Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

Modeling motivation for alcohol in humans using traditional and machine learning approaches.

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.

Chronic opioid exposure differentially modulates oxycodone self-administration in male and female rats.

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.

Central but not peripheral oxytocin administration reduces risk-based decision-making in male rats.

The hormone oxytocin has long been associated with social behaviors, but recent evidence suggests that it may also affect reward processing in non-social contexts. Decisions are an integral component of many social and reward-based behavioral paradigms. Thus, a broad role for oxytocin in decision-making may explain the wide variety of effects that have been previously observed and resolve controversies in the literature about its role. To determine if oxytocin can selectively modulate decision-making in male rats, we assessed the dose-dependent effects of central (intracerebroventricular) or peripheral (intraperitoneal) administration of oxytocin on probability and delay discounting, two commonly used decision-making tasks that are free of social contexts. Our results showed that central administration of oxytocin dose-dependently reduced preference for risky outcomes in the probability discounting task, but had no impact on delay discounting or reward sensitivity. This effect was blocked by the co-administration of an oxytocin antagonist. Additionally, we found no effect of peripheral oxytocin administration on any task. To identify potential cognitive mechanisms of central oxytocin's effect on decision-making, we determined if central or peripheral oxytocin affects reward sensitivity using an intracranial self-stimulation task, and motivation using a progressive ratio task. These results showed that at the dosage that affects decision-making, central oxytocin had a mild and short-lasting effect on motivation, but no observable effect on reward sensitivity. This pattern of results suggests that oxytocin may selectively reduce risky decisions in male rats, even at dosages that have no major effects on reward processing and motivation. These findings highlight a potentially novel role for oxytocin in non-social cognitive processes and expand our understanding of the mechanism by which oxytocin may regulate social behavior.

Sex differences in cocaine self-administration behaviour under long access versus intermittent access conditions.

Studies in humans suggest that women progress more rapidly from initial cocaine use to addiction. Similarly, female rats can show more incentive motivation for cocaine than male rats do. Most preclinical studies on this issue have used self-administration procedures that provide continuous cocaine access during each session ("long-access" or LgA and "short-access"). However, intermittent access (IntA) cocaine self-administration better models the intermittency of human cocaine use. Here, we compared cocaine use in female and male rats that received ten, daily 6-hour LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. Only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine, and sensitization was greatest in females. Five and 25 days after the last self-administration session, we quantified responding for cocaine (0.083-0.75 mg/kg/infusion) under a progressive ratio (PR) schedule, a measure of motivation for drug. Across conditions, females earned more cocaine infusions than males under the PR schedule. Across sexes, IntA rats earned more infusions than LgA rats, even though IntA rats had previously taken much less cocaine. Cumulative cocaine intake significantly predicted responding for cocaine under the PR schedule in male LgA rats only. In IntA rats, the extent of locomotor sensitization significantly predicted responding under the PR schedule. Thus, LgA might be appropriate to study sex differences in cocaine intake, whereas IntA might be best suited to study sex differences in sensitization-related neuroadaptations involved in cocaine addiction. This has implications for modelling distinct features of cocaine addiction in preclinical studies.

Revisiting long-access versus short-access cocaine self-administration in rats: intermittent intake promotes addiction symptoms independent of session length.

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.

Motivation to run measured by progressive ratio tests: Failure to support the addiction hypothesis for rats.

When laboratory rats are given repeated access to an activity wheel, the amount that they run steadily increases. This suggests an analogy with drug dependency in animals and humans, in that this is marked by both increasing intakes of the drug and increasing motivation to obtain the drug (craving). This analogy was examined by measuring motivation to obtain an opportunity to run using a progressive ratio (PR) schedule, whereby the number of lever presses required to release a brake on an activity wheel was increased progressively. Each of two experiments included two groups of rats that differed in running experience. In Experiment 1, both groups were given 17 wheel-running sessions before they were given the PR test, with sessions for the short group lasting only 30 min, while those for the long group lasted 4.5 hrs. In Experiment 2, both groups were given 3-hr wheel sessions, with the short group given only four such sessions and the medium groups given 12 such sessions prior to their PR test. In both experiments, the PR tests revealed that motivation to run was greater when the rats had not had an opportunity to run for at least 24 hrs prior to the test than when they had run the previous day. However, neither experiment produced evidence that motivation to run increased with the amount of previous running. Given only limited support for the analogy between running and drug addiction, steady increases in running may instead reflect circadian adaptation and/or increases in fitness.

Oxygen responses within the nucleus accumbens are associated with individual differences in effort exertion in rats.

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.

Housing and testing in mixed-sex rooms increases motivation and accuracy during operant testing in both male and female mice.

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.

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease.

UNLABELLED: Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood. We therefore tested whether altered NAc dopamine release accompanies motivational deficits in the Q175 knock-in HD mouse model. Q175 mice express a CAG expansion of the human mutant huntingtin allele in the native mouse genome and gradually manifest symptoms late in life, closely mimicking the genotypic context and disease progression in human HD. Sub-second extracellular dopamine release dynamics were monitored using fast-scan cyclic voltammetry, whereas motivation was assessed using a progressive ratio reinforcement schedule. As the response ratio (lever presses per reward) escalated, Q175 mice exerted less effort to earn fewer rewards versus wild-type (WT). Moreover, dopamine released at reward delivery dynamically encoded increasing reward cost in WT but not Q175 mice. Deficits were specific to situations of high effortful demand as no difference was observed in locomotion, free feeding, hedonic processing, or reward seeking when the response requirement was low. This compromised dopaminergic encoding of reward delivery coincident with suppressed motivation to work for reward in Q175 mice provides novel, neurobiological insight into an established and clinically relevant endophenotype of prodromal HD. SIGNIFICANCE STATEMENT: Psychiatric impairments in Huntington's disease (HD) typically manifest early in disease progression, before motor deficits. However, the neurobiological factors contributing to psychiatric symptoms are poorly understood. We used a mouse HD model and assessed whether impaired dopamine release in the nucleus accumbens (NAc), a brain region critical to goal-directed behaviors, accompanies motivational deficits, one of the most common early HD symptoms. HD mice exhibited blunted motivation to work for food reward coincident with diminished dopamine release to reward receipt. Motivational and NAc dopaminergic deficits were not associated with gross motor deficits or impaired food seeking when effortful demands were low. This work identifies a specific prodromal HD phenotype associated with a prominent and previously unidentified neurobiological impairment.

The Medial Orbitofrontal Cortex Regulates Sensitivity to Outcome Value.

An essential component of goal-directed decision-making is the ability to maintain flexible responding based on the value of a given reward, or "reinforcer." The medial orbitofrontal cortex (mOFC), a subregion of the ventromedial prefrontal cortex, is uniquely positioned to regulate this process. We trained mice to nose poke for food reinforcers and then stimulated this region using CaMKII-driven Gs-coupled designer receptors exclusively activated by designer drugs (DREADDs). In other mice, we silenced the neuroplasticity-associated neurotrophin brain-derived neurotrophic factor (BDNF). Activation of Gs-DREADDs increased behavioral sensitivity to reinforcer devaluation, whereas Bdnf knockdown blocked sensitivity. These changes were accompanied by modifications in breakpoint ratios in a progressive ratio task, and they were recapitulated in Bdnf(+/-)mice. Replacement of BDNF selectively in the mOFC in Bdnf(+/-)mice rescued behavioral deficiencies, as well as phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2). Thus, BDNF expression in the mOFC is both necessary and sufficient for the expression of typical effort allocation relative to an anticipated reinforcer. Additional experiments indicated that expression of the immediate-early gene c-fos was aberrantly elevated in the Bdnf(+/-)dorsal striatum, and BDNF replacement in the mOFC normalized expression. Also, systemic administration of an MAP kinase kinase inhibitor increased breakpoint ratios, whereas the addition of discrete cues bridging the response-outcome contingency rescued breakpoints in Bdnf(+/-)mice. We argue that BDNF-ERK1/2 in the mOFC is a key regulator of "online" goal-directed action selection. SIGNIFICANCE STATEMENT: Goal-directed response selection often involves predicting the consequences of one's actions and the value of potential payoffs. Lesions or chemogenetic inactivation of the medial orbitofrontal cortex (mOFC) in rats induces failures in retrieving outcome identity memories (Bradfield et al., 2015), suggesting that the healthy mOFC serves to access outcome value information when it is not immediately observable and thereby guide goal-directed decision-making. Our findings suggest that the mOFC also bidirectionally regulates effort allocation for a given reward and that expression of the neurotrophin BDNF in the mOFC is both necessary and sufficient for mice to sustain stable representations of reinforcer value.

Basolateral amygdala supports the maintenance of value and effortful choice of a preferred option.

The basolateral amygdala (BLA) is known to be involved in appetitive behavior, yet its role in cost-benefit choice of qualitatively different rewards (more/less preferred), beyond magnitude differences (larger/smaller), is poorly understood. We assessed the effects of BLA inactivations on effortful choice behavior. Rats were implanted with cannulae in BLA and trained to stable lever pressing for sucrose pellets on a progressive ratio schedule. Rats were then introduced to a choice: chow was concurrently available while they could work for the preferred sucrose pellets. Rats were infused with either vehicle control (aCSF) or baclofen/muscimol prior to test. BLA inactivations produced a significant decrease in lever presses for sucrose pellets compared to vehicle, and chow consumption was unaffected. Inactivation had no effect on sucrose pellet preference when both options were freely available. Critically, when lab chow was not concurrently available, BLA inactivations had no effect on the number of lever presses for sucrose pellets, indicating that primary motivation in the absence of choice remains intact with BLA offline. After a test under specific satiety for sucrose pellets, BLA inactivation rendered animals less sensitive to devaluation relative to control. The effects of BLA inactivations in our task are not mediated by decreased appetite, an inability to perform the task, a change in food preference, or decrements in primary motivation. Taken together, BLA supports the specific value and effortful choice of a preferred option.

Anterior cingulate cortex supports effort allocation towards a qualitatively preferred option.

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.

Maternal immune activation alters sensitivity to action-outcome contingency in adult rat offspring.

Epidemiological studies have provided convincing evidence for a role of maternal immune activation in the pathogenesis of neurodevelopmental disorders such as autism and schizophrenia. In recent years, several research groups have capitalised on this discovery and developed animal models such as the maternal immune activation (MIA) model that emulates many phenotypes characteristic of disorders such as schizophrenia. In the present series of experiments we used the MIA model to examine motivation, a core component of the negative symptomatology in schizophrenia. Contrary to what we expected, in the progressive ratio task, which assesses an animals' willingness to work for a reward under increasing effort requirements, we found that MIA rats appeared more motivated than controls. Subsequent tests showed that this seemingly enhanced motivation was not due to an overall increase in responding, nor due to enhanced attribution of incentive salience to reward associated responses. Instead, we found that the increased willingness to work exhibited by MIA animals was due to an inability to detect changes in the contingency between their behaviour and the resulting rewarding outcome. With regard to motivation, the experiments reported here are the first to subject the MIA model to a rigorous experimental analysis of behaviour by parsing underlying processes that give rise to the overt symptoms in psychiatric disease.

Adding a reward increases the reinforcing value of fruit.

Adolescents' snack choices could be altered by increasing the reinforcing value (RV) of healthy snacks compared with unhealthy snacks. This study assessed whether the RV of fruit increased by linking it to a reward and if this increased RV was comparable with the RV of unhealthy snacks alone. Moderation effects of sex, hunger, BMI z-scores and sensitivity to reward were also explored. The RV of snacks was assessed in a sample of 165 adolescents (15·1 (sd 1·5) years, 39·4 % boys and 17·4 % overweight) using a computerised food reinforcement task. Adolescents obtained points for snacks through mouse clicks (responses) following progressive ratio schedules of increasing response requirements. Participants were (computer) randomised to three experimental groups (1:1:1): fruit (n 53), fruit+reward (n 60) or unhealthy snacks (n 69). The RV was evaluated as total number of responses and breakpoint (schedule of terminating food reinforcement task). Multilevel regression analyses (total number of responses) and Cox's proportional hazard regression models (breakpoint) were used. The total number of responses made were not different between fruit+reward and fruit (b -473; 95 % CI -1152, 205, P=0·17) or unhealthy snacks (b410; 95 % CI -222, 1043, P=0·20). The breakpoint was slightly higher for fruit than fruit+reward (HR 1·34; 95 % CI 1·00, 1·79, P=0·050), whereas no difference between unhealthy snacks and fruit+reward (HR 0·86; 95 % CI 0·62, 1·18, P=0·34) was observed. No indication of moderation was found. Offering rewards slightly increases the RV of fruit and may be a promising strategy to increase healthy food choices. Future studies should however, explore if other rewards, could reach larger effect sizes.

Extended nicotine self-administration increases sensitivity to nicotine, motivation to seek nicotine and the reinforcing properties of nicotine-paired cues.

An array of pharmacological and environmental factors influence the development and maintenance of tobacco addiction. The nature of these influences likely changes across the course of an extended smoking history, during which time drug seeking can become involuntary and uncontrolled. The present study used an animal model to examine the factors that drive nicotine-seeking behavior after either brief (10 days) or extended (40 days) self-administration training. In Experiment 1, extended training increased rats' sensitivity to nicotine, indicated by a leftward shift in the dose-response curve, and their motivation to work for nicotine, indicated by an increase in the break point achieved under a progressive ratio schedule. In Experiment 2, extended training imbued the nicotine-paired cue with the capacity to maintain responding to the same high level as nicotine itself. However, Experiment 3 showed that the mechanisms involved in responding for nicotine or a nicotine-paired cue are dissociable, as treatment with the partial nicotine receptor agonist, varenicline, suppressed responding for nicotine but potentiated responding for the nicotine-paired cue. Hence, across extended nicotine self-administration, pharmacological and environmental influences over nicotine seeking increase such that nicotine seeking is controlled by multiple sources, and therefore highly resistant to change.

Optimisation of cognitive performance in rodent operant (touchscreen) testing: Evaluation and effects of reinforcer strength.

Operant testing is a widely used and highly effective method of studying cognition in rodents. Performance on such tasks is sensitive to reinforcer strength. It is therefore advantageous to select effective reinforcers to minimize training times and maximize experimental throughput. To quantitatively investigate the control of behavior by different reinforcers, performance of mice was tested with either strawberry milkshake or a known powerful reinforcer, super saccharin (1.5% or 2% (w/v) saccharin/1.5% (w/v) glucose/water mixture). Mice were tested on fixed (FR)- and progressive-ratio (PR) schedules in the touchscreen-operant testing system. Under an FR schedule, both the rate of responding and number of trials completed were higher in animals responding for strawberry milkshake versus super saccharin. Under a PR schedule, mice were willing to emit similar numbers of responses for strawberry milkshake and super saccharin; however, analysis of the rate of responding revealed a significantly higher rate of responding by animals reinforced with milkshake versus super saccharin. To determine the impact of reinforcer strength on cognitive performance, strawberry milkshake and super saccharin-reinforced animals were compared on a touchscreen visual discrimination task. Animals reinforced by strawberry milkshake were significantly faster to acquire the discrimination than animals reinforced by super saccharin. Taken together, these results suggest that strawberry milkshake is superior to super saccharin for operant behavioral testing and further confirms that the application of response rate analysis to multiple ratio tasks is a highly sensitive method for the detection of behavioral differences relevant to learning and motivation.

Assessment of the motivation to use artificial sweetener among individuals with an eating disorder.

Eating disorders are associated with a range of abnormalities in eating behavior. Some individuals consume large amounts of non-caloric artificial sweeteners, suggesting abnormalities in appetitive responding. The current study aimed to quantify hedonic and motivating effects of artificial sweetener in individuals with and without an eating disorder. Two laboratory studies were conducted. Hedonic preference was estimated using the number of artificial sweetener packets (0-10) added to unsweetened cherry flavored Kool-Aid (study 1). Motivation to obtain sweetener was assessed by a progressive ratio (PR) work task (study 2). Ninety-three participants (25 anorexia nervosa restricting type (AN-R), 23 AN binge/purge type (AN-B/P), 20 bulimia nervosa (BN), and 25 normal controls (NC)) completed the study. No significant difference in hedonic preference was found among participant groups. Work completed at the PR task ranged from 0 to 9500 key-board presses. The AN-B/P group had a significantly higher breakpoint and performed significantly more work for sweetener compared to the BN and NC groups. Among AN-B/P and AN-R participants, the preferred number of Equal packets was significantly correlated with the breakpoint and total work. The increased amount of work for sweetener among individuals with AN-B/P supports an enhanced reward value of sweet taste in this population, and suggests that the characteristic food avoidance in AN cannot be accounted for by decreased reward value of all taste-related stimuli. This study also supports the novel application of a PR ratio task to quantify the motivating effect of sweet taste among individuals with an eating disorder.

Yokukansankachimpihange increased body weight but not food-incentive motivation in wild-type mice.

Yokukansankachimpihange (YKSCH), a traditional Japanese medicine, is widely used for the amelioration of the behavioral and psychological symptoms of dementia with digestive dysfunction. Regardless of its successful use for digestive dysfunction, the effect of YKSCH on body weight was unknown. Furthermore, if YKSCH increased body weight, it might increase motivation according to Kampo medicine theory. Therefore, we investigated whether YKSCH had the potential to increase body weight and enhance motivation in mice. To address this, C57BL/6J mice were used to evaluate the long-term effect of YKSCH on body weight and food-incentive motivation. As part of the evaluation, we optimized an operant test for use over the long-term. We found that feeding mice YKSCH-containing chow increased body weight, but did not increase their motivation to food reward. We propose that YKSCH may be a good treatment option for preventing decrease in body weight in patients with dementia.

Delayed extinction and stronger drug-primed reinstatement of methamphetamine seeking in rats prenatally exposed to morphine.

Prenatal morphine (PM) affects the development of brain reward system and cognitive function. The present study aimed to determine whether PM exposure increases the vulnerability to MA addiction. Pregnant Sprague-Dawley rats were administered saline or morphine during embryonic days 3-20. The acquisition, extinction and reinstatement of methamphetamine (MA) conditioned place preference (CPP) and intravenous self-administration (SA) paradigms were assessed in the male adult offspring. There was no difference in the acquisition and expression of MA CPP between saline- and PM-exposed rats, whereas PM-exposed rats exhibited slower extinction and greater MA priming-induced reinstatement of drug-seeking behavior than controls. Similarly, MA SA under progressive ratio and fixed ratio schedules was not affected by PM exposure, but PM-exposed rats required more extinction sessions to reach the extinction criteria and displayed more severe MA priming-, but not cue-induced, reinstatement. Such alterations in extinction and reinstatement were not present when PM-exposed rats were tested in an equivalent paradigm assessing operant responding for food pellets. Our results demonstrate that PM exposure did not affect the association memory formation during acquisition of MA CPP or SA, but impaired extinction learning and increased MA-primed reinstatement in both tasks. These findings suggest that the offspring of women using morphine or heroin during pregnancy might predict persistent MA seeking during extinction and enhanced propensity to MA relapse although they might not be more susceptible to the reinforcing effect of MA during initiation of drug use.