Reward Motivation Research Articles

Male DAT Val559 Mice Exhibit Compulsive Behavior under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes.

Identified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose poke behavior appropriately to match context, but demonstrate a perseverative checking behavior. Although DAT Val559 mice display no issues with the cognitive flexibility required to acquire and re-learn a visual pairwise discrimination task, devaluation of reward evoked habitual reward seeking in DAT Val559 mutants in operant tasks regardless of reinforcement schedule. The direct DA agonist apomorphine also elicits locomotor stereotypies in DAT Val559, but not WT mice. Our observation that dendritic spine density is increased in the dorsal medial striatum (DMS) of DAT Val559 mice speaks to an imbalance in striatal circuitry that might underlie the propensity of DAT Val559 mutants to exhibit compulsive behaviors when reward is devalued. Thus, DAT Val559 mice represent a model for dissection of how altered DA signaling perturbs circuits that normally balance habitual and goal-directed behaviors.

The Angiotensin Antagonist Losartan Modulates Social Reward Motivation and Punishment Sensitivity via Modulating Midbrain-Striato-Frontal Circuits.

Social deficits and dysregulations in dopaminergic midbrain-striato-frontal circuits represent transdiagnostic symptoms across psychiatric disorders. Animal models suggest that interactions between the dopamine (DA) and renin-angiotensin system (RAS) may modulate learning and reward-related processes. The present study therefore examined the behavioral and neural effects of the Angiotensin II type 1 receptor (AT1R) antagonist losartan on social reward and punishment processing in humans. A preregistered randomized double-blind placebo-controlled between-subject pharmacological design was combined with a social incentive delay (SID) functional MRI (fMRI) paradigm during which subjects could avoid social punishment or gain social reward. Healthy volunteers received a single-dose of losartan (50 mg, n = 43, female = 17) or placebo (n = 44, female = 20). We evaluated reaction times (RTs) and emotional ratings as behavioral and activation and functional connectivity as neural outcomes. Relative to placebo, losartan modulated the reaction time and arousal differences between social punishment and social reward. On the neural level the losartan-enhanced motivational salience of social rewards was accompanied by stronger ventral striatum-prefrontal connectivity during reward anticipation. Losartan increased the reward-neutral difference in the ventral tegmental area (VTA) and attenuated VTA associated connectivity with the bilateral insula in response to punishment during the outcome phase. Thus, losartan modulated approach-avoidance motivation and emotional salience during social punishment versus social reward via modulating distinct core nodes of the midbrain-striato-frontal circuits. The findings document a modulatory role of the renin-angiotensin system in these circuits and associated social processes, suggesting a promising treatment target to alleviate social dysregulations.SIGNIFICANCE STATEMENT Social deficits and anhedonia characterize several mental disorders and have been linked to the midbrain-striato-frontal circuits of the brain. Based on initial findings from animal models we here combine the pharmacological blockade of the Angiotensin II type 1 receptor (AT1R) via losartan with functional MRI (fMRI) to demonstrate that AT1R blockade enhances the motivational salience of social rewards and attenuates the negative impact of social punishment via modulating the communication in the midbrain-striato-frontal circuits in humans. The findings demonstrate for the first time an important role of the AT1R in social reward processing in humans and render the AT1R as promising novel treatment target for social and motivational deficits in mental disorders.

Value restructures the organization of free recall

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

The Activity Of Posyandu Cadres At Healt Center Siulak Mukai Kerinci Regency

Posyandu is one form of community-sourced health efforts, which is managed from, by, for and with the community. Based on data from the Kerinci regency Health Office in 2020-2021, it was found that in kerinci regency there were 21 health centers with 293 posyandu and only 61 Posyandu were active, in the profile of the siulak mukai Health Center in 2020-2021 there were 14 posyandu and only 1 posyandu was active with a cadre of 70 people. This research is a quantitative research with cross sectional design. The sample is a whole cadre of 70 people. Data collection was carried out from March 2022 to April 2022. Data were collected using questionnaires that have been tested for validity and reliability. Data analysis with multiple logistic regression test. There were (p=0.001) PR=469 (95% CI=302-727) motivation award (p=0.001) PR=2,540(95% CI=1,3184.892) motivation reward (p=0.000) PR=2,583 (95% CI=1,400-4,767)with cadre activity. There was no relationship between age (p=1,000) PR=0.866 (95% CI=567-1, 325) marital status (p=0.974) PR=0.877 (95% CI=490-1, 571) occupation (p=0.788) PR=1.121 (95% CI=720-1, 747) length of Service (p=0.501) PR=1.246 (95% CI=765 - 2,028) responsibility (P=0,133) PR=2,190 (95% CI=1,458-3,290) interpersonal relationships (P=308) PR=1,308 (95% CI=860-1, 990) with cadre activeness. Based on the results of multivariate tests, it is known that the education variable has a significant relationship with the p value (0.038), and has a value of B (1.074) and the value of OR 2.928 is the highest when compared with other variables. These results show that education is the most dominant variable that affects the activity of cadres.Education variable is the most dominant variable that affects the activity of cadres. It is expected that the Healt Center Siulak Mukai pay attention to the level of education of cadres during recruitment. For posyandu cadres to better carry out posyandu activities in accordance with their duties and responsibilities and are expected to be more active in visiting people's homes to continue to monitor their health and motivate them to take advantage of posyandu.

Neural Mechanisms Mediating Sex Differences in Motivation for Reward: Cognitive Bias, Food, Gambling, and Drugs of Abuse.

Sex differences in motivation for food rewards, gambling, and drugs of abuse are modulated by multiple factors, including sensory stimuli, gonadal hormones, and cognitive bias. Cues, drugs of abuse, and a high-fat diet can significantly impact neural signaling in the reward system and functioning of neural systems that regulate executive functions differentially in males and females. Additionally, sex differences in risky decision-making, cognitive bias, and motivation for food and drugs of abuse are mediated by gonadal hormones in both sexes. As neuroscientists analyze data from both sexes, it is becoming apparent that these differences are not simply mediated by hormones in females, but involve sex differences in the specific neural responses to stimuli, including both external stimuli and internal hormonal signals. Understanding sex differences in the mechanisms underlying reward-seeking behaviors and the development of substance use disorders will help uncover potential therapies and treatments that will benefit both men and women. Based on these observations, it is essential that females are included in neuroscience research.

Arousal-driven interactions between reward motivation and categorization of emotional facial expressions.

Reward motivation and emotion share common dimensions of valence and arousal, but the nature of interactions between the two constructs is relatively unclear. On the one hand, based on the common valence dimension, valence-compatible interactions are expected where reward motivation would facilitate the processing of compatible (i.e., positive) emotion and hamper the processing of incompatible (i.e., negative) emotion. On the other hand, one could hypothesize valence-general interactions driven by the arousal dimension, where the processing of both positive and negative emotions would be facilitated under reward motivation. Currently, the evidence for valence-compatible vs. valence-general type interactions between reward motivation and goal-relevant emotion is relatively mixed. Moreover, as most of the previous work focused primarily on appetitive motivation, the influence of aversive motivation on goal-relevant emotion is largely unexplored. To address these important gaps, in the present study, we investigated the interactions between motivation and categorization of facial emotional expressions by manipulating the valence dimension of motivation (appetitive and aversive motivation levels) together with that of emotion (positive and negative valence stimuli). Specifically, we conducted two behavioral experiments to separately probe the influence of appetitive and aversive motivation (manipulated via an advance cue signaling the prospect of monetary gains in Experiment 1 and losses in Experiment 2, respectively) on the categorization of happy, fearful, and neutral faces. We tested the two competing hypotheses regarding the interactions between appetitive/aversive motivation and emotional face categorization: Valence-compatible vs. Valence-general. We found evidence consistent with valence-general interactions where both appetitive and aversive motivation facilitated the categorization of happy and fearful faces relative to the neutral ones. Our findings demonstrate that interactions between reward motivation and categorization of emotional faces are driven by the arousal dimension, not by valence.

ODP321 Impact of a Maternal High-Sucrose Diet in Rats on Fetal Physiology and the Placenta

Abstract Consumption of sucrose (table sugar) is high in much of the world. The effects of maternal sucrose intake on the placenta and fetal brain remain unknown. In rats, maternal consumption of sucrose at a human-relevant level alters the mother's physiology and steroids, as well as the adult offspring's brain and behavior. Effects in mothers are impaired glucose tolerance, increased liver lipids, increased adipose inflammation, and decreased corticosterone levels in the blood but not in the brain. In contrast, in adult female offspring, maternal sucrose intake increases corticosterone levels in the blood and the brain. In adult male offspring, maternal sucrose intake increases preference for high-sucrose and high-fat diets as well as motivation for sugar rewards in a progressive ratio task. In this study, we investigate the underlying mechanisms of the observed behavioral and endocrine effects in the adult offspring. We examine anti-inflammatory steroids, steroidogenic enzymes and cytokines in the placenta, amniotic fluid, fetal blood and brain. In our model, we feed rat dams either a high-sucrose diet (26% of kCal) or an isocaloric, matched, control diet (1% sucrose) 10 weeks prior to and during gestation. At embryonic day 19 (E19), we collected maternal serum, placenta, amniotic fluid, fetal blood, and fetal brain. We used Palkovits punch to microdissect the placenta and fetal brain. Next, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is highly sensitive and specific, to measure multiple steroids (e. g. corticosterone, estrone, allopregnanolone). We examined multiple regions of the fetal brain (e. g. prefrontal cortex, nucleus accumbens, hypothalamus, hippocampus). We will also examine neuronal proliferation, microglia and tyrosine hydroxylase immunoreactivity in the fetal brain. Maternal high-sucrose diet increased 11-dehydrocorticosterone (inactive metabolite of corticosterone) and aldosterone in maternal serum and amniotic fluid. Testosterone and androstenedione were significantly higher in the amniotic fluid of male fetuses than female fetuses. Placental steroidogenic enzymes 3β-HSD and CYP19 were not affected by maternal diet or fetal sex; however, 3β-HSD activity was higher in the decidua than in the fetal part of the placenta. Steroid and cytokine data from the placenta, fetal blood and fetal brain are currently being analyzed. Ongoing analyses examine how a maternal high-sucrose diet affects brain development possibly by increasing inflammation. Presentation: No date and time listed

Early resource scarcity alters motivation for natural rewards in a sex- and reinforcer-dependent manner.

Early life adversity impacts reward-related behaviors, including reward seeking for drugs of abuse. However, the effects of early stress on natural rewards, such as food and social rewards, which have strong implications for symptoms of psychiatric conditions such as major depressive disorder (MDD), are understudied. To fill this gap, we used the limited bedding and nesting (LBN) procedure to assess the impact of early resource scarcity on motivational drive for both food and social rewards in rats. Male and female Long Evans rats were reared in either an LBN environment, with limited nesting materials and no enrichment, from their postnatal day 2-9 or control environment with ample nesting materials and enrichment. As adults, they were tested for reward-seeking behavior on progressive ratio operant tasks: food reward (sucrose) or social reward (access to a same-sex/age conspecific). We observed sex differences in the impact of LBN on motivation for natural rewards. In males, LBN increased motivation for both a sucrose and social reward. In females, LBN reduced motivation for sucrose but had no effect on social reward. These results suggest that the effects of LBN on motivation for natural rewards are both sex- and reinforcer-dependent, with males and females showing differential motivation for food and social rewards following early scarcity. Our previous data revealed an LBN-driven reduction in motivation for morphine in males and no effect in females, highlighting the reinforcer-dependent impact of early resource scarcity on motivated behavior more widely.

Activity of a direct VTA to ventral pallidum GABA pathway encodes unconditioned reward value and sustains motivation for reward.

Dopamine signaling from the ventral tegmental area (VTA) plays critical roles in reward-related behaviors, but less is known about the functions of neighboring VTA GABAergic neurons. We show here that a primary target of VTA GABA projection neurons is the ventral pallidum (VP). Activity of VTA-to-VP–projecting GABA neurons correlates consistently with size and palatability of the reward and does not change following cue learning, providing a direct measure of reward value. Chemogenetic stimulation of this GABA projection increased activity of a subset of VP neurons that were active while mice were seeking reward. Optogenetic stimulation of this pathway improved performance in a cue-reward task and maintained motivation to work for reward over days. This VTA GABA projection provides information about reward value directly to the VP, likely distinct from the prediction error signal carried by VTA dopamine neurons.

α-Dystrobrevin knockout mice have increased motivation for appetitive reward and altered brain cannabinoid receptor 1 expression

α-Dystrobrevin (α-DB) is a major component of the dystrophin-associated protein complex (DAPC). Knockout (KO) of α-DB in the brain is associated with astrocytic abnormalities and loss of neuronal GABA receptor clustering. Mutations in DAPC proteins are associated with altered dopamine signaling and cognitive and psychiatric disorders, including schizophrenia. This study tested the hypothesis that motivation and associated underlying biological pathways are altered in the absence of α-DB expression. Male wildtype and α-DB KO mice were tested for measures of motivation, executive function and extinction in the rodent touchscreen apparatus. Subsequently, brain tissues were evaluated for mRNA and/or protein levels of dysbindin-1, dopamine transporter and receptor 1 and 2, mu opioid receptor 1 (mOR1) and cannabinoid receptor 1 (CB1). α-DB KO mice had significantly increased motivation for the appetitive reward, while measures of executive function and extinction were unaffected. No differences were observed between wildtype and KO animals on mRNA levels of dysbindin-1 or any of the dopamine markers. mRNA levels of mOR1were significantly decreased in the caudate-putamen and nucleus accumbens of α-DB KO compared to WT animals, but protein levels were unaltered. However, CB1 protein levels were significantly increased in the prefrontal cortex and decreased in the nucleus accumbens of α-DB KO mice. Triple-labelling immunohistochemistry confirmed that changes in CB1 were not specific to astrocytes. These results highlight a novel role for α-DB in the regulation of appetitive motivation that may have implications for other behaviours that involve the dopaminergic and endocannabinoid systems.

Prenatal dexamethasone exposure alters effort decision making and triggers nucleus accumbens and anterior cingulate cortex functional changes in male rats

Daily, individuals select actions based on cost-benefit to allocate resources into goal-directed actions. Different brain regions coordinate this complex decision, including the nucleus accumbens (NAc), anterior cingulate cortex (ACC), and ventral tegmental area (VTA). In utero exposure to synthetic glucocorticoids (iuGC), such as dexamethasone, triggers prominent motivation deficits but the impact of this exposure in the ACC-NAc and/or ACC-VTA circuits is unknown. Here, we show that iuGC exposure causes decreased motivation for natural rewards (food) and impaired effort-based decision-making. Importantly, reduced neuronal activation (number of c-fos+ neurons) was observed in the NAc core and ACC of iuGC rats in comparison to CTR rats after performing the effort-based decision-making task. In addition, iuGC treatment led to increased NAc and ACC basal neuronal activity. Electrophysiological recordings during optogenetic modulation of ACC terminals in the NAc revealed that the ACC-NAc circuit is dysfunctional in iuGC animals. These data suggest that iuGC animals present motivational and effort-based decision-making deficits that can be associated with the observed ACC-NAc dysfunction.

Eyes wide open: sleep disturbance, not melatonin, is the real issue to address for suicide risk.

Eyes wide open: sleep disturbance, not melatonin, is the real issue to address for suicide risk.

Reward Enhances Memory via Age-Varying Online and Offline Neural Mechanisms across Development.

Reward motivation enhances memory through interactions between mesolimbic, hippocampal, and cortical systems, both during and after encoding. Developmental changes in these distributed neural circuits may lead to age-related differences in reward-motivated memory and the underlying neural mechanisms. Converging evidence from cross-species studies suggests that subcortical dopamine signaling is increased during adolescence, which may lead to stronger memory representations of rewarding, relative to mundane, events and changes in the contributions of underlying subcortical and cortical brain mechanisms across age. Here, we used fMRI to examine how reward motivation influences the "online" encoding and "offline" postencoding brain mechanisms that support long-term associative memory from childhood to adulthood in human participants of both sexes. We found that reward motivation led to both age-invariant enhancements and nonlinear age-related differences in associative memory after 24 h. Furthermore, reward-related memory benefits were linked to age-varying neural mechanisms. During encoding, interactions between the prefrontal cortex (PFC) and ventral tegmental area (VTA) were associated with better high-reward memory to a greater degree with increasing age. Preencoding to postencoding changes in functional connectivity between the anterior hippocampus and VTA were also associated with better high-reward memory, but more so at younger ages. Our findings suggest that there may be developmental differences in the contributions of offline subcortical and online cortical brain mechanisms supporting reward-motivated memory.SIGNIFICANCE STATEMENT A substantial body of research has examined the neural mechanisms through which reward influences memory formation in adults. However, despite extensive evidence that both reward processing and associative memory undergo dynamic change across development, few studies have examined age-related changes in these processes. We found both age-invariant and nonlinear age-related differences in reward-motivated memory. Moreover, our findings point to developmental differences in the processes through which reward modulates the prioritization of information in long-term memory, with greater early reliance on offline subcortical consolidation mechanisms and increased contribution of systems-level online encoding circuitry with increasing age. These results highlight dynamic developmental changes in the cognitive and neural mechanisms through which motivationally salient information is prioritized in memory from childhood to adulthood.

Negative schizotypal traits predict the reduction of reward motivation in effort-reward imbalance.

The schizotypy construct is useful for studying the effects of environmental stress on development of subclinical negative symptoms. The relationship among self-report motivation, effort-reward imbalance (ERI), and schizotypal features has seldom been studied. We aimed to examine the possible moderation effect of schizotypal traits on ERI and reward motivation. Eight-hundred-and-forty-three college students were recruited online to complete a set of self-reported measures capturing schizotypal traits, effort-reward imbalance and reward motivation, namely the Schizotypal Personality Questionnaire (SPQ), the Effort-Reward Imbalance-School Version Questionnaire (C-ERI-S) and the Motivation and Pleasure Scale-Self Report (MAP-SR). We conducted multiple linear regression to construct models to investigate the moderating effects of schizotypal traits on the relationship between ERI and reward motivation. Stressful ERI situation predicted the reduction of reward motivation. Negative schizotypal traits showed a significant negative moderating effect on the relationship between ERI and reward motivation, while positive and disorganized schizotypal traits had significant positive moderating effects. Schizotypal traits subtypes differently moderate the relationship between ERI and reward motivation. Only negative schizotypal traits and stressful ERI situation together have negative impact on reward motivation.

0108 The Effect of Reward Motivation on Placekeeping Performance After Sleep Deprivation

Abstract Introduction Sleep deprivation impairs some higher-order cognitive processes, but this impairment may reflect changes in motivation as well as changes in the cognitive capacity to perform the task, which has implications for intervention strategies. Here, we asked whether reward motivation could offset the effects of sleep deprivation on placekeeping, a higher-order cognitive process that is prevalent in performance of everyday tasks. To conduct this study under pandemic conditions, we developed a method for online data collection that promises to facilitate sleep-deprivation research more generally, by allowing for larger and more diverse samples to be collected at lower cost compared to in-person methods. Methods In the evening, participants joined a Zoom meeting and completed the Psychomotor Vigilance Task (PVT) and a placekeeping task (UNRAVEL). Afterwards, participants were randomly assigned to remain in the meeting and stay awake (Deprivation) or leave the meeting and sleep (Rested). Deprivation participants were monitored remotely overnight by two research assistants. Rested participants left the meeting at 00:00 and returned at 08:30. At 08:30, all participants completed the PVT and UNRAVEL again. Some participants had the opportunity to earn a monetary reward based on their morning UNRAVEL performance (Motivated) and some did not (Nonmotivated). We analyzed morning performance with a 2 (Sleep: Rested, Deprivation) x 2 (Reward: Motivated, Nonmotivated) design using evening performance as a covariate. Results Preliminary results from 206 participants show Deprivation participants had more placekeeping errors and lapses in the PVT than Rested participants. Motivated participants made fewer placekeeping errors after task interruption than Nonmotivated participants. The Sleep and Reward factors did not interact. Conclusion These results suggest that motivational interventions can mitigate some effects of sleep deprivation on complex task performance. However, reward motivation affected Rested and Deprivation performance similarly rather than compensating for any effects specific to sleep deprivation. This pattern does not rule out an effect of sleep deprivation on motivation, but does suggest that a different approach will be necessary to isolate this effect. Support (If Any) This research is funded by the Office of Naval Research (N00014-20-1-2739).

Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.

The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 (33) that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.

Objective measures of reward sensitivity and motivation in people with high v. low anhedonia.

Anhedonia - a diminished interest or pleasure in activities - is a core self-reported symptom of depression which is poorly understood and often resistant to conventional antidepressants. This symptom may occur due to dysfunction in one or more sub-components of reward processing: motivation, consummatory experience and/or learning. However, the precise impairments remain elusive. Dissociating these components (ideally, using cross-species measures) and relating them to the subjective experience of anhedonia is critical as it may benefit fundamental biology research and novel drug development. Using a battery of behavioural tasks based on rodent assays, we examined reward motivation (Joystick-Operated Runway Task, JORT; and Effort-Expenditure for Rewards Task, EEfRT) and reward sensitivity (Sweet Taste Test) in a non-clinical population who scored high (N = 32) or low (N = 34) on an anhedonia questionnaire (Snaith-Hamilton Pleasure Scale). Compared to the low anhedonia group, the high anhedonia group displayed marginal impairments in effort-based decision-making (EEfRT) and reduced reward sensitivity (Sweet Taste Test). However, we found no evidence of a difference between groups in physical effort exerted for reward (JORT). Interestingly, whilst the EEfRT and Sweet Taste Test correlated with anhedonia measures, they did not correlate with each other. This poses the question of whether there are subgroups within anhedonia; however, further work is required to directly test this hypothesis. Our findings suggest that anhedonia is a heterogeneous symptom associated with impairments in reward sensitivity and effort-based decision-making.

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward. The GPR139 agonist TAK-041 is currently under development for treatment of negative symptoms in schizophrenia which include apathy. To date, however, there are no published preclinical data regarding its potential effect on reward motivation or deficiencies thereof. Here we report in vitro evidence confirming that TAK-041 increases intracellular Ca2+ mobilization and has high selectivity for GPR139. In vivo, TAK-041 was brain penetrant and showed a favorable pharmacokinetic profile. It was without effect on extracellular dopamine concentration in the nucleus accumbens. In addition, TAK-041 did not alter the effort exerted to obtain sweet gustatory reward in rats that were moderately food deprived. By contrast, TAK-041 increased the effort exerted to obtain sweet gustatory reward in mice that were only minimally food deprived; furthermore, this effect of TAK-041 occurred both in control mice and in mice in which deficient effortful responding was induced by chronic social stress. Overall, this study provides preclinical evidence in support of GPR139 agonism as a molecular target mechanism for treatment of apathy.

A history of low dose ethanol modulates ventral hippocampus activity during motivated behavior

More than half of the 130 million people in the U.S. who consumed alcohol within the last month did so at a level that did not meet diagnostic criteria for an alcohol binge. However, even these sub diagnostic drinking levels can have neurobehavioral outcomes. Clinical studies have shown that low levels of acute ethanol drinking soon after learning can enhance task consolidation and memory recall. Our preclinical data in C57BL6J mice show that a history of repeated, low dose ethanol (0.5g/kg) exposure increases sucrose reward motivation as measured by progressive ratio. The ventral hippocampus (vHPC) is increasingly considered a critical contributor to reward seeking and has been shown to be sensitive to chronic ethanol exposure at higher doses. The present study sought to determine whether daily, post‐training, low dose ethanol exposure can modulate vHPC activity during motivated behavior. To investigate this, we implanted mice with an electrode array to record vHPC neural activity during performance of a progressive ratio task. We also investigated vHPC activity around important behavioral events in the task, including lever pressing (when the animal is seeking the reward) and magazine entries (when the animal is checking for reward delivery). Our results demonstrate that saline control mice show suppression of vHPC activity following a lever press, while mice with a history of low dose ethanol exposure exhibit this suppression prior to a lever press. In contrast, both saline and ethanol‐exposed mice exhibit similar vHPC activity patterns surrounding magazine entry. These results suggest that a history of post‐training low dose ethanol exposure modulates vHPC activity during reward seeking. Further, this shift in vHPC suppression around a lever press may be associated with the enhanced motivation for sucrose observed in ethanol‐exposed mice. Future studies will use optogenetics to determine whether this shift in activity contributes to heightened reward motivation in ethanol exposed mice. A greater understanding of the neurobiological substrates impacted by ethanol exposure can help identify factors placing casual drinkers at risk for transition to alcohol use disorder.

Mice Exposed to Chronic low‐dose Ethanol Exhibit Reduced Sensitivity to Changes in Magnitude of Reward

While approximately 2 billion individuals consume alcohol worldwide, the majority of these individuals to not exhibit drinking patterns consistent with alcohol use disorders (AUDs). Efforts have been made in investigating and characterizing the adverse effects on learning, memory and reward seeking with individuals afflicted with AUDs in a pursuit of therapeutic advancements. However, sub‐diagnostic alcohol effects have been understudied, despite the large number of low‐dose alcohol drinkers and the potential for low dose alcohol to impact both brain and behavior.Data from our lab has shown that low‐dose alcohol exposure enhances reward motivation in male, but not female, mice, but the mechanism of this is effect is unclear. Thus, we investigated the effects of low‐dose alcohol exposure on sensitivity to change in reward magnitude. A group of adult male C57BL6J mice were trained to self‐administer a 20 ul sucrose reward and received either a low‐dose ethanol (0.5g/kg) or saline injection 1 hour after training. To assess motivation, we used a progressive ratio (PR) task in which the effort required to earn the sucrose reward was increased linearly. Mice received multiple counterbalanced PR sessions in which the progressive schedule remained the same, but the reward magnitude was changed from 20ul (baseline) to 35ul, 25ul, 15ul or 5ul in counterbalanced sessions.Consistent with sensitivity to changes in reward value, saline control mice reduced or increased responding when reward volume was reduced or increased, respectively. Similar to saline controls, chronic low‐dose ethanol exposed mice increased their responding when reward volumes were increased compared to the 20ul baseline. However, ethanol exposed mice did not reduce responding to small reductions in reward magnitude. This observation in low‐dose ethanol mice suggests either a failure to detect reductions in reward magnitude or a dissociation between reduced reward magnitude and behavioral response. This lack of strategizing behavior to maintain effort‐to‐reward balance by ethanol exposed mice may imply that chronic low‐dose ethanol exposed mice may perceive greater reward value than controls even at reduced volume and implicates even low‐dose ethanol as a contributor to aberrant reward processing.