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Environmental conditioning factors have a profound impact on alcohol-seeking behavior and the maintenance of alcohol use in individuals with alcohol dependence. Cues associated with alcohol, depending on the perceived value of the primary reinforcer, gain salience and can trigger relapse. This study investigates the correlation between the reward magnitude of the primary reinforcer and the reinstatement evoked by cues predictive of their availability in male rats. Rat self-administration procedures were used to test reinstatement, with reinforcers consisting of 10% alcohol, 10% sucrose, or 2% sodium chloride (NaCl) experienced under need-state conditions. The effect of MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, on motivation and reinstatement behaviors was also evaluated. RESULTS: demonstrate that under Fixed Ratio 1 (FR1) schedule, the three reinforcers maintain operant responding with the following order of magnitude 10% sucrose >2% NaCl >10% alcohol > water. Under a progressive ratio (PR) schedule of reinforcement, rats exhibit a significantly higher breakpoint for 2% NaCl (under Na-depletion), followed by 10% sucrose and 10% alcohol. After extinction, a significant reinstatement is observed with the magnitude order of 10% sucrose >10% alcohol >2% NaCl. However, only re-exposure to alcohol-paired cues induced significant reinstatement of alcohol-seeking after 4 and 8 months. Treatment with MTEP significantly reduces reinstatement of responding across all reinforcers, with the strongest effect observed on alcohol-seeking. These findings suggest that mGluR5 plays a general role in controlling cue-reactivity, but the effect is prominent in the case of alcohol compared to natural rewards. In conclusion, the results demonstrate a remarkable dissociation between the rewarding magnitude of the primary reinforcer and its ability to trigger relapse upon presentation of a cue previously associated with it. Importantly, alcohol, despite having lower intrinsic motivational value compared to a natural reward (sucrose) or a consummatory stimulus experienced under need state conditions (NaCl), can elicit more robust and longer-term reinstatement of seeking responses. Finally, our data demonstrate a significant involvement of the mGluR5 system in the regulation of seeking behavior.

Simple Summary: In this study, researchers aimed to compare the effectiveness of food and leisure stimuli as reinforcers for domestic dogs. While preference assessments have been conducted for various species, including humans and animals like cockroaches and wolves, to our knowledge, no study has specifically examined the preference between food and leisure stimuli in dogs. This study found that, overall, domestic dogs showed a preference for food over leisure items. Additionally, food was found to be a more effective reinforcer for dog behavior compared to leisure items. These findings have important implications for dog owners and trainers, suggesting that using food as a reinforcer may yield better results in training dogs. Preference assessments are often used to identify stimuli that function as potential reinforcers for training or intervention purposes. Specifically, various preference assessment formats have been used to identify preferred stimuli for humans, cockroaches, cotton-top tamarins, tortoises, and wolves, to name a few. However, to date, no study has evaluated the differential efficacy between food and leisure stimuli within domestic dogs. The current study aimed to compare the reinforcing value and efficacy between food and leisure stimuli for domestic dogs by comparing rates of behavior when receiving access to either their top-preferred food or leisure items. Overall results suggest (1) domestic dogs prefer food over leisure items, and (2) food is more likely to function as a reinforcer than leisure items for domestic dog's behavior. These results suggest that dog owners and trainers should consider using food reinforcers over leisure items as reinforcers when attempting to train dogs. [ABSTRACT FROM AUTHOR]

Given the significant cost of alcohol use disorder (AUD), identifying risk factors for alcohol seeking represents a research priority. Prominent addiction theories emphasize the role of motivation in the alcohol seeking process, which has largely been studied using preclinical models. In order to bridge the gap between preclinical and clinical studies, this study examined predictors of motivation for alcohol self-administration using a novel paradigm. Heavy drinkers (n = 67) completed an alcohol infusion consisting of an alcohol challenge (target breath alcohol = 60 mg%) and a progressive-ratio alcohol self-administration paradigm (maximum breath alcohol 120 mg%; ratio requirements range = 20-3 139 response). Growth curve modeling was used to predict breath alcohol trajectories during alcohol self-administration. K-means clustering was used to identify motivated (n = 41) and unmotivated (n = 26) self-administration trajectories. The data were analyzed using two approaches: a theory-driven test of a-priori predictors and a data-driven, machine learning model. In both approaches, steeper delay discounting, indicating a preference for smaller, sooner rewards, predicted motivated alcohol seeking. The data-driven approach further identified phasic alcohol craving as a predictor of motivated alcohol self-administration. Additional application of this model to AUD translational science and treatment development appear warranted.

Background: The heritability of alcohol use disorder is close to 50%, yet common genetic variants account for less than 5% of risk. The missing heritability may reflect environmental exposure in the parents prior to conception. Indeed, paternal alcohol exposure has many behavioral and biological consequences for rodent offspring. We recently found that paternal alcohol exposure attenuated the acquisition of operant alcohol self‐administration in offspring of rats of both sexes. Here we test whether this effect extends to other phases of operant self‐administration thought to model motivation, craving, and relapse. Methods: Wistar male rats exposed to alcohol vapors or air for 6 weeks were mated with alcohol‐naïve females 8 weeks later. The adult offspring were trained to lever press for alcohol and tested under several conditions: (1) maintenance responding under a progressive ratio schedule, (2) extinction responding due to removal of the alcohol delivery contingency, (3) reinstatement of extinguished responding in the presence of alcohol‐associated cues, and (4) reinitiation of lever press responding for alcohol delivery under fixed and progressive ratio schedules. Results: Alcohol‐sired offspring showed reduced responding under the progressive ratio schedule and blunted cue‐induced reinstatement of extinguished responding. Alcohol‐sired offspring also emitted fewer responses during extinction sessions and did not reinitiate responding to the same extent as control‐sired rats after alcohol delivery was restored. Conclusions: Across all conditions, paternal alcohol exposure led to a reduction in the reinforcing effects of alcohol in offspring. These results are consistent with studies conducted with paternal cocaine exposure except that here we find effects in rats of both sexes. [ABSTRACT FROM AUTHOR]

Rationale : After a history of intermittent cocaine intake, rats develop patterns of drug use characteristic of substance use disorder. The dorsal striatum is involved in the increased pursuit of cocaine after intermittent drug self-administration experience. Within the dorsal striatum, chronic cocaine use changes metabotropic glutamate type II receptor (mGlu2/3) density and function. Objectives: We examined the extent to which activity at Glu2/3 receptors mediates responding for cocaine after intermittent cocaine use. Methods: Male (n = 11) and female (n = 10) Wistar rats self-administered 0.25 mg/kg/infusion cocaine during 10 daily intermittent access (IntA) sessions (5 min ON/25 min OFF, for 5 h/session). We then examined the effects of microinjections of the mGlu2/3 receptor agonist LY379268 (0, 1, and 3 µg/hemisphere) into the ventrolateral part of the dorsal striatum on cocaine self-administration under a progressive ratio schedule of reinforcement. Results: Across 10 IntA sessions, the sexes showed similar levels of cocaine intake. In females only, locomotion significantly increased over sessions, suggesting that female rats developed psychomotor sensitization to self-administered cocaine. After 10 IntA sessions, intra-dorsal striatum LY379268 significantly reduced breakpoints achieved for cocaine, active lever presses, and cocaine infusions earned under progressive ratio. LY379268 had no effects on locomotion or inactive lever presses, indicating no motor effects. Conclusions: These results suggest that mGlu2/3 receptor activation in the ventrolateral dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for new treatments to manage substance use disorder. [ABSTRACT FROM AUTHOR]

Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d -Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females. • Progressive ratio breakpoint for sucrose was assessed in females. • Intra-accumbens DAMGO increased breakpoint for sucrose. • MCHR1 antagonist blocked the DAMGO-induced increase in breakpoint. • Accumbens MCHR1 has a specific role in motivation for palatable food in females. [ABSTRACT FROM AUTHOR]

Anhedonia and avolition are emotions frequently endorsed by individuals with stress related disorders. Kappa opioid receptor (KOR) activation can induce negative emotions and recent clinical evidence suggests that KOR antagonism can alleviate anhedonia in a transdiagnostic cohort of patients. However, the behavioral consequences of KOR activation and antagonism in modulating motivation, as assessed by schedule-controlled behavioral performance without preexisting conditions (stress or substance use), have not been formally assessed. To address this gap in the literature, this report utilized male and female Sprague Dawley rats to (1) evaluate the impact of the selective KOR agonist U50,488, on the performance of animals responding for sucrose pellets under a progressive ratio (PR) schedule and (2) determine the effects of the short-acting KOR antagonist LY2444296 alone and on U50,488 mediated reductions in PR performance. Overall, U50,488 5 mg/kg significantly reduced the breakpoint and number of rewards obtained by animals. This occurred in the absence of motor impairment and independent of evidence for satiation. LY2444296 did not alter PR performance when administered alone but effectively blocked the deficits induced by U50,488. To further delineate the behavioral alterations that underlie these reductions in responding, a more detailed analysis was conducted on PR performance in the first 15 min of the session, the period of time when animals obtained the most reinforcers. During this period, U50,488 increased the length of the post-reinforcement pause and reduced the running rate on PR schedules. These changes in behavior produced by acute activation of KORs are consistent with a reduction of effort-related motivation in rodents. These data contribute to the understanding of how KORs modulate motivation, which is critical to future efforts to evaluate performance in the context of stress and assess how KOR antagonists alleviate anhedonic behaviors associated with stress. • U50,488 reduced the breakpoint and number of rewards earned in the PR session. • LY2444296 did not alter PR performance but blocked U50,488 induced deficits. • U50,488 increased the post-reinforcement pause duration. • U50,488 decreased the run rates of animals in the PR session. [ABSTRACT FROM AUTHOR]

Chronic pain can be a debilitating condition, leading to profound changes in nearly every aspect of life. However, the reliance on opioids such as oxycodone for pain management is thought to initiate dependence and addiction liability. The neurobiological intersection at which opioids relieve pain and possibly transition to addiction is poorly understood. Using RNA sequencing pathway analysis in rats with complete Freund's adjuvant (CFA)-induced chronic inflammation, we found that the transcriptional signatures in the medial prefrontal cortex (mPFC; a brain region where pain and reward signals integrate) elicited by CFA in combination with oxycodone differed from those elicited by CFA or oxycodone alone. However, the expression of Egr3 was augmented in all animals receiving oxycodone. Furthermore, virus-mediated overexpression of EGR3 in the mPFC increased mechanical pain relief but not the affective aspect of pain in animals receiving oxycodone, whereas pharmacological inhibition of EGR3 via NFAT attenuated mechanical pain relief. Egr3 overexpression also increased the motivation to obtain oxycodone infusions in a progressive ratio test without altering the acquisition or maintenance of oxycodone self-administration. Taken together, these data suggest that EGR3 in the mPFC is at the intersection of nociceptive and addictive-like behaviors. [ABSTRACT FROM AUTHOR]

Preference assessments are often used to identify stimuli that function as potential reinforcers for training or intervention purposes. Specifically, various preference assessment formats have been used to identify preferred stimuli for humans, cockroaches, cotton-top tamarins, tortoises, and wolves, to name a few. However, to date, no study has evaluated the differential efficacy between food and leisure stimuli within domestic dogs. The current study aimed to compare the reinforcing value and efficacy between food and leisure stimuli for domestic dogs by comparing rates of behavior when receiving access to either their top-preferred food or leisure items. Overall results suggest (1) domestic dogs prefer food over leisure items, and (2) food is more likely to function as a reinforcer than leisure items for domestic dog’s behavior. These results suggest that dog owners and trainers should consider using food reinforcers over leisure items as reinforcers when attempting to train dogs.

The anterior cingulate cortex (ACC) is known to be involved in effortful choice, yet its role in cost-benefit evaluation of qualitatively different rewards (more/less preferred), beyond magnitude differences (larger/smaller), is poorly understood. Selecting between qualitatively different options is a decision type commonly faced by humans. Here, we assessed the role of ACC on a task that has primarily been used to probe striatal function in motivation. Rats were trained to stable performance on a progressive ratio schedule for sucrose pellets and were then given sham surgeries (control) or excitotoxic NMDA lesions of ACC. Subsequently, a choice was introduced: chow was concurrently available while animals could work for the preferred sucrose pellets. ACC lesions produced a significant decrease in lever presses for sucrose pellets compared to control, whereas chow consumption was unaffected. Lesions had no effect on sucrose pellet preference when both options were freely available. When laboratory chow was not concurrently available, ACC-lesioned rats exhibited similar lever pressing as controls. During a test under specific satiety for sucrose pellets, ACC-lesioned rats also showed intact devaluation effects. The effects of ACC lesions in our task are not mediated by decreased appetite, a change in food preference, a failure to update value or a learning deficit. Taken together, we found that ACC lesions decreased effort for a qualitatively preferred option. These results are discussed with reference to effects of striatal manipulations and our recent report of a role for basolateral amygdala in effortful choice.

Background: Depressive disorders have been associated with altered effort-cost decision making (ECDM) in behavioral investigations, such as a decreased willingness to expend effort for reward attainment. However, little is known about neural mechanisms implicated in altered ECDM.Methods: The study investigates neural correlates of reward attainment during a progressive ratio task in participants with a current depressive disorder (n = 65) and never-depressed healthy individuals (n = 44). On each trial, participants completed an increasing number of button presses to attain a fixed monetary reward, indicated by an auditory reward signal. Participants could decide to quit the task anytime (breakpoint). EEG was recorded during the task and P300 amplitudes were examined in response to the auditory signal of reward attainment.Results: There was no difference in breakpoint, as both groups completed comparable numbers of button presses. In contrast, results from mixed-effects models of trial-level ERP responses indicated depression-related effects on P300 amplitudes over the course of the task. Generally, the reward-locked P300 increased with ascending effort expenditure; however, compared to healthy participants, individuals with current depression were characterized by an attenuated trajectory of the reward-locked P300, pointing towards decreased reactivity to reward attainment with increasing effort.Limitations: Sample size and reward magnitude were possibly not large enough to detect differences in breakpoint.Conclusions: The results of the current study demonstrate that the investigation of reward-related P300 trajectory may represent an informative novel addition to the progressive ratio task, which could help shed light on depression-related alterations in motivation and ECDM. [ABSTRACT FROM AUTHOR]

The progressive ratio procedure is used across fields to assess motivation for different reinforcers, define the effects of experimental interventions on motivation, and determine experience‐dependent changes in motivation. However, less is known about how operant training schedules affect performance on this widely utilized task. Here we designed an experiment to examine the effect of variable ratio versus fixed ratio training schedules of reinforcement on progressive ratio performance while holding other performance variables constant between groups. We found a robust increase in maximum ratio completed between the pretest and posttraining test highlighting a robust training effect on progressive ratio performance. However, it did not matter if the training was under a fixed or variable ratio schedule. Additionally, we show that neither individual rates during training nor extinction responding correlated with maximum ratio achieved during the sessions. Finally, we show that rates during the training sessions do correlate with extinction performance, suggesting that these variables measure a different aspect of performance that does not predict motivation. [ABSTRACT FROM AUTHOR]

Maternal diets can have dramatic effects on the physiology, meta bolism, and behaviour of offspring that persist into adulthood. However, the effects of maternal sucrose consumption on offspring remain unclear. Here, female rats were fed either a sucrose diet with a human-relevant level of sucrose (25% of kcal) or a macronutrient-matched, isocaloric control diet before, during, and after pregnancy. Af ter weaning, all offspring were fed a standard low-sucrose rodent chow. We measured indicators of metabolism (weight, adipose, glucose tolerance, and liver lipids) during development and adulthood (16-24 weeks). We also measured food preference and motivation for sugar rewards in adulthood. Finally, in brain regions regulating these behaviours, we measured steroids and transcripts for steroidogenic enzymes, steroid receptors, and dopamine receptors. In male offspring, maternal sucrose intake decreased body mass a nd visceral adipose tissue, increased preference for high-sucrose and high-fat diets, increased motivation for sugar rewards, and decreased mRNA levels of Cyp17a1 (an androgenic enzyme) in the nucleus accumbens. In female offspring, maternal sucrose int ake increased basal corticosterone levels. These data demonstrate the enduring, div erse, and sex-specific effects of maternal sucrose consumption on offspring phenotype. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the demand by possums for foods under different arrangements of concurrent progressive-ratio and fixed-ratio schedules of reinforcement. In Experiment 1, every possible food pair made up of berries, chicken, egg, foliage, insects and mushroom was presented (30 pairs in total). The requirement on the progressive-ratio schedule increased within a session and the fixed-ratio was kept constant at 30. In Experiment 2, a subset of the foods from Experiment 1 were used (chicken, mushroom, egg and berries) and in separate conditions the fixed-ratio was either 30 or 10 responses. In Experiment 3, the foods were the same as used in Experiment 2 and the progressive-ratio schedule increased every five sessions and the fixed-ratio schedule was 30 responses. Exponential models of demand were applied to consumption rates to compare the parameters of initial demand, essential value and P max, and break point and cross point across foods. The models described the data well and consumption rates were similar when the incrementing schedules increased within- and across sessions. Demand was highest for berries, egg and locust in Experiment 1 and egg and chicken in Experiments 2 and 3. This finding has practical implications for understanding possum food preferences in the wild as a function of other available food sources.

The purpose of the current study was to explore the scientific utility of two behavior analytic assessments (i.e., progressive ratio and demand assessments) for psychotropic medication evaluation. For a sample of 23 children with disabilities who were prescribed medication, we conducted a series of generalizability and optimization studies to identify sources of score variance and conditions in which stable estimates of behavior can be obtained. To inform construct validity, we calculated correlations between scores from each assessment and those from a standardized behavior rating scale (Aberrant Behavior Checklist-Second Edition; ABC-2). Results offer initial support for the scientific utility of progressive ratio scores. More research is needed to evaluate sensitivity to change and construct validity of scores from these and other behavior analytic assessments. [ABSTRACT FROM AUTHOR]

Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10–40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state.

Problematic internet use (PIU) is of increasing concern to society and is correlated with negative behavioral and health issues. Human laboratory procedures to assess economic demand for internet use may be useful in translational efforts to better understand PIU and to assess potential treatments. One such procedure involves hypothetical purchases of access to internet use. Little is known about how such hypothetical purchases relate to actual behavior. In the current study, we assessed the correlation between measures of demand via an internet purchase task (IPT) and breakpoints on a progressive ratio (PR) schedule (n = 52). Participants responded on a computer-based task on an escalating work requirement that resulted in 30-s of access to their internet-enabled smartphone. We found a statistically significant correlation between demand intensity (Qo) and total responses (r(29) =.83, p <.001), and between Omax (maximum response expenditure) and total responses (r(29) =.34, p =.03) on the PR schedule. We did not find a relationship between measures of demand elasticity and measures of PR behavior. Because Omax is reflective of both demand and elasticity and Q0 is primarily influenced by demand alone, the results of this study indicate that demand intensity of internet use may be a better predictor of real-world behavior than other measures of demand. These results suggest that demand intensity for internet access may be a valuable proxy for behavior-based measures in the assessment and treatment of PIU. [ABSTRACT FROM AUTHOR]

Recent estimates suggest increased popularity of the concurrent use of opioids and stimulants, with over 50% of treatment-seeking opioid users reporting regular stimulant use. The goal of the current study was to determine how opioid dependence and withdrawal affect the reinforcing effects of fentanyl, cocaine, and methamphetamine. Male Sprague-Dawley rats were allowed to self-administer fentanyl under a progressive ratio (PR) schedule of reinforcement. Baseline evaluations of reinforcing effectiveness of fentanyl, cocaine, and methamphetamine were determined. Opioid dependence was then established by administering escalating doses of morphine (10–40 mg/kg) twice-daily for four days and subsequently maintained by once-daily injections of 40 mg/kg morphine. To evaluate the impact of opioid dependence and withdrawal on the self-administration of fentanyl, cocaine, and methamphetamine, sessions occurred either 12 or 20 h after the morphine, respectively. During opioid withdrawal, the fentanyl dose-response curve was shifted rightward with an increase in maximal effectiveness, whereas it was shifted rightward with a reduction in maximal effectiveness when evaluated in rats currently dependent on opioids, relative to baseline. The reinforcing effects of cocaine and methamphetamine were unchanged by either condition. The current studies provide direct evidence that the reinforcing effects of fentanyl are increased in opioid-withdrawn rats and reduced in opioid-dependent rats, relative to rats that are not physically dependent on opioids. These findings suggest that motivations to use opioids are dependent on the state of the individual whereas stimulants retain their reinforcing effects regardless of whether the individual is in an opioid-dependent or withdrawn state. [ABSTRACT FROM AUTHOR]

Withdrawal from opioid painkillers can produce short‐lived physical symptoms and protracted psychological symptoms including anxiety and depressive‐like states that often lead to opioid misuse and opioid use disorder (OUD). Studies testing the hypothesis that opioid withdrawal potentiates the reinforcing effects of opioid self‐administration (SA) are largely inconclusive and have focused on males. Although some clinical evidence indicates that women are more likely than men to misuse opioids to self‐medicate, preclinical studies in both sexes are lacking. Based on clinical reports, we hypothesized that withdrawal from escalating‐dose morphine injections that approximates a prescription painkiller regimen would lead to increased oxycodone SA to a greater extent in female compared to male rats. After escalating‐dose morphine (5–30 mg/kg or vehicle, twice/day for 12 days), rats underwent a 2‐week abstinence period during which withdrawal signs were measured. The impact of this treatment was assessed on oxycodone SA acquisition, maintenance, dose response, and progressive ratio responding, with additional analyses to compare sexes. We found that both sexes expressed somatic withdrawal, whereas only males demonstrated hyperalgesia in the warm water tail flick assay. During SA acquisition, males with prior morphine exposure took significantly more oxycodone than females. Finally, females with prior morphine exposure demonstrated the lowest motivation to SA oxycodone in the progressive ratio test. Contrary to our initial hypothesis, our findings suggest that prior opioid exposure increases vulnerability to initiate misuse more in males and decreases the reinforcing efficacy of oxycodone in females. [ABSTRACT FROM AUTHOR]

Rationale: Currently there is little research into the role of frustration in substance use disorders despite research showing that frustration tolerance in humans is associated with a lower likelihood of developing substance use problems, better outcomes in recovery, and fewer relapses. Objective: In order to address this need, our studies use a rat model to focus on frustration-related behavior in natural reward and addiction-related behavioral procedures. Frustration is defined as when a subject is unable to achieve a reinforcer, receives less of a reinforcer than anticipated, or has to work harder to achieve a reinforcer. Results: In these studies, bar-press durations increase when rats are in a state of frustration during self-administration of sucrose, fentanyl, or cocaine. Conclusions: These data also show that average bar-press durations do not correlate with the number of bar presses, meaning that press duration is an independent measurement that represents a behavioral construct distinct from craving, which is typically measured with number of bar presses. Essentially, these results support that bar press durations can be used as a real-time measure of frustration as a 4th major facet of addiction-related behavior, adding to craving, impulsivity, and habit. [ABSTRACT FROM AUTHOR]

The reduction of tau or hyperphosphorylated tau (p-tau) has been proposed as a therapeutic strategy for Alzheimer's disease (AD) and frontotemporal dementia (FTD). Cognitive decline and sleep-wake dysregulation seen in AD and FTD patients are mimicked in transgenic and null-mutation mouse models of tauopathy. Alterations in the reward system are additional symptoms of AD and FTD. However, the role of tau in reward processes is not well understood. The present study aimed to examine reward and reward-motivated cognitive processes in male and female tau knockout (tau−/−) and wild-type mice using progressive ratio and reversal learning tasks. Tau−/− mice were heavier, ate more in the home cage, and reached criterion in operant lever training faster than wild-type mice. Tau−/− mice had a higher breakpoint in progressive ratio but were unimpaired in reversal learning or reward sensitivity. These data indicate that tau loss of function alters reward processing. This may help to explain aberrant reward-related behaviors in tauopathy patients and highlights a potentially important area for consideration in the development of anti-tau therapies. • Reward motivation and cognitive flexibility were assessed in tau knockout mice. • Increased body weight in tau knockout mice was associated with elevated food intake. • Tau null mutation increased reward motivation in mice, but not reward sensitivity. • Tau knockout mice were unimpaired in a reversal learning task. • Tau has an important role in reward motivation. [ABSTRACT FROM AUTHOR]

The imprinted genes Grb10 and Nesp influence impulsive behavior on a delay discounting task in an opposite manner. A recently developed theory suggests that this pattern of behavior may be representative of predicted effects of imprinted genes on tolerance to risk. Here we examine whether mice lacking paternal expression of Grb10 show abnormal behavior across a number of measures indicative of risk‐taking. Although Grb10+/p mice show no difference from wild type (WT) littermates in their willingness to explore a novel environment, their behavior on an explicit test of risk‐taking, namely the Predator Odor Risk‐Taking task, is indicative of an increased willingness to take risks. Follow‐up tests suggest that this risk‐taking is not simply because of a general decrease in fear, or a general increase in motivation for a food reward, but reflects a change in the trade‐off between cost and reward. These data, coupled with previous work on the impulsive behavior of Grb10+/p mice in the delayed reinforcement task, and taken together with our work on mice lacking maternal Nesp, suggest that maternally and paternally expressed imprinted genes oppositely influence risk‐taking behavior as predicted. [ABSTRACT FROM AUTHOR]

Rationale and objectives: Although clozapine is effective in treating schizophrenia, it is associated with adverse side effects including weight gain and metabolic syndrome. Despite this, the role of clozapine on feeding behaviour and food intake has not been thoroughly characterised. Clozapine has a broad pharmacological profile, with affinities for several neurotransmitter receptors, including serotonin (5-hydroxytriptamine, 5-HT) and histamine. Given that the serotonin 5-HT2C receptor and histaminergic H1 receptor are involved in aspects of feeding behaviour, the effect of clozapine on feeding may be linked to its action at these receptors. Methods: We assessed, in rats, the effect of acute and subchronic administration of clozapine on responding for food under a progressive ratio (PR) schedule under conditions of food restriction and satiety. We also examined the effect of antagonists of the serotonin 5-HT2C and histaminergic H1 receptors on the same schedule. Clozapine reliably increased responding for food, even when rats had ad libitum access to food. The effect of clozapine on responding for food was reproduced by combined (but not individual) antagonism of the serotonin 5-HT2C and histaminergic H1 receptors. Conclusion: These findings show that clozapine enhances the motivation to work for food, that this effect is stable over repeated testing, and is independent of hunger state of the animal. This effect may relate to a combined action of clozapine at the serotonin 5-HT2C and histaminergic H1 receptors. [ABSTRACT FROM AUTHOR]

Here we present a novel effort-based task for laboratory rats: the weight lifting task (WLT). Studies of effort expenditure in rodents have typically involved climbing barriers within T-mazes or operant lever pressing paradigms. These task designs have been successful for neuropharmacological and neurophysiological investigations, but both tasks involve simple action patterns. High climbing barriers may also present risk of injury to animals and/or issues with tethered recording equipment. In the WLT, a rat is placed in a large rectangular arena and tasked with pulling a rope 30 cm to trigger food delivery at a nearby spout; weights can be added to the rope in 45 g increments to increase the intensity of effort. As compared to lever pressing and barrier jumping, 30 cm of rope pulling is a multi-step action sequence requiring sustained effort. The actions are carried out on the single plane of the arena floor, making it safer for the animal and more suitable for tethered equipment and video tracking. A microcontroller and associated sensors enable precise timestamping of specific behaviors to synchronize with electrophysiological recordings. The rope and reward spout are spatially segregated to allow for spatial discrimination of the effort zone and the reward zone. We validated the task across five cohorts of rats (total n = 35) and report consistent behavioral metrics. The WLT is well-suited for neuropharmacological and/or in vivo neurophysiological investigations surrounding effortful behaviors, particularly when wanting to probe different aspects of effort expenditure (intensity vs. duration).

Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions.

Here we present a novel effort-based task for laboratory rats: the weight lifting task (WLT). Studies of effort expenditure in rodents have typically involved climbing barriers within T-mazes or operant lever pressing paradigms. These task designs have been successful for neuropharmacological and neurophysiological investigations, but both tasks involve simple action patterns. High climbing barriers may also present risk of injury to animals and/or issues with tethered recording equipment. In the WLT, a rat is placed in a large rectangular arena and tasked with pulling a rope 30 cm to trigger food delivery at a nearby spout; weights can be added to the rope in 45 g increments to increase the intensity of effort. As compared to lever pressing and barrier jumping, 30 cm of rope pulling is a multi-step action sequence requiring sustained effort. The actions are carried out on the single plane of the arena floor, making it safer for the animal and more suitable for tethered equipment and video tracking. A microcontroller and associated sensors enable precise timestamping of specific behaviors to synchronize with electrophysiological recordings. The rope and reward spout are spatially segregated to allow for spatial discrimination of the effort zone and the reward zone. We validated the task across five cohorts of rats (total n = 35) and report consistent behavioral metrics. The WLT is well-suited for neuropharmacological and/or in vivo neurophysiological investigations surrounding effortful behaviors, particularly when wanting to probe different aspects of effort expenditure (intensity vs. duration). [ABSTRACT FROM AUTHOR]

Apathy is pervasive across many neuropsychiatric disorders but is poorly characterized mechanistically, so targeted therapeutic interventions remain elusive. A key impediment has been the lack of validated assessment tools to facilitate translation of promising findings between preclinical disease models and patients. Apathy is a common symptom in Huntington's disease. Due to its established genetic basis and the availability of defined animal models, this disease offers a robust translational framework for linking motivated behavior with underlying neurobiology and an ideal context in which to evaluate a quantitative, translational apathy assessment method. In this study we therefore aimed to demonstrate the validity of using touchscreen-delivered progressive ratio tasks to mirror apathy assessment in Huntington's disease patients and a representative mouse model. To do this we evaluated Huntington's disease patients (n = 23) and age-matched healthy controls (n = 20), and male R6/1 mice (n = 23) and wildtype controls (n = 29) for apathy-like behavior using touchscreen-delivered progressive ratio tasks. The primary outcome measure of the assessment was breakpoint, defined as the highest number of touchscreen responses emitted before task engagement ceased. Patients and R6/1 mice were both found to exhibit significantly reduced breakpoints relative to their respective control groups, consistent with apathy-like behavior. This performance was also not associated with motoric differences in either species. These data demonstrate the utility of touchscreen-delivered progressive ratio tasks in detecting clinically relevant motivational deficits in Huntington's disease. This approach may offer a platform from which clinically relevant mechanistic insights concerning motivation symptoms can be derived and provide an effective route for translation of promising preclinical findings into viable therapeutic interventions. [ABSTRACT FROM AUTHOR]

In rats, continuous cocaine access during long self-administration sessions (6 versus 1-2 hours) promotes the development of behavioral symptoms of addiction. This has led to the assumption that taking large amounts of drug during extended daily bouts is necessary to develop an addiction phenotype. Recent work shows that within-session intermittent access (IntA) to cocaine produces much less drug intake than continuous-access procedures (i.e. long-access sessions) but evokes addiction symptoms more effectively. IntA-sessions are also long, typically lasting 6 hours. It is not known whether IntA-sessions must be extended to promote addiction-relevant changes in drug use over time. Here, we determined the influence of IntA-session length on patterns of cocaine use relevant to addiction. Two groups of male Wistar rats self-administered cocaine (0.25 mg/kg/injection, injected over 5 seconds) during 18 daily IntA-sessions. One group had long 6-hour sessions (Long-IntA), the other group had shorter, 2-hour sessions (Short-IntA). Only Long-IntA rats escalated their cocaine intake over sessions, but both groups developed a burst-like pattern of drug use over time and similar levels of psychomotor sensitization. The two groups also showed robust and similar levels of both responding for cocaine under a progressive ratio schedule of reinforcement and cocaine-induced reinstatement of extinguished drug-seeking behavior. In summary, long IntA-sessions lead to greater cocaine intake than shorter IntA-sessions, but the two conditions are equally effective in evoking the patterns of drug-taking and drug-seeking that define addiction. This suggests that chronic intermittent cocaine use, even during short daily bouts, is sufficient to promote addiction symptoms. [ABSTRACT FROM AUTHOR]

Abstract Deficits in cognition and motivation are common and debilitating aspects of psychiatric disorders, yet still go largely untreated. The neuropeptide oxytocin (OT) is a potential novel therapeutic for deficits in social cognition and motivation in psychiatric patients. However, the effects of OT on clinically relevant domains of non-social cognition and motivation remain under studied. The present study investigated the effects of acute and chronic (21-day) administration of subcutaneous OT (0.04, 0.2, and 1 mg/kg) in cross-species translatable operant paradigms of reward learning and effortful motivation in male and female Brown Norway (BN) rats (n = 8–10/group). Reward learning was assessed using the probabilistic reversal learning task (PRLT) and effortful motivation was measured using the progressive ratio breakpoint task (PRBT). As predicted, BN rats exhibited baseline deficits in the detection of reversals of reward contingency in the PRLT relative to Long Evans (LE) rats. The two strains performed equally in the PRBT. Thirty minutes after a single OT injection (1 mg/kg), measures of both initial probabilistic learning (trials to first criterion) and subsequent reversal learning (contingency switches) were significantly improved to levels comparable with LE rats. The OT effect on switches persisted in male, but not female, BN rats 30 min, 24 h, and 6 days after long-term OT administration, suggesting the induction of neuroplastic changes. OT did not affect effortful motivation at any time-point. The beneficial effects of OT on reward learning in the absence of increased effortful motivation support the development of OT as a novel therapeutic to improve cognitive functioning. Graphical abstract Image 1 Highlights • Rats received daily OT for 21 days and tested in a reward learning task (PRLT). • Rats also assessed in a effortful motivation task (PRBT). • OT improved PRLT performance in males throughout testing. • Only acute OT improved PRLT in females. • Neither acute nor chronic OT had any significant effect on PRBT. [ABSTRACT FROM AUTHOR]

Abstract Sigma-1 (σ 1) receptors have been investigated for their involvement in learning, rewarding and motivational processes, particularly as it relates to substances of abuse. Few studies have examined the effects of σ 1 receptor agonists and antagonists on the rewarding and motivational properties of natural reinforcers, such as food. Studies that have investigated σ 1 receptor agonists and antagonists has produced conflicting results. σ 1 receptor antagonist PD144418 has been found to produce a dose-dependent attenuation of locomotor activity induced by cocaine, and by itself, does not suppress basal locomotor activity in mice. However, its effects on reward and motivation as it relates to food are unknown. The present study examined the involvement of σ 1 receptors in mediating the rewarding and motivational properties of food using an operant task. The results indicated that at the highest dose (10 μmol/kg), PD144418 significantly attenuated the number of active lever responses for chow pellets but did not decrease the number of active lever responses for sucrose pellets under a fixed ratio (FR2) schedule of reinforcement. However, under a progressive ratio (PR) reinforcement schedule, 10 μmol/kg of PD14418 significantly reduced the breakpoint, a measure indicative of effort or motivation, for both chow and sucrose pellets. When ad libitum chow or sucrose pellets were made freely available (i.e. no lever press required) inside the operant chamber, 10 μmol/kg, PD144418 did not have an effect on number of pellets consumed. These findings indicate that PD144418 reduces the motivational effort of a food reinforced behavior. [ABSTRACT FROM AUTHOR]

Highlights • Study one found an interaction between impulsivity and fatigue predicting points earned on a progressive ratio task. • Study two was a replication study which was pre-registered and well-powered. It had null findings. • Taken together, the results of study one seem to be a type I error. • Study two found no interaction between impulsivity and fatigue predicting points earned on a progressive ratio task. Abstract This manuscript consists of a study and a direct replication of it examining the interactive effect of self-regulatory depletion and impulsivity on points earned in a progressive ratio task. In study 1 (n = 238), participants first completed a measure of delay discounting. Next, they underwent depletion exercises or control exercises. Finally, they completed a progressive ratio task in which they were able to earn points. Non-depleted people performed the same on this task regardless of their level of impulsivity. However, for depleted people, impulsive people earned the most points. This study suggested that when depleted, people prone to instant gratification will work harder than their less impulsive counterparts to earn rewards. To examine the reliability of these findings, we then did a high-powered, direct replication of this study (n = 782). In the replication, we found null results. This pre-registered, well-powered study suggests the findings of study one were a type I error. The findings of study 2 suggest no effect of self-regulatory attention on tasks related to earning points. [ABSTRACT FROM AUTHOR]

Abstract Feeding behaviors can be modified via homeostatic and hedonic mechanisms. Homeostasis, while primarily concerned with maintaining energy balance via food consumption and energy expenditure, can alter food reward and motivation in response to food deprivation. Alternatively, reward and motivation of food is also driven by its palatability or hedonic nature, and this process can be augmented by opioid receptor activation. The present study examined sex differences in the motivational properties of sucrose pellets through manipulation of homeostatic and hedonic processes via acute food deprivation and acute systemic administration of morphine, respectively. The results showed that regardless of sex, systemic injections of morphine did not alter the motivation to obtain a sucrose pellet on a progressive ratio schedule of reinforcement but does significantly increase consumption of sucrose pellets when freely available. Male and female rats demonstrated similar increased consumption of sucrose pellets under free feeding conditions following acute (24-hours) food deprivation, compared to the non-deprived conditions. Overall, the findings from these experiments indicate that female rats work harder in order to obtain a sucrose pellet (under a Progressive Ratio (PR) schedule of reinforcement) and consume more sucrose pellets than males. However, while acute morphine administration causes similar increases on feeding in males and females, it does not alter motivation as measured by breakpoint on a PR schedule of reinforcement. [ABSTRACT FROM AUTHOR]

Highlights • Perinatal anesthesia exposure altered performance on a progressive ratio responding task. • Perinatal anesthesia may have altered motivation or motor control in the non-human primate. • Early life anesthesia exposure may result in cognitive problems later in life. Abstract Despite the widespread use of general anesthesia, a growing body of research suggests that anesthesia exposure early in life may be associated with acute neurotoxicity and lasting behavioral changes. To better evaluate the risk posed by early life anesthesia on cognitive development, infant rhesus monkeys were exposed to an anesthesia regimen previously shown to be neurotoxic and their cognitive development was subsequently measured using a translational operant test battery. On postnatal day 5 or 6, animals were exposed to 8 h of isoflurane (n = 6, 1% isoflurane in a vehicle gas of 70% nitrous oxide and 30% oxygen) or a control condition (n = 8). Starting at 7 months of age, the monkeys were continuously trained and assessed on the NCTR Operant Test Battery (OTB). The OTB consists of cognitive tests which also exist in near identical forms for use in rats and humans, and includes tests of learning, memory, color discrimination, and motivation. Monkeys previously exposed to anesthesia showed a clear decrease in responding in a measure of motivation, as well as a lower response rate in a learning task. These data further support the hypothesis that prolonged anesthesia early in life may increase the risk of developing cognitive impairments later in life. [ABSTRACT FROM AUTHOR]

Background: Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. A case report has demonstrated that a ketamine addict experienced a significant reduction in craving and ketamine use after taking lamotrigine. The present study determined whether lamotrigine can reduce the motivation for ketamine and prevent the relapse to ketamine seeking behavior in rats.Methods: Male Sprague-Dawley rats were trained to respond for intravenous ketamine (0.5 mg/kg/infusion) self-administration or food pellets. The effects of lamotrigine on the motivation for ketamine or food were assessed using breakpoint test under a progressive ratio (PR) paradigm. Furthermore, the effects of lamotrigine on reinstatement of ketamine-seeking and food-seeking behaviors were examined after extinction.Results: Lamotrigine significantly decreased the breakpoint for ketamine and prevented cue- and ketamine priming-induced reinstatement of ketamine seeking behavior. However, lamotrigine did not affect the breakpoint for food reinforcement, cue-induced reinstatement of food-seeking behavior, or spontaneous locomotor activity.Conclusions: Our data reveal that lamotrigine is capable of attenuating the reinforcing efficacy of ketamine and reducing ketamine craving and relapse risk, which lays the foundation for conducting clinical trials in patients with ketamine use disorder. [ABSTRACT FROM AUTHOR]

Cognitive disturbances often predate characteristic motor dysfunction in individuals with Huntington’s disease (HD) and place an increasing burden on the HD patients and caregivers with the progression of the disorder. Therefore, application of maximally translational cognitive tests to animal models of HD is imperative for the development of treatments that could alleviate cognitive decline in human patients. Here, we examined the performance of the Q175 mouse knock-in model of HD in the touch screen version of the paired associates learning (PAL) task. We found that 10–11-month-old heterozygous Q175 mice had severely attenuated learning curve in the PAL task, which was conceptually similar to previously documented impaired performance of individuals with HD in the PAL task of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Besides high rate of errors in PAL task, Q175 mice exhibited considerably lower responding rate than age-matched wild-type (WT) animals. Our examination of effortful operant responding during fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in a separate cohort of similar age confirmed slower and unselective performance of mutant animals, as observed during PAL task, but suggested that motivation to work for nutritional reward in the touch screen setting was similar in Q175 and WT mice. We also demonstrated that pronounced sensorimotor disturbances in Q175 mice can be detected at early touch screen testing stages, (e.g., during “Punish Incorrect” phase of operant pretraining), so we propose that shorter test routines may be utilised for more expedient studies of treatments aimed at the rescue of HD-related phenotype.

Environmental conditioning factors have a profound impact on alcohol-seeking behavior and the maintenance of alcohol use in individuals with alcohol dependence. Cues associated with alcohol, depending on the perceived value of the primary reinforcer, gain salience and can trigger relapse. This study investigates the correlation between the reward magnitude of the primary reinforcer and the reinstatement evoked by cues predictive of their availability in male rats. Rat self-administration procedures were used to test reinstatement, with reinforcers consisting of 10% alcohol, 10% sucrose, or 2% sodium chloride (NaCl) experienced under need-state conditions. The effect of MTEP ([(2-methyl-1,3-thiazol-4-yl) ethynyl] pyridine), a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, on motivation and reinstatement behaviors was also evaluated. RESULTS: demonstrate that under Fixed Ratio 1 (FR1) schedule, the three reinforcers maintain operant responding with the following order of magnitude 10% sucrose >2% NaCl >10% alcohol > water. Under a progressive ratio (PR) schedule of reinforcement, rats exhibit a significantly higher breakpoint for 2% NaCl (under Na-depletion), followed by 10% sucrose and 10% alcohol. After extinction, a significant reinstatement is observed with the magnitude order of 10% sucrose >10% alcohol >2% NaCl. However, only re-exposure to alcohol-paired cues induced significant reinstatement of alcohol-seeking after 4 and 8 months. Treatment with MTEP significantly reduces reinstatement of responding across all reinforcers, with the strongest effect observed on alcohol-seeking. These findings suggest that mGluR5 plays a general role in controlling cue-reactivity, but the effect is prominent in the case of alcohol compared to natural rewards. In conclusion, the results demonstrate a remarkable dissociation between the rewarding magnitude of the primary reinforcer and its ability to trigger relapse upon presentation of a cue previously associated with it. Importantly, alcohol, despite having lower intrinsic motivational value compared to a natural reward (sucrose) or a consummatory stimulus experienced under need state conditions (NaCl), can elicit more robust and longer-term reinstatement of seeking responses. Finally, our data demonstrate a significant involvement of the mGluR5 system in the regulation of seeking behavior., Competing Interests: Declaration of competing interest This work was supported by grant R01AA014351 (to RC and FW), R01AA017447 (to RC and MR) and by the TRDRP -T31KT1859 (to MK)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abstract Aims The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. Methods Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. Results LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. Conclusions The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs. [ABSTRACT FROM AUTHOR]

Highlights • Developmental exposure to low concentration CAPS male-specific cognitive impairments. • Learning impairments in males emerged when rules of reward changed. • Male impairments did not appear to be attributable to non-cognitive behavioral changes. • Low level CAPS produced alterations in motivation-based behaviors in females. • Females did not show impairments in cognitive performance. Abstract Developmental exposures to ambient ultrafine particles (UFPs) can produce multiple neuropathological and neurochemical changes that might contribute to persistent alterations in cognitive-type functions. The objective of the current study was to test the hypothesis that developmental UFP exposure produced impairments in learning, memory and impulsive-like behaviors and to determine whether these were selective and thus independent of deficits in other behavioral domains such as motor activity or motivation. Performance on measures of learning (repeated learning), memory (novel object recognition, NOR), impulsive-like behavior (differential reinforcement of low rate (DRL), schedule of reward and delay of reward (DOR)), motor activity (locomotor behavior) and motivation (progressive ratio schedule) were examined in adult mice that had been exposed to concentrated (10–20x) ambient ultrafine particles (CAPS) averaging approximately 45 ug/m3 particle mass concentrations from postnatal day (PND) 4–7 and 10–13 for 4 h/day. Given the number of behavioral tests, animals were tested in different groups. Results showed male-specific alterations in learning and memory functions (repeated learning, NOR and DRL) specifically during transitions in reinforcement contingencies (changes in rules governing behavior) that did not appear to be related to alterations in locomotor function or motivation. Females did not exhibit cognitive-like deficits at these exposure concentrations, but displayed behaviors consistent with altered motivation, including increases in response rates during repeated learning, significantly increased latencies to respond on the delay of reward paradigm, and reductions in the progressive ratio break point. Consistent with our prior findings, male-specific learning and memory-related deficits were seen and occurred even at relatively low level developmental UFP exposures, while females show alterations in motivational behaviors but not final performance. These findings add to the evidence suggesting the need to regulate UFP levels. [ABSTRACT FROM AUTHOR]

Highlights • A multiple stimulus assessment identified food preferences in rhesus macaques. • The consistency of food preferences across subjects and time was variable. • Using preferred foods increased engagement during husbandry training sessions. • Using preferred foods increased performance in a progressive ratio task. Abstract The use of systematic preference assessments can enhance positive reinforcement training with captive animals. We found that the multiple stimulus without replacement (MSWO) technique identified food preferences in laboratory housed rhesus macaques, with raisins and grapes being ranked higher on average than dried apricot, pasta, and green beans (Friedman Test, χ2 (4) = 35.52, p <.001). Agreement between individuals (N = 21) was moderate (Kendall's W = 0.42), and consistency across time varied among individuals (W =.03–.90). Highly preferred items identified by the MSWO assessment were subsequently found to increase subjects' engagement in a husbandry task on which they were being trained (Mann-Whitney U = 6.00, p =.002) and to improve performance on a progressive ratio schedule (Wilcoxon signed-rank test, Z = −2.17, p =.03) when compared with low preference items. The progressive ratio technique supplements other preference assessment techniques by measuring the amount of work a subject will do to gain access to an item. The use of more effective reinforcers identified through systematic assessment has the potential to increase animal performance on husbandry and research tasks and to improve animal welfare in the laboratory setting. [ABSTRACT FROM AUTHOR]

Goal‐directed motivated behaviour is crucial for everyday life. Such behaviour is often measured, in rodents, under a progressive ratio (PR) schedule of reinforcement. Previous studies have identified a few brain structures critical for supporting PR performance. However, the association between neural activity within these regions and individual differences in effort‐related behaviour is not known. Presently, we used constant potential in vivo oxygen amperometry, a surrogate for functional resonance imaging in rodents, to assess changes in tissue oxygen levels within the nucleus accumbens (NAc) and orbitofrontal cortex (OFC) in male Wistar rats performing a PR task. Within both regions, oxygen responses to rewards increased as the effort exerted to obtain the rewards was larger. Furthermore, higher individual breakpoints were associated with greater magnitude NAc oxygen responses. This association could not be explained by temporal confounds and remained significant when controlling for the different number of completed trials. Animals with higher breakpoints also showed greater magnitude NAc oxygen responses to rewards delivered independently of any behaviour. In contrast, OFC oxygen responses were not associated with individual differences in behavioural performance. The present results suggest that greater NAc oxygen responses following rewards, through a process of incentive motivation, may allow organisms to remain on task for longer and to overcome greater effort costs. Using a highly translatable measure of neural activity, we found an association between nucleus accumbens oxygen responses and effort exertion for food rewards. High responding rats, which displayed higher progressive ratio performance, showed significantly greater magnitude oxygen responses to rewards. This work highlights how variations in NAc activity may underlie individual differences in motivated behaviour. [ABSTRACT FROM AUTHOR]

Resurgence is defined as the recurrence of a previously reinforced and then extinguished target response when reducing or eliminating a more recently reinforced alternative response. In experiments with children and pigeons, we evaluated patterns of resurgence across and within sessions through decreases in reinforcer availability by challenging alternative responding with extinction and progressive‐ratio schedules. In Phase 1, we reinforced only target responding. In Phase 2, we extinguished target responding while reinforcing an alternative response. Finally, Phase 3 assessed resurgence by (a) extinguishing alternative responding versus (b) introducing a progressive‐ratio schedule of reinforcement for alternative responding. In both children and pigeons, resurgence of target responding occurred in both conditions but generally was greater when assessed during extinction than with progressive ratios. Importantly, within‐session patterns of resurgence did not differ between testing with progressive ratios and extinction. Resurgence with progressive ratios tended to be greater with longer durations between reinforcers but we observed similar findings with only simulated reinforcers during extinction testing. Therefore, the present investigation reveals that the events contributing to instances of resurgence remain to be understood, and presents an approach from which to examine variables influencing within‐session patterns of resurgence. [ABSTRACT FROM AUTHOR]

Background: Stimulant drugs such as nicotine (NIC) and methylphenidate (MPH) are hypothesized to increase the reinforcing value of sensory stimuli, thus increasing the effectiveness of such reinforcers as alternatives to sucrose reinforcers.Methods: Inbred Fischer-344 rats (n = 30) were assigned to three groups: saline (SAL; n = 10), nicotine (NIC; n = 10), or methylphenidate (MPH; n = 10). Testing was done in three phases: sucrose only, (SUC), sucrose and drug (SUC/DRUG), and sucrose, drug, and social reinforcement (SUC/DRUG/SOC). During the SUC phase, rats were trained on a progressive ratio 5 (PR5) reinforcement schedule for sucrose (20% solution). In the SUC/DRUG phase, animals were treated with SAL, NIC (0.4 mg/kg, n = 10 SC), or MPH (2.0 mg/kg, n = 10 IP) 30 min prior to testing. In the SUC/DRUG/SOC phase, animals continued receiving drug treatment, and social reinforcement was introduced concurrently with the sucrose reinforcer. The progressive ratio for each reinforcer ran independently of the others. Reinforcing value was measured as break point (BP), the highest number of responses resulting in a reinforcer.Results: SAL-treated animals showed no significant change in sucrose BP. MPH-treated animals showed decreased sucrose BP in the SUC/DRUG phase, with a further reduction in the SUC/DRUG/SOC phase. NIC-treated animals decreased sucrose BP only when a social alternative was offered.Conclusion: Both NIC and MPH reduce the sucrose BP in the presence of a social alternative. The decrease in sucrose responding, coupled with increased social responding, suggests that the social alternative acted as an effective alternative reinforcer to sucrose. From a translational perspective, these results suggest that stimulant drugs such as NIC and MPH may increase the effectiveness of treatments that use alternative social reinforcers to decrease eating. [ABSTRACT FROM AUTHOR]

Operant behavior tasks are widely used in neuroscience research, but little is known about how variables such as housing and testing conditions affect rodent operant performance. We have previously observed differences in operant performance in male and female mice depending on whether mice were housed and tested in rooms containing only one sex versus rooms containing both sexes. Here, male and female mice in either single-sex or mixed sex housing rooms were trained on fixed ratio 1 (FR1) and progressive ratio (PR) tasks. For both sexes, animals in the mixed sex room had more accurate performance in FR1 and were more motivated in the PR task. We then moved the single sex housed animals to the mixed sex room and vice versa. Animals that started in mixed sex housing had no change to PR, but both sexes who started in single sex housing were more motivated after the switch. Additionally, the females that moved into single-sex housing performed less accurately in FR1. We conclude that housing and testing conditions can affect performance on FR1 and PR tasks. As these tasks are commonly used as training steps to more complex tasks, housing and testing conditions should be carefully considered during experiment design and reported in publications. [ABSTRACT FROM AUTHOR]

Mesolimbic dopamine perturbations modulate performance of reward-seeking behavior, with tasks requiring high effort being especially vulnerable to disruption of dopamine signaling. Previous work primarily investigated long-term perturbations such as receptor antagonism and dopamine depletion, which constrain the ability to assess dopamine contributions to effort expenditure in isolation from other behavior events, such as reward consumption. Also unclear is if dopamine is required for both initiation and maintenance when a sequence of multiple instrumental responses is required. Here we used optogenetic inhibition of midbrain TH+  neurons to probe the role of dopamine neuron activity during instrumental responding for reward by varying the time epoch of neural inhibition relative to the time of response initiation. Within a fixed-ratio procedure, requiring eight nosepoke responses per reinforcer delivery, or a progressive ratio (PR) procedure, in which within-session response requirements increased exponentially, inhibiting dopamine neurons while mice were engaged in response bouts decreased the probability of continued responding. If inhibition occurred during each attempted bout, the effect was to decrease total responses, and thus amount of rewards earned, over a session. In contrast, if inhibition was applied only during some bouts, mice increased the number of bouts initiated to earn control levels of reward. Inhibiting dopamine neurons while mice were not responding decreased the probability of initiating an instrumental response but had no effect on the amount of effort exerted over the entire session. We conclude that midbrain dopamine signaling promotes initiation of instrumental responding and maintains motivation to continue ongoing bouts of effortful responses. [ABSTRACT FROM AUTHOR]