Glucocorticoid-Regulated Kinase CAMKIγ in the Central Amygdala Controls Anxiety-like Behavior in Mice.

The expression of the Calcium/Calmodulin-Dependent Protein Kinase I gamma (encoded by the Camk1g gene) depends on the activation of glucocorticoid receptors (GR) and is strongly regulated by stress. Since Camk1g is primarily expressed in neuronal cells of the limbic system in the brain, we hypothesized that it could be involved in signaling mechanisms that underlie the adaptive or maladaptive responses to stress. Here, we find that restraint-induced stress and the GR agonist dexamethasone robustly increase the expression of Camk1g in neurons of the amygdalar nuclei in the mouse brain. To assess the functional role of Camk1g expression, we performed a virally induced knock-down of the transcript. Mice with bilateral amygdala-specific Camk1g knock-down showed increased anxiety-like behaviors in the light-dark box, and an increase in freezing behavior after fear-conditioning, but normal spatial working memory during exploration of a Y-maze. Thus, we confirm that Camk1g is a neuron-specific GR-regulated transcript, and show that it is specifically involved in behaviors related to anxiety, as well as responses conditioned by aversive stimuli.

Time elapsed between choices in a probabilistic task correlates with repeating the same decision.

Reinforcement learning causes an action that yields a positive outcome more likely to be taken in the future. Here, we investigate how the time elapsed from an action affects subsequent decisions. Groups of C57BL6/J mice were housed in IntelliCages with access to water and chow ad libitum; they also had access to bottles with a reward: saccharin solution, alcohol, or a mixture of the two. The probability of receiving a reward in two of the cage corners changed between 0.9 and 0.3 every 48 hr over a period of ~33 days. As expected, in most animals, the odds of repeating a corner choice were increased if that choice was previously rewarded. Interestingly, the time elapsed from the previous choice also influenced the probability of repeating the choice, and this effect was independent of previous outcome. Behavioral data were fitted to a series of reinforcement learning models. Best fits were achieved when the reward prediction update was coupled with separate learning rates from positive and negative outcomes and additionally a "fictitious" update of the expected value of the nonselected choice. Additional inclusion of a time-dependent decay of the expected values improved the fit marginally in some cases.

Expression of alternatively spliced variants of the Dclk1 gene is regulated by psychotropic drugs.

BACKGROUND: The long-term effects of psychotropic drugs are associated with the reversal of disease-related alterations through the reorganization and normalization of neuronal connections. Molecular factors that trigger drug-induced brain plasticity remain only partly understood. Doublecortin-like kinase 1 (Dclk1) possesses microtubule-polymerizing activity during synaptic plasticity and neurogenesis. However, the Dclk1 gene shows a complex profile of transcriptional regulation, with two alternative promoters and exon splicing patterns that suggest the expression of multiple isoforms with different kinase activities. RESULTS: Here, we applied next-generation sequencing to analyze changes in the expression of Dclk1 gene isoforms in the brain in response to several psychoactive drugs with diverse pharmacological mechanisms of action. We used bioinformatics tools to define the range and levels of Dclk1 transcriptional regulation in the mouse nucleus accumbens and prefrontal cortex. We also sought to investigate the presence of DCLK1-derived peptides using mass spectrometry. We detected 15 transcripts expressed from the Dclk1 locus (FPKM > 1), including 2 drug-regulated variants (fold change > 2). Drugs that act on serotonin receptors (5-HT2A/C) regulate a subset of Dclk1 isoforms in a brain-region-specific manner. The strongest influence was observed for the mianserin-induced expression of an isoform with intron retention. The drug-activated expression of novel alternative Dclk1 isoforms was validated using qPCR. The drug-regulated isoform contains genetic variants of DCLK1 that have been previously associated with schizophrenia and hyperactivity disorder in humans. We identified a short peptide that might originate from the novel DCLK1 protein product. Moreover, protein domains encoded by the regulated variant indicate their potential involvement in the negative regulation of the canonical DCLK1 protein. CONCLUSIONS: In summary, we identified novel isoforms of the neuroplasticity-related gene Dclk1 that are expressed in the brain in response to psychotropic drug treatments.

Molecular profile of dissociative drug ketamine in relation to its rapid antidepressant action.

BACKGROUND: The NMDA receptor antagonist ketamine was found to act as a fast-acting antidepressant. The effects of single treatment were reported to persist for days to weeks, even in otherwise treatment-refractory cases. Identification of the mechanisms underlying ketamine's antidepressant action may permit development of novel drugs, with similar clinical properties but lacking psychotomimetic, sedative and other side effects. METHODS: We applied whole-genome microarray profiling to analyze detailed time-course (1, 2, 4 and 8 h) of transcriptome alterations in the striatum and hippocampus following acute administration of ketamine, memantine and phencyclidine in C57BL/6 J mice. The transcriptional effects of ketamine were further analyzed using next-generation sequencing and quantitative PCR. Gene expression alterations induced by the NMDA antagonists were compared to the molecular profiles of psychotropic drugs: antidepressants, antipsychotics, anxiolytics, psychostimulants and opioids. RESULTS: We identified 52 transcripts (e.g. Dusp1, Per1 and Fkbp5) with altered expression (FDR < 1 %) in response to treatment with NMDA receptor antagonists. Functional links that connect expression of the regulated genes to the MAPK, IL-6 and insulin signaling pathways were indicated. Moreover, ketamine-regulated expression of specific gene isoforms was detected (e.g. Tsc22d3, Sgk1 and Hif3a). The comparison with other psychotropic drugs revealed that the molecular effects of ketamine are most similar to memantine and phencyclidine. Clustering based on expression profiles placed the NMDA antagonists among fluoxetine, tianeptine, as well as opioids and ethanol. CONCLUSIONS: The identified patterns of gene expression alteration in the brain provided novel molecular classification of ketamine. The transcriptional profile of ketamine reflects its multi-target pharmacological nature. The results reveal similarities between the effects of ketamine and monoaminergic antidepressants that may explain the mechanisms of its rapid antidepressant action.

Dopamine Receptor-Expressing Neurons Are Differently Distributed throughout Layers of the Motor Cortex to Control Dexterity.

The motor cortex comprises the primary descending circuits for flexible control of voluntary movements and is critically involved in motor skill learning. Motor skill learning is impaired in patients with Parkinson's disease, but the precise mechanisms of motor control and skill learning are still not well understood. Here we have used transgenic mice, electrophysiology, in situ hybridization, and neural tract-tracing methods to target genetically defined cell types expressing D1 and D2 dopamine receptors in the motor cortex. We observed that putative D1 and D2 dopamine receptor-expressing neurons (D1+ and D2+, respectively) are organized in highly segregated, nonoverlapping populations. Moreover, based on ex vivo patch-clamp recordings, we showed that D1+ and D2+ cells have distinct morphological and electrophysiological properties. Finally, we observed that chemogenetic inhibition of D2+, but not D1+, neurons disrupts skilled forelimb reaching in adult mice. Overall, these results demonstrate that dopamine receptor-expressing cells in the motor cortex are highly segregated and play a specialized role in manual dexterity.

Non-motor symptoms associated with progressive loss of dopaminergic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterized by three main motor symptoms: bradykinesia, rigidity and tremor. PD is also associated with diverse non-motor symptoms that may develop in parallel or precede motor dysfunctions, ranging from autonomic system dysfunctions and impaired sensory perception to cognitive deficits and depression. Here, we examine the role of the progressive loss of dopaminergic transmission in behaviors related to the non-motor symptoms of PD in a mouse model of the disease (the TIF-IADATCreERT2 strain). We found that in the period from 5 to 12 weeks after the induction of a gradual loss of dopaminergic neurons, mild motor symptoms became detectable, including changes in the distance between paws while standing as well as the swing speed and step sequence. Male mutant mice showed no apparent changes in olfactory acuity, no anhedonia-like behaviors, and normal learning in an instrumental task; however, a pronounced increase in the number of operant responses performed was noted. Similarly, female mice with progressive dopaminergic neuron degeneration showed normal learning in the probabilistic reversal learning task and no loss of sweet-taste preference, but again, a robustly higher number of choices were performed in the task. In both males and females, the higher number of instrumental responses did not affect the accuracy or the fraction of rewarded responses. Taken together, these data reveal discrete, dopamine-dependent non-motor symptoms that emerge in the early stages of dopaminergic neuron degeneration.

Glucocorticoid receptor dimerization is required for survival in septic shock via suppression of interleukin-1 in macrophages.

Sepsis is controlled by endogenous glucocorticoids (GCs). Previous studies provided evidence that crosstalk of the monomeric GC receptor (GR) with proinflammatory transcription factors is the crucial mechanism underlying the suppressive GC effect. Here we demonstrate that mice with a dimerization-deficient GR (GR(dim)) are highly susceptible to sepsis in 2 different models, namely cecal ligation and puncture and lipopolysaccharide (LPS)-induced septic shock. TNF-α is normally regulated in these mice, but down-regulation of IL-6 and IL-1ß is diminished. LPS-treated macrophages derived from GR(dim) mice are largely resistant to GC actions in vitro in terms of morphology, surface marker expression, and gene expression. Treatment with recombinant IL-1 receptor antagonist improved survival of GR(dim) mice and mice lacking the GR in macrophages (GR(LysMCre)) mice. This suggests that regulation of IL-1ß in macrophages by GCs is pivotal to control sepsis.

Prosocial behavior, social reward and affective state discrimination in adult male and female mice.

Prosocial behavior, defined as voluntary behavior intended to benefit another, has long been regarded as a primarily human characteristic. In recent years, it was reported that laboratory animals also favor prosocial choices in various experimental paradigms, thus demonstrating that prosocial behaviors are evolutionarily conserved. Here, we investigated prosocial choices in adult male and female C57BL/6 laboratory mice in a task where a subject mouse was equally rewarded for entering any of the two compartments of the experimental cage, but only entering of the compartment designated as "prosocial" rewarded an interaction partner. In parallel we have also assessed two traits that are regarded as closely related to prosociality: sensitivity to social reward and the ability to recognize the affective state of another individual. We found that female, but not male, mice increased frequency of prosocial choices from pretest to test. However, both sexes showed similar rewarding effects of social contact in the conditioned place preference test, and similarly, there was no effect of sex on affective state discrimination measured as the preference for interaction with a hungry or relieved mouse over a neutral animal. These observations bring interesting parallels to differences between sexes observed in humans, and are in line with reported higher propensity for prosocial behavior in human females, but differ with regard to sensitivity to social stimuli in males.

Prospects for personalization of depression treatment with genome sequencing.

The effectiveness of antidepressants in the treatment of major depressive disorder varies considerably between patients. With these interindividual differences and a number of antidepressants to choose from, the first choice of treatment often fails to produce improvement in the patient's condition. A substantial part of the variation in response to antidepressants can be explained by genetic factors. Accordingly, variants related to drug metabolism in two pharmacogenes, CYP2D6 and CYP2C19, have already been translated into guidelines for antidepressant prescriptions. The role of variants in other genes that influence antidepressant responses is not yet understood. Furthermore, rare and individual variants account for a substantial part of genetic differences in antidepressant efficacy. Recent years have brought a tremendous increase in the accessibility of genome sequencing in terms of data availability and its clinical use. In this review, we summarize recent developments and current issues in the personalization of major depressive disorder treatment through pharmacogenomics. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.

C57BL/6N mice show a sub-strain specific resistance to the psychotomimetic effects of ketamine.

Repeated administration of subanesthetic doses of ketamine is a model of psychosis-like state in rodents. In mice, this treatment produces a range of behavioral deficits, including impairment in social interactions and locomotion. To date, these phenotypes were described primarily in the Swiss and C3H/HeHsd mouse strains. A few studies investigated ketamine-induced behaviors in the C57BL/6J strain, but to our knowledge the C57BL/6N strain was not investigated thus far. This is surprising, as both C57BL/6 sub-strains are widely used in behavioral and neuropsychopharmacological research, and are de facto standards for characterization of drug effects. The goal of this study was to determine if C57BL/6N mice are vulnerable to develop social deficits after 5 days withdrawal from sub-chronic ketamine treatment (5 days, 30 mg/kg, i.p.), an experimental schedule shown before to cause deficits in social interactions in C57BL/6J mice. Our results show that sub-chronic administration of ketamine that was reported to cause psychotic-like behavior in C57BL/6J mice does not induce appreciable behavioral alterations in C57BL/6N mice. Thus, we show that the effects of sub-chronic ketamine treatment in mice are sub-strain specific.

Establishment of a social conditioned place preference paradigm for the study of social reward in female mice.

Social interactions can be and often are rewarding. The effect of social contact strongly depends on circumstances, and the reward may be driven by varied motivational processes, ranging from parental or affiliative behaviors to investigation or aggression. Reward associated with nonreproductive interactions in rodents is measured using the social conditioned place preference (sCPP) paradigm, where a change in preference for an initially neutral context confirms reinforcing effects of social contact. Here, we revised the sCPP method and reexamined social reward in adult female mice. Contrary to earlier studies, we found that robust rewarding effects of social contact could be detected in adult (14-week-old) female C57BL/6 mice when the sCPP task was refined to remove confounding factors. Strikingly, the rewarding effects of social interaction were only observed among female siblings who remained together from birth. Contact with same-age nonsiblings was not rewarding even after 8 weeks of cohousing. Other factors critical for the social reward effect in the sCPP paradigm included the number of conditioning sessions and the inherent preference for contextual cues. Thus, we show that social interaction is rewarding in adult female mice, but this effect strictly depends on the familiarity of the interaction partners. Furthermore, by identifying confounding factors, we provide a behavioral model to study the mechanisms underlying the rewarding effects of nonreproductive social interaction in adult mice.

Incentive learning underlying cocaine-seeking requires mGluR5 receptors located on dopamine D1 receptor-expressing neurons.

Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms of striatal synaptic plasticity proposed to underpin associative learning and memory processes that enable drug-paired stimuli to acquire incentive motivational properties and trigger relapse. Using cell type-specific RNA interference, we have generated a novel mouse line with a selective knock-down of mGluR5 in dopamine D1 receptor-expressing neurons. Although mutant mice self-administer cocaine, we show that reinstatement of cocaine-seeking induced by a cocaine-paired stimulus is impaired. By examining different aspects of associative learning in the mutant mice, we identify deficits in specific incentive learning processes that enable a reward-paired stimulus to directly reinforce behavior and to become attractive, thus eliciting approach toward it. Our findings show that glutamate signaling through mGluR5 located on dopamine D1 receptor-expressing neurons is necessary for incentive learning processes that contribute to cue-induced reinstatement of cocaine-seeking and which may underpin relapse in drug addiction.

Effects of L-DOPA on Gene Expression in the Frontal Cortex of Rats with Unilateral Lesions of Midbrain Dopaminergic Neurons.

The development of Parkinson's disease (PD) causes dysfunction of the frontal cortex, which contributes to the hallmark motor symptoms and is regarded as one of the primary causes of the affective and cognitive impairments observed in PD. Treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) alleviates motor symptoms but has mixed efficacy in restoring normal cognitive functions, which is further complicated by the psychoactive effects of the drug. We investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We performed RNA sequencing (RNA-Seq) analysis of gene expression in the frontal cortex of rats with 6-hydroxydopamine (6-OHDA)-induced unilateral dopaminergic lesions treated with L-DOPA, for two weeks. The analysis of variance identified 48 genes with a significantly altered transcript abundance after L-DOPA treatment. We also performed a weighted gene coexpression network analysis (WGCNA), which resulted in the detection of five modules consisting of genes with similar expression patterns. The analyses led to three primary observations. First, the changes in gene expression induced by L-DOPA were bilateral, although only one hemisphere was lesioned. Second, the changes were not restricted to neurons but also appeared to affect immune or endothelial cells. Finally, comparisons with databases of drug-induced gene expression signatures revealed multiple nonspecific effects, indicating that a part of the observed response is a common pattern activated by multiple types of drugs in different target tissues. Taken together, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment.

Loss of mu and delta opioid receptors on neurons expressing dopamine receptor D1 has no effect on reward sensitivity.

Opioid signaling controls the activity of the brain's reward system. It is involved in signaling the hedonic effects of rewards and has essential roles in reinforcement and motivational processes. Here, we focused on opioid signaling through mu and delta receptors on dopaminoceptive neurons and evaluated the role these receptors play in reward-driven behaviors. We generated a genetically modified mouse with selective double knockdown of mu and delta opioid receptors in neurons expressing dopamine receptor D1. Selective expression of the transgene was confirmed using immunostaining. Knockdown was validated by measuring the effects of selective opioid receptor agonists on neuronal membrane currents using whole-cell patch clamp recordings. We found that in the nucleus accumbens of control mice, the majority of dopamine receptor D1-expressing neurons were sensitive to a mu or delta opioid agonist. In mutant mice, the response to the delta receptor agonist was blocked, while the effects of the mu agonist were strongly attenuated. Behaviorally, the mice had no obvious impairments. The mutation did not affect the sensitivity to the rewarding effects of morphine injections or social contact and had no effect on preference for sweet taste. Knockdown had a moderate effect on motor activity in some of the tests performed, but this effect did not reach statistical significance. Thus, we found that knocking down mu and delta receptors on dopamine receptor D1-expressing cells does not appreciably affect some of the reward-driven behaviors previously attributed to opioid signaling.

Ablation of NMDA receptors in dopamine neurons disrupts attribution of incentive salience to reward-paired stimuli.

Midbrain dopamine (DA) neurons play a crucial role in the formation of conditioned associations between environmental cues and appetitive events. Activation of N-methyl-d-aspartate (NMDA) receptors is a key mechanism responsible for the generation of conditioned responses of DA neurons to reward cues. Here, we tested the effects of the cell type-specific inactivation of NMDA receptors in DA neurons in adult mice on stimulus-reward learning. Animals were trained in a Pavlovian learning paradigm in which they had to learn the predictive value of two conditioned stimuli, one of which (CS+) was paired with the delivery of a water reward. Over the course of conditioning, mutant mice learned that the CS+ predicted reward availability, and they approached the reward receptacle more frequently during CS+ trials than CS- trials. However, conditioned responses to the CS+ were weaker in the mutant mice, possibly indicating that they did not attribute incentive salience to the CS+. To further assess whether the attribution of incentive salience was impaired by the mutation, animals were tested in a conditioned reinforcement test. The test revealed that mutant mice made fewer instrumental responses paired with CS+ presentation, confirming that the CS+ had a weaker incentive value. Taken together, these results indicate that reward prediction learning does occur in the absence of NMDA receptors in DA neurons, but the ability of reward-paired cues to invigorate and reinforce behavior is attenuated.

Decoding the transcriptional programs activated by psychotropic drugs in the brain.

Analysis of drug-induced gene expression in the brain has long held the promise of revealing the molecular mechanisms of drug actions as well as predicting their long-term clinical efficacy. However, despite some successes, this promise has yet to be fulfilled. Here, we present an overview of the current state of understanding of drug-induced gene expression in the brain and consider the obstacles to achieving a robust prediction of the properties of psychoactive compounds based on gene expression profiles. We begin with a comprehensive overview of the mechanisms controlling drug-inducible transcription and the complexity resulting from expression of noncoding RNAs and alternative gene isoforms. Particular interest is placed on studies that examine the associations within drug classes with regard to the effects on gene transcription, alterations in cell signaling and neuropharmacological drug properties. While the ability of gene expression signatures to distinguish specific clinical classes of psychotropic and addictive drugs remains unclear, some reports show that under specific constraints, drug properties can be predicted based on gene expression. Such signatures offer a simple and effective way to classify psychotropic drugs and screen novel psychoactive compounds. Finally, we note that the amount of data regarding molecular programs activated in the brain by drug treatment has grown exponentially in recent years and that future advances may therefore come in large part from integrating the currently available high-throughput data sets.

Antagonism of µ-opioid receptors reduces sensation seeking-like behavior in mice.

Novelty- and sensation-seeking behaviors induce activity of the brain reward system and are associated with increased susceptibility to drug abuse. Endogenous opioids have been implicated in reward-related behavior; however, the involvement of specific opioid receptors in the mechanism of sensation seeking is unknown. Here, we show that selective inhibition of opioid receptors reduce operant sensation seeking in mice. Administration of naltrexone (a nonselective opioid antagonist) reduced instrumental responding for sensory stimuli at one of the tested doses (2 mg/kg). More robust effects were observed in the case of cyprodime, a selective µ opioid receptor antagonist, which reduced instrumental responses by ∼50% at doses of 0.5 mg/kg and larger. Conversely, selective δ and κ receptor antagonists (naltrindole and nor-binaltorphimine, respectively) had no effect on sensation-seeking behavior. Importantly, while naltrexone produces aversion in the conditioned place preference test, cyprodime had no such effect. Therefore, reduced instrumental responding was not correlated with aversive effects of the opioid antagonists. In conclusion, our results revealed a novel mechanism of action of selective opioid receptors antagonists, which may have relevance for their efficacy in the treatment of drug abuse.

Sensitivity to negative and positive feedback as a stable and enduring behavioural trait in rats.

RATIONALE: According to psychological theories, cognitive distortions play a pivotal role in the aetiology and recurrence of mood disorders. Although clinical evidence for the coexistence of depression and altered sensitivity to performance feedback is relatively coherent, we still do not know whether increased or decreased sensitivity to positive or negative feedback is associated with 'pro-depressive' profile in healthy subjects. OBJECTIVE: Our research has been designed to answer this question, and here, we present the first steps in that direction. METHODS: Using a rat version of the probabilistic reversal-learning (PRL) paradigm, we evaluated how sensitivity to negative and positive feedback influences other cognitive processes associated with mood disorders, such as motivation in the progressive ratio schedule of reinforcement (PRSR) paradigm, hedonic status in the sucrose preference (SP) test, locomotor and exploratory activity in the open field (OF) test, and anxiety in the light/dark box (LDB) test. RESULTS: The results of our study demonstrated for the first time that in rodents, sensitivity to negative and positive feedback could be considered a stable and enduring behavioural trait. Importantly, we also showed that these traits are independent of each other and that trait sensitivity to positive feedback is associated with cognitive flexibility in the PRL test. The computational modelling results also revealed that in animals classified as sensitive to positive feedback, the α learning rates for both positive and negative reward prediction errors were higher than those in animals classified as insensitive. We observed no statistically significant interactions between sensitivity to negative or positive feedback and the parameters measured in the PRSR, SP, OF or LDB tests. CONCLUSIONS: Further studies using animal models of depression based on chronic stress should reveal whether sensitivity to feedback is a latent trait that when interacts with stressful life events, could produce correlates of depressive symptoms in rats.

The Fat Mass and Obesity-Associated Protein (FTO) Regulates Locomotor Responses to Novelty via D2R Medium Spiny Neurons.

Variations in the human FTO gene have been linked to obesity and altered connectivity of the dopaminergic neurocircuitry. Here, we report that fat mass and obesity-associated protein (FTO) in dopamine D2 receptor-expressing medium spiny neurons (D2 MSNs) of mice regulate the excitability of these cells and control their striatopallidal globus pallidus external (GPe) projections. Lack of FTO in D2 MSNs translates into increased locomotor activity to novelty, associated with altered timing behavior, without impairing the ability to control actions or affecting reward-driven and conditioned behavior. Pharmacological manipulations of dopamine D1 receptor (D1R)- or D2R-dependent pathways in these animals reveal altered responses to D1- and D2-MSN-mediated control of motor output. These findings reveal a critical role for FTO to control D2 MSN excitability, their projections to the GPe, and behavioral responses to novelty.

Selective Effects of the Loss of NMDA or mGluR5 Receptors in the Reward System on Adaptive Decision-Making.

Selecting the most advantageous actions in a changing environment is a central feature of adaptive behavior. The midbrain dopamine (DA) neurons along with the major targets of their projections, including dopaminoceptive neurons in the frontal cortex and basal ganglia, play a key role in this process. Here, we investigate the consequences of a selective genetic disruption of NMDA receptor and metabotropic glutamate receptor 5 (mGluR5) in the DA system on adaptive choice behavior in mice. We tested the effects of the mutation on performance in the probabilistic reinforcement learning and probability-discounting tasks. In case of the probabilistic choice, both the loss of NMDA receptors in dopaminergic neurons or the loss mGluR5 receptors in D1 receptor-expressing dopaminoceptive neurons reduced the probability of selecting the more rewarded alternative and lowered the likelihood of returning to the previously rewarded alternative (win-stay). When observed behavior was fitted to reinforcement learning models, we found that these two mutations were associated with a reduced effect of the expected outcome on choice (i.e., more random choices). None of the mutations affected probability discounting, which indicates that all animals had a normal ability to assess probability. However, in both behavioral tasks animals with targeted loss of NMDA receptors in dopaminergic neurons or mGluR5 receptors in D1 neurons were significantly slower to perform choices. In conclusion, these results show that glutamate receptor-dependent signaling in the DA system is essential for the speed and accuracy of choices, but at the same time probably is not critical for correct estimation of probable outcomes.