is important because cravings and habitual consumption of PFs in the absence of homeostatic need contribute to obesity. MethodsN = 30 adults with a mean 34.8 BMI completed a seven-response choice version of the PEMS (PEMS-7) before and after Gut-Cued Eating (GCE), an intervention that did not ban PFs but instructed them to eat only when stomach-hungry and stop eating before feeling too full. Photos of PFs were also rated pre- and post-GCE. ResultsFrequency of eating PFs for social, reward enhancement, and coping, but not conformity motives, decreased after GCE. The decreases predicted amount of weight loss independent of initial weight and demographics. PF craving also decreased and, while correlated with decreasing PF intake, it did not predict weight loss. DiscussionThe study is preliminary because GCE was uncontrolled. However, results warrant a controlled investigation. That craving and frequency of consuming PFs for non-homeostatic motives declined with an intervention that did not ban PFs suggests a method that may voluntarily decrease one's intake of PFs. This should facilitate weight-loss and healthy-weight maintenance. Finally, decreased eating for non-homeostatic motives suggests that individuals were no longer using PFs to cope, socialize, and enhance reward, a change with benefits beyond weight loss.

Reward-enhancing effects of d-amphetamine and its interactions with nicotine were greater in female rats and persisted across schedules of reinforcement.

Nicotine enhances the value of environmental stimuli and rewards, and reward enhancement can maintain nicotine consumption. Stimulants such as d-amphetamine are misused more by women and are commonly co-used with nicotine. d-Amphetamine potentiates nicotine's effects in human and animal research. To date, there are no published studies examining this interaction in a reward-enhancement task. The current study sought to investigate the reward-enhancing effects of nicotine alongside and coadministered with d-amphetamine. Further, we evaluated the persistence of reward enhancement across ratio and temporal schedules of reinforcement. We used 10 male and 10 female Sprague-Dawley rats. Enhancement was assessed within subjects by examining active lever pressing for a visual stimulus reinforcer on variable ratio 3, variable interval 30 s and variable time 30 s - variable ratio 3 schedules. Before 1-h sessions, rats received one injection of saline, 0.1 or 0.3 mg/kg d-amphetamine and one of saline or 0.4 mg/kg nicotine, making six possible drug combinations (saline + saline, saline + nicotine, 0.1 d-amphetamine + aline, 0.1 d-amphetamine + nicotine, 0.3 d-amphetamine + saline and 0.3 d-amphetamine + nicotine) experienced in a randomized order by each rat. When d-amphetamine was coadministered with nicotine, we found an interaction effect on reward enhancement that persisted across schedules of reinforcement. Males and females exhibited reward enhancement by 0.3 d-amphetamine, while only females showed reward enhancement by 0.1 d-amphetamine. Further, females responded more for the visual stimulus than males in all d-amphetamine conditions. Future studies should assess how reward enhancement is involved in high nicotine-amphetamine comorbidity rates and enhanced amphetamine misuse in women.

Rewarding Effects of Nicotine Self-administration Increase Over Time in Male and Female Rats.

Smoking and the use of other nicotine-containing products is rewarding in humans. The self-administration of nicotine is also rewarding in male rats. However, it is unknown if there are sex differences in the reward-enhancing effects of nicotine self-administration and if the rewarding effects of nicotine change over time. Rats were prepared with catheters and intracranial self-stimulation (ICSS) electrodes to investigate the effects of nicotine and saline self-administration on reward function. A decrease in thresholds in the ICSS procedure reflects an enhancement of reward function. The ICSS parameters were determined before and after the self-administration sessions from days 1 to 10, and after the self-administration sessions from days 11 to 15. During the first 10 days, there was no sex difference in nicotine intake, but during the last 5 days, the females took more nicotine than the males. During the first 10 days, nicotine self-administration did not lower the brain reward thresholds but decreased the response latencies. During the last 5 days, nicotine lowered the reward thresholds and decreased the response latencies. An analysis with the 5-day averages (days 1-5, 6-10, and 11-15) showed that the reward enhancing and stimulatory effects of nicotine increased over time. There were no sex differences in the reward-enhancing and stimulatory effects of nicotine. The nicotinic receptor antagonist mecamylamine diminished the reward-enhancing and stimulatory effects of nicotine. These findings indicate that the rewarding effects of nicotine self-administration increase over time, and there are no sex differences in the reward-enhancing effects of nicotine self-administration in rats. This study investigated the rewarding effect of nicotine and saline self-administration in male and female rats. The self-administration of nicotine, but not saline, enhanced brain reward function and had stimulatory effects. The rewarding effects of nicotine increased over time in the males and the females. Despite that the females had a higher level of nicotine intake than the males, the reward-enhancing effects of nicotine self-administration were the same. These findings suggest that in new tobacco and e-cigarette users, nicotine's rewarding effects might increase quickly, and a higher level of nicotine use in females might not translate into greater rewarding effects.

Certain Safeties or Safe Certainties: Infrastructure Reliability versus Rewards

Public sector entities devote a tremendous amount of time to avoiding risk, especially political risk. It feels far safer to spend a large number of small sums of money on ten different studies, rather than solve one problem for the same cost. If a political problem arises, then the response “we had it under review” is of more political value than “we ignored nine similar problems because we hoped to eliminate one long-term problem once-and-for-all, but this one of the nine caught us out”. Infrastructure, however, needs to be reliable, not a subject of political whimsy or backside-covering. How can we go about setting public policy that sensibly balances risks, rewards and reliability of infrastructure? Risk/Reward management defines three types of activity that improve organizational performance - risk avoidance, reward enhancement and volatility reduction. Risk avoidance activities reduce large exposures, e.g. continuity planning, insurance or legal compliance. Reward enhancement activities are normal management projects to increase performance such as training, cost reduction or production improvement. Volatility reduction is more subtle, yet activities that reduce volatility or improve consistent delivery add measurable value.

Optogenetic brain-stimulation reward: A new procedure to re-evaluate the rewarding versus aversive effects of cannabinoids in dopamine transporter-Cre mice.

Despite extensive research, the rewarding effects of cannabinoids are still debated. Here, we used a newly established animal procedure called optogenetic intracranial self-stimulation (ICSS) (oICSS) to re-examine the abuse potential of cannabinoids in mice. A specific adeno-associated viral vector carrying a channelrhodopsin gene was microinjected into the ventral tegmental area (VTA) to express light-sensitive channelrhodopsin in dopamine (DA) neurons of transgenic dopamine transporter (DAT)-Cre mice. Optogenetic stimulation of VTA DA neurons was highly reinforcing and produced a classical "sigmoidal"-shaped stimulation-response curve dependent upon the laser pulse frequency. Systemic administration of cocaine dose-dependently enhanced oICSS and shifted stimulation-response curves upward, in a way similar to previously observed effects of cocaine on electrical ICSS. In contrast, Δ9 -tetrahydrocannabinol (Δ9 -THC), but not cannabidiol, dose-dependently decreased oICSS responding and shifted oICSS curves downward. WIN55,212-2 and ACEA, two synthetic cannabinoids often used in laboratory settings, also produced dose-dependent reductions in oICSS. We then examined several new synthetic cannabinoids, which are used recreationally. XLR-11 produced a cocaine-like increase, AM-2201 produced a Δ9 -THC-like reduction, while 5F-AMB had no effect on oICSS responding. Immunohistochemistry and RNAscope in situ hybridization assays indicated that CB1 Rs are expressed mainly in VTA GABA and glutamate neurons, while CB2 Rs are expressed mainly in VTA DA neurons. Together, these findings suggest that most cannabinoids are not reward enhancing, but rather reward attenuating or aversive in mice. Activation of CB1 R and/or CB2 R in different populations of neurons in the brain may underlie the observed actions.

Temporal parameters of enhanced opioid reward after initial opioid exposure in rats.

Mu opioid receptor agonists are indispensable for the treatment of pain, but clinical use carries the inherent risk of transition from effective treatment to abuse. Abuse potential appears to increase rapidly during periods of initial opioid exposure in humans, and this increase in opioid reward during initial opioid exposure can be modeled in rats using an intracranial self-stimulation (ICSS) procedure. The goal of the present study was to examine temporal parameters of this phenomenon. Adult male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure. In the first experiment, rats received daily morphine injections for 6days, and morphine effects on ICSS were re-determined 1day, 1week, or 1month after the repeated morphine treatment regimen to evaluate the persistence of enhanced opioid reward. In the second experiment, rats received six repeated morphine injections with different interdose intervals (two per day, one per day, every other day, every fourth day), and morphine effects were re-determined 1day after the last dose to determine dosing frequencies sufficient to produce enhanced opioid reward. Results of the first experiment indicated that enhanced opioid reward was greatest 1day after the morphine treatment regimen and completely dissipated after 4weeks. The second experiment indicated that all dosing frequencies tested were sufficient to produce enhanced reward. Taken together, these results suggest that enhancement of opioid reward after initial opioid exposure is relatively transient but can be produced by a range of different dosing frequencies.

Examination of nicotine and saccharin reward in the Goto-Kakizaki diabetic rat model

Morbidity and mortality attributed to type 2 diabetes have exponentially increased in the US. At exceptionally high risk is a subpopulation of persons with type 2 diabetes who smoke, which are shown to have decreased success rates of smoking cessation than euglycemic smokers. Preclinical research in our laboratory has shown that the rewarding effects of nicotine are enhanced in the streptozotocin and high-fat diet rodent model of diabetes. It is presently unclear whether this enhancement of nicotine reward can be demonstrated in other insulin resistant rat models. This study aimed to determine if a similar increase in nicotine reward is found in Goto-Kakizaki (GK) rats, a model of the spontaneous formation of insulin resistance in an inbred sub-strain of Wistar rat. Nicotine conditioned place preference (CPP) was examined in Sprague-Dawley (SD), Wistar, and GK rats. A robust nicotine CPP was found in SD and Wistar rats, but nicotine CPP was not detected in GK rats. Locomotor activity was also evaluated in all three strains, and GK rats demonstrated significantly less activity as compared to SD and Wistar rats. To further assess reward behavior in GK rats, consumption of saccharin solution was measured over a 48 -h period. GK rats showed a significant increase in saccharin intake compared to SD rats. These findings suggest that GK rats experience an enhanced hedonic processing as compared to SD rats. The lack of nicotine CPP in GK rats may be due to deficits in learning and memory, thus hindering their ability to acquire or express a place preference.

Incisional Injury Modulates Morphine Reward and Morphine-Primed Reinstatement: A Role of Kappa Opioid Receptor Activation.

Persistent use of prescription opioids beyond the period of surgical recovery is a large part of a public health problem linked to the current opioid crisis in the United States. However, few studies have been conducted to examine whether morphine reward is influenced by acute pain and injury. In a mouse model of incisional injury and minor trauma, animals underwent conditioning, extinction, and drug-primed reinstatement with morphine to examine the rewarding properties of morphine in the presence of acute incisional injury and drug-induced relapse, respectively. In addition, we sought to determine whether these behaviors were influenced by kappa opioid receptor signaling and measured expression of prodynorphin messenger RNA in the nucleus accumbens and medial prefrontal cortex after conditioning and before reinstatement with morphine and incisional injury. In the presence of incisional injury, we observed enhancement of morphine reward with morphine-conditioned place preference but attenuated morphine-primed reinstatement to reward. This adaptation was not present in animals conditioned 12 days after incisional injury when nociceptive sensitization had resolved; however, they showed enhancement of morphine-primed reinstatement. Prodynorphin expression was greatly enhanced in the nucleus accumbens and medial prefrontal cortex of mice with incisional injury and morphine conditioning and remained elevated up to drug-primed reinstatement. These changes were not observed in mice conditioned 12 days after incisional injury. Further, kappa opioid receptor blockade with norbinaltorphimine before reinstatement reversed the attenuation induced by injury. These findings suggest enhancement of morphine reward as a result of incisional injury but paradoxically a protective adaptation with incisional injury from drug-induced relapse resulting from kappa opioid receptor activation in the reward circuitry. Remote injury conferred no such protection and appeared to enhance reinstatement.

Cannabinoid CB1 and CB2 receptor mechanisms underlie cannabis reward and aversion in rats.

Endocannabinoids are critically involved in brain reward functions, mediated by activation of CB1 receptors, reflecting their high density in the brain. However, the recent discovery of CB2 receptors in the brain, particularly in the midbrain dopamine neurons, has challenged this view and inspired us to re-examine the roles of both CB1 and CB2 receptors in the effects of cannabis. In the present study, we used the electrical intracranial self-stimulation paradigm to evaluate the effects of various cannabinoid drugs on brain reward in laboratory rats and the roles of CB1 and CB2 receptors activation in brain reward function(s). Two mixed CB1 / CB2 receptor agonists, Δ9 -tetrahydrocannabinol (Δ9 -THC) and WIN55,212-2, produced biphasic effects-mild enhancement of brain-stimulation reward (BSR) at low doses but inhibition at higher doses. Pretreatment with a CB1 receptor antagonist (AM251) attenuated the low dose-enhanced BSR, while a CB2 receptor antagonist (AM630) attenuated high dose-inhibited BSR. To confirm these opposing effects, rats were treated with selective CB1 and CB2 receptor agonists. These compounds produced significant BSR enhancement and inhibition, respectively. CB1 receptor activation produced reinforcing effects, whereas CB2 receptor activation was aversive. The subjective effects of cannabis depend on the balance of these opposing effects. These findings not only explain previous conflicting results in animal models of addiction but also explain why cannabis can be either rewarding or aversive in humans, as expression of CB1 and CB2 receptors may differ in the brains of different subjects.

Role of agonist efficacy in exposure-induced enhancement of mu opioid reward in rats

The abuse potential of opioid analgesics in humans appears to increase rapidly during initial regimens of opioid exposure. Previous work using intracranial self-stimulation (ICSS), a preclinical procedure useful for studying rewarding drug effects in drug-naïve animals, has similarly shown that rewarding effects of mu opioid receptor (MOR) agonists increase rapidly in rats during initial regimens of opioid administration. The goal of the present study was to evaluate the role of MOR agonist efficacy as a determinant in eliciting this trajectory of increased rewarding effects during initial opioid exposure in opioid-naïve rats. Separate groups of adult, male Sprague-Dawley rats responded for electrical brain stimulation using a frequency-rate ICSS procedure and received repeated daily treatment with vehicle or one of five MOR agonists that ranged from low to high efficacy (NAQ, nalbuphine, buprenorphine, fentanyl, methadone). Two additional groups were used to evaluate effects of repeated treatment with non-opioids (the cannabinoid CP55940 or the monoamine releaser amphetamine). Morphine was tested after each repeated treatment. In opioid-naïve rats tested before repeated dosing, MOR agonists produced primarily dose- and efficacy-dependent decreases in ICSS. Following repeated treatment, all MOR agonists except NAQ produced tolerance to opioid-induced rate-decreasing effects and enhanced expression of ICSS facilitation (indicative of opioid reward) by both the repeatedly administered drug and morphine. Repeated treatment with CP55940 and amphetamine produced different effects. Collectively, these results provide evidence to suggest that enhanced expression of opioid reward after initial regimens of opioid exposure has a low requirement for MOR agonist efficacy and is pharmacologically selective.This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.

Synthetic cathinone MDPV enhances reward function through purinergic P2X7 receptor-dependent pathway and increases P2X7 gene expression in nucleus accumbens

Background and purposePurinergic P2X7 receptors are present on neurons, astrocytes and microglia and activated by extracellular ATP. Since P2X7 receptor activation releases endogenous substrates (e.g., pro-inflammatory cytokines, dopamine, and glutamate) that facilitate psychostimulant reward and reinforcement, we investigated the hypothesis that the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) produces rewarding effects that are dependent on active P2X7 receptors. MethodsReward function was measured in male mice using intracranial self-stimulation (ICSS). MDPV (0.1, 0.3, 0.5 mg/kg, SC) and a selective P2X7 antagonist (A438079) (5, 10, 50 mg/kg, IP) were tested alone and in combination. In separate mice, gene and protein expression of P2X7 and mitochondrial adenosine triphosphate (ATP) synthase (an enzyme that catalyzes synthesis of ATP, an endogenous ligand for P2X7 receptors) in the nucleus accumbens (NAcc) were quantified following MDPV exposure (0.1, 0.5, 5 mg/kg, SC). Key resultsMDPV (0.5 mg/kg, SC) facilitated ICSS as quantified by a significant reduction in brain reward threshold. A438079 (5, 10, 50 mg/kg, IP) did not affect ICSS by itself; however, for combined administration, A438079 (10 mg/kg, IP) inhibited facilitation of ICSS by MDPV (0.5 mg/kg, SC). At the cellular level, MDPV exposure increased gene and protein expression of P2X7 and ATP synthase in the NAcc. Conclusion and implicationWe provide evidence that a psychostimulant drug produces reward enhancement that is influenced by P2X7 receptor activity and enhances P2X7 receptor expression in the brain reward circuit.