Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice.

Impulsive choice, often characterized by excessive preference for small, short-term rewards over larger, long-term rewards, is a prominent feature of substance use and other neuropsychiatric disorders. The neural mechanisms underlying impulsive choice are not well understood, but growing evidence implicates nucleus accumbens (NAc) dopamine and its actions on dopamine D2 receptors (D2Rs). Because several NAc cell types and afferents express D2Rs, it has been difficult to determine the specific neural mechanisms linking NAc D2Rs to impulsive choice. Of these cell types, cholinergic interneurons (CINs) of the NAc, which express D2Rs, have emerged as key regulators of striatal output and local dopamine release. Despite these relevant functions, whether D2Rs expressed specifically in these neurons contribute to impulsive choice behavior is unknown. Here, we show that D2R upregulation in CINs of the mouse NAc increases impulsive choice as measured in a delay discounting task without affecting reward magnitude sensitivity or interval timing. Conversely, mice lacking D2Rs in CINs showed decreased delay discounting. Furthermore, CIN D2R manipulations did not affect probabilistic discounting, which measures a different form of impulsive choice. Together, these findings suggest that CIN D2Rs regulate impulsive decision-making involving delay costs, providing new insight into the mechanisms by which NAc dopamine influences impulsive behavior.

Prior experience modifies acquisition trajectories via response-strategy sampling.

Few studies have considered how signal detection parameters evolve during acquisition periods. We addressed this gap by training mice with differential prior experience in a conditional discrimination, auditory signal detection task. Naïve mice, mice given separate experience with each of the later correct choice options (Correct Choice Response Transfer, CCRT), and mice experienced in conditional discriminations (Conditional Discrimination Transfer, CDT) were trained to detect the presence or absence of a tone in white noise. We analyzed data assuming a two-period model of acquisition: a pre-solution and solution period (Heinemann EG (1983) in The Presolution period and the detection of statistical associations. In: Quantitative analyses of behavior: discrimination processes, vol. 4, pp. 21-36). Ballinger. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.536.1978andrep=rep1andtype=pdf ). The pre-solution period was characterized by a selective sampling of biased response strategies until adoption of a conditional responding strategy in the solution period. Correspondingly, discriminability remained low until the solution period; criterion took excursions reflecting response-strategy sampling. Prior experience affected the length and composition of the pre-solution period. Whereas CCRT and CDT mice had shorter pre-solution periods than naïve mice, CDT and Naïve mice developed substantial criterion biases and acquired asymptotic discriminability faster than CCRT mice. To explain these data, we propose a learning model in which mice selectively sample and test different response-strategies and corresponding task structures until they exit the pre-solution period. Upon exit, mice adopt the conditional responding strategy and task structure, with action values updated via inference and generalization from the other task structures. Simulations of representative mouse data illustrate the viability of this model.

Temporal encoding: Relative and absolute representations of time guide behavior.

Temporal information-processing is critical for adaptive behavior and goal-directed action. It is thus crucial to understand how the temporal distance between behaviorally relevant events is encoded to guide behavior. However, research on temporal representations has yielded mixed findings as to whether organisms utilize relative versus absolute judgments of time intervals. To address this fundamental question about the timing mechanism, we tested mice in a duration discrimination procedure in which they learned to correctly categorize tones of different durations as short or long. After being trained on a pair of target intervals, the mice were transferred to conditions in which cue durations and corresponding response locations were systematically manipulated so that either the relative or absolute mapping remained constant. The findings indicate that transfer occurred most readily when relative relationships of durations and response locations were preserved. In contrast, when subjects had to re-map these relative relations, even when positive transfer initially occurred based on absolute mappings, their temporal discrimination performance was impaired, and they required extensive training to re-establish temporal control. These results demonstrate that mice can represent experienced durations both as having a certain magnitude (absolute representation) and as being shorter or longer of the two durations (an ordinal relation to other cue durations), with relational control having a more enduring influence in temporal discriminations. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Dopamine D2 receptors in nucleus accumbens cholinergic interneurons increase impulsive choice.

Impulsive choice, often characterized by excessive preference for small, short-term rewards over larger, long-term rewards, is a prominent feature of substance use and other neuropsychiatric disorders. The neural mechanisms underlying impulsive choice are not well understood, but growing evidence implicates nucleus accumbens (NAc) dopamine and its actions on dopamine D2 receptors (D2Rs). Because several NAc cell types and afferents express D2Rs, it has been difficult to determine the specific neural mechanisms linking NAc D2Rs to impulsive choice. Of these cell types, cholinergic interneurons (CINs) of the NAc, which express D2Rs, have emerged as key regulators of striatal output and local dopamine release. Despite these relevant functions, whether D2Rs expressed specifically in these neurons contribute to impulsive choice behavior is unknown. Here, we show that D2R upregulation in CINs of the mouse NAc increases impulsive choice as measured in a delay discounting task without affecting reward magnitude sensitivity or interval timing. Conversely, mice lacking D2Rs in CINs showed decreased delay discounting. Furthermore, CIN D2R manipulations did not affect probabilistic discounting, which measures a different form of impulsive choice. Together, these findings suggest that CIN D2Rs regulate impulsive decision-making involving delay costs, providing new insight into the mechanisms by which NAc dopamine influences impulsive behavior.

Temporal scaling and computing time in neural circuits: Should we stop watching the clock and look for its gears?

Timing underlies a variety of functions, from walking to perceiving causality. Neural timing models typically fall into one of two categories-"ramping" and "population-clock" theories. According to ramping models, individual neurons track time by gradually increasing or decreasing their activity as an event approaches. To time different intervals, ramping neurons adjust their slopes, ramping steeply for short intervals and vice versa. In contrast, according to "population-clock" models, multiple neurons track time as a group, and each neuron can fire nonlinearly. As each neuron changes its rate at each point in time, a distinct pattern of activity emerges across the population. To time different intervals, the brain learns the population patterns that coincide with key events. Both model categories have empirical support. However, they often differ in plausibility when applied to certain behavioral effects. Specifically, behavioral data indicate that the timing system has a rich computational capacity, allowing observers to spontaneously compute novel intervals from previously learned ones. In population-clock theories, population patterns map to time arbitrarily, making it difficult to explain how different patterns can be computationally combined. Ramping models are viewed as more plausible, assuming upstream circuits can set the slope of ramping neurons according to a given computation. Critically, recent studies suggest that neurons with nonlinear firing profiles often scale to time different intervals-compressing for shorter intervals and stretching for longer ones. This "temporal scaling" effect has led to a hybrid-theory where, like a population-clock model, population patterns encode time, yet like a ramping neuron adjusting its slope, the speed of each neuron's firing adapts to different intervals. Here, we argue that these "relative" population-clock models are as computationally plausible as ramping theories, viewing population-speed and ramp-slope adjustments as equivalent. Therefore, we view identifying these "speed-control" circuits as a key direction for evaluating how the timing system performs computations. Furthermore, temporal scaling highlights that a key distinction between different neural models is whether they propose an absolute or relative time-representation. However, we note that several behavioral studies suggest the brain processes both scales, cautioning against a dichotomy.

Dopamine encodes real-time reward availability and transitions between reward availability states on different timescales.

Optimal behavior requires interpreting environmental cues that indicate when to perform actions. Dopamine is important for learning about reward-predicting events, but its role in adapting to inhibitory cues is unclear. Here we show that when mice can earn rewards in the absence but not presence of an auditory cue, dopamine level in the ventral striatum accurately reflects reward availability in real-time over a sustained period (80 s). In addition, unpredictable transitions between different states of reward availability are accompanied by rapid (~1-2 s) dopamine transients that deflect negatively at the onset and positively at the offset of the cue. This Dopamine encoding of reward availability and transitions between reward availability states is not dependent on reward or activity evoked dopamine release, appears before mice learn the task and is sensitive to motivational state. Our findings are consistent across different techniques including electrochemical recordings and fiber photometry with genetically encoded optical sensors for calcium and dopamine.

Developmental impact of glutamate transporter overexpression on dopaminergic neuron activity and stereotypic behavior.

Obsessive-compulsive disorder (OCD) is a disabling condition that often begins in childhood. Genetic studies in OCD have pointed to SLC1A1, which encodes the neuronal glutamate transporter EAAT3, with evidence suggesting that increased expression contributes to risk. In mice, midbrain Slc1a1 expression supports repetitive behavior in response to dopaminergic agonists, aligning with neuroimaging and pharmacologic challenge studies that have implicated the dopaminergic system in OCD. These findings suggest that Slc1a1 may contribute to compulsive behavior through altered dopaminergic transmission; however, this theory has not been mechanistically tested. To examine the developmental impact of Slc1a1 overexpression on compulsive-like behaviors, we, therefore, generated a novel mouse model to perform targeted, reversible overexpression of Slc1a1 in dopaminergic neurons. Mice with life-long overexpression of Slc1a1 showed a significant increase in amphetamine (AMPH)-induced stereotypy and hyperlocomotion. Single-unit recordings demonstrated that Slc1a1 overexpression was associated with increased firing of dopaminergic neurons. Furthermore, dLight1.1 fiber photometry showed that these behavioral abnormalities were associated with increased dorsal striatum dopamine release. In contrast, no impact of overexpression was observed on anxiety-like behaviors or SKF-38393-induced grooming. Importantly, overexpression solely in adulthood failed to recapitulate these behavioral phenotypes, suggesting that overexpression during development is necessary to generate AMPH-induced phenotypes. However, doxycycline-induced reversal of Slc1a1/EAAT3 overexpression in adulthood normalized both the increased dopaminergic firing and AMPH-induced responses. These data indicate that the pathologic effects of Slc1a1/EAAT3 overexpression on dopaminergic neurotransmission and AMPH-induced stereotyped behavior are developmentally mediated, and support normalization of EAAT3 activity as a potential treatment target for basal ganglia-mediated repetitive behaviors.

Dopamine D2 receptors modulate the cholinergic pause and inhibitory learning.

Cholinergic interneurons (CINs) in the striatum respond to salient stimuli with a multiphasic response, including a pause, in neuronal activity. Slice-physiology experiments have shown the importance of dopamine D2 receptors (D2Rs) in regulating CIN pausing, yet the behavioral significance of the CIN pause and its regulation by dopamine in vivo is still unclear. Here, we show that D2R upregulation in CINs of the nucleus accumbens (NAc) lengthens the pause in CIN activity ex vivo and enlarges a stimulus-evoked decrease in acetylcholine (ACh) levels during behavior. This enhanced dip in ACh levels is associated with a selective deficit in the learning to inhibit responding in a Go/No-Go task. Our data demonstrate, therefore, the importance of CIN D2Rs in modulating the CIN response induced by salient stimuli and point to a role of this response in inhibitory learning. This work has important implications for brain disorders with altered striatal dopamine and ACh function, including schizophrenia and attention-deficit hyperactivity disorder (ADHD).

How changes in dopamine D2 receptor levels alter striatal circuit function and motivation.

It was first posited, more than five decades ago, that the etiology of schizophrenia involves overstimulation of dopamine receptors. Since then, advanced clinical research methods, including brain imaging, have refined our understanding of the relationship between striatal dopamine and clinical phenotypes as well as disease trajectory. These studies point to striatal dopamine D2 receptors, the main target for all current antipsychotic medications, as being involved in both positive and negative symptoms. Simultaneously, animal models have been central to investigating causal relationships between striatal dopamine D2 receptors and behavioral phenotypes relevant to schizophrenia. We begin this article by reviewing the circuit, cell-type and subcellular locations of dopamine D2 receptors and their downstream signaling pathways. We then summarize results from several mouse models in which D2 receptor levels were altered in various brain regions, cell-types and developmental periods. Behavioral, electrophysiological and anatomical consequences of these D2 receptor perturbations are reviewed with a selective focus on striatal circuit function and alterations in motivated behavior, a core negative symptom of schizophrenia. These studies show that D2 receptors serve distinct physiological roles in different cell types and at different developmental time points, regulating motivated behaviors in sometimes opposing ways. We conclude by considering the clinical implications of this complex regulation of striatal circuit function by D2 receptors.

A role for reward valuation in the serotonergic modulation of impulsivity.

RATIONALE: Impulsive behavior is a deleterious component of a number of mental health disorders but has few targeted pharmacotherapies. One contributing factor to the difficulty in understanding the neural substrates of disordered impulsivity is the diverse presentations of impulsive behavior. Defining the behavioral and cognitive processes which contribute to different subtypes of impulsivity is important for understanding the neural underpinnings of dysregulated impulsive behavior. METHODS: Using a mouse model for disordered impulsivity, our goal was to identify behavioral and cognitive processes that are associated with increased impulsivity. Specifically, we were interested in the facets of impulsivity modulated by serotonin signaling. We used mice lacking the serotonin 1B receptor (5-HT1BR) and measured different types of impulsivity as well as goal-directed responding, extinction, habitual-like behavior, cue reactivity, and reward reactivity. RESULTS: Mice lacking expression of 5-HT1BR had increased levels of impulsive action, goal-directed responding, and motivation, with no differences seen in rate of extinction, development of habitual behavior, delay discounting, or effort-based discounting. Interestingly, mice lacking 5-HT1BR expression also showed an overall increase in the choice of higher value rewards, increased hedonic responses to sweet rewards, and responded more for cues that predict reward. We developed a novel paradigm to demonstrate that increasing anticipated reward value could directly increase impulsive action. Furthermore, we found that 5-HT1BR KO-induced impulsivity could be ameliorated by decreasing the reward value relative to controls, suggesting that the increased 5-HT1BR-associated impulsive action may be a result of increased reward valuation. CONCLUSIONS: Taken together, these data show that the effects of serotonin on impulsive action are mediated through the modulation of hedonic value, which may alter the reward representations that motivate action. Overall, this data supports a role for reward value as an important substrate in impulsive action which may drive clinically relevant increases in impulsivity.

Dopamine D2R upregulation in ventral striatopallidal neurons does not affect Pavlovian or go/no-go learning.

Ventral striatal dopamine is thought to be important for associative learning. Dopamine exerts its role via activation of dopamine D1 and D2 receptors in the ventral striatum. Upregulation of dopamine D2R in ventral striatopallidal neurons impairs incentive motivation via inhibiting synaptic transmission to the ventral pallidum. Here, we determined whether upregulation of D2Rs and the resulting impairment in ventral striatopallidal pathway function modulates associative learning in an auditory Pavlovian reward learning task as well as Go/No-Go learning in an operant based reward driven Go/No-Go task. We found that upregulation of D2Rs did not affect Pavlovian learning or the extinction of Pavlovian responses, and neither did it alter No-Go learning. We however observed a delay in the Go component of the task which may indicate a deficit in learning though it could also be attributed to the established locomotor hyperactivity of the mice. In combination with previously published findings, our data suggest that D2Rs in ventral striatopallidal neurons play a specific role in regulating motivation by balancing cost/benefit computations but do not necessarily affect associative learning. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Dissociating the effects of dopamine D2 receptors on effort-based versus value-based decision making using a novel behavioral approach.

Cost-benefit decision making is essential for organisms to adapt to their ever-changing environment. Most studies of cost-benefit decision making involve choice conditions in which effort and value are varied simultaneously. This prevents identification of the aspects of cost-benefit decision making that are affected by experimental manipulations. We developed operant assays to isolate the individual impacts of effort and value manipulations on cost-benefit decision making. In the concurrent effort choice (CEC) task, mice choose between exerting two distinct types of effort: the number of responses and the duration of a response, to earn the same reward. By parametrically varying response cost, psychometric functions are obtained that reflect how the two types of effort scale against one another. Direct manipulations of effort shift the functions. Because reward value is held constant in this task, differences in scaling of the two response types must be related to the effort manipulations. In the concurrent value choice (CVC) task, mice make the same type of response to earn rewards of different value (e.g., pellets vs. sucrose solutions). Here the effort required to earn one reward type is parametrically varied to obtain the psychometric function that scales the value of the two rewards into the number of responses subjects will pay to earn one reward over the other. Direct value manipulations shift these functions. We tested the effect of the dopamine D2 receptor antagonist, haloperidol, on performance in the CEC and CVC assays and found that D2R signaling is important for effort-based, but not value-based decision making. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Emerging roles of striatal dopamine D2 receptors in motivated behaviour: Implications for psychiatric disorders.

Impaired motivation has been a long recognized negative symptom of schizophrenia, as well as a common feature of non-psychotic psychiatric disorders, responsible for a significant share of functional burden, and with limited treatment options. The striatum and dopamine signalling system play a central role in extracting motivationally relevant information from the environment, selecting which behavioural direction the animal should follow, and the vigour with which to engage it. Much of this function relies on striatal projection neurons, known as medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2Rs), or D2-MSNs. However, determining the precise nature of D2-MSNs in regulating motivated behaviour in both healthy individuals and experimental manipulations of D2-MSN function has at times yielded a somewhat confusing picture since their activity has been linked to either enhancement or dampening of motivation in animal models. In this MiniReview, we describe the latest data from rodent studies that investigated how D2Rs exert their modulatory effect on motivated behaviour by regulating striatal indirect pathway neuronal activity. We will include a discussion about how functional selectivity of D2Rs towards G protein-dependent or ß-arrestin-dependent signalling differentially affects motivated behaviour. Lastly, we will describe a recent preclinical attempt to improve motivation by exploiting serotonin receptor-mediated modulation of dopamine transmission in the striatum.

Overexpression of striatal D2 receptors reduces motivation thereby decreasing food anticipatory activity.

Dopamine has been implicated in circadian timing underlying the food entrainable oscillator (FEO) circuitry and overexpression of the dopamine D2 receptor (D2R) in the striatum has been reported to reduce motivation to obtain food rewards in operant tasks. In the present study, we explored both of these mechanisms by examining food anticipatory activity (FAA) in dopamine D2 receptor-overexpressing (D2R-OE) mice under various durations of food availability. First, we noted that at baseline, there were no differences between D2R-OE mice and their littermates in activity level, food intake, and body weight or in circadian activity. Under conditions of very restricted food availability (4 or 6 hr), both genotypes displayed FAA. In contrast, under 8-hr food availability, control mice showed FAA, but D2R-OE mice did not. Normalization of D2R by administration of doxycycline, a tetracycline analogue, rescued FAA under 8-hr restricted food. We next tested for circadian regulation of FAA. When given ad libitum access to food, neither D2R-OE nor controls were active during the daytime. However, after an interval of food restriction, all mice showed elevated locomotor activity at the time of previous food availability in the day, indicating circadian timing of anticipatory activity. In summary, motivation is reduced in D2R-OE mice but circadian timing behavior is not affected. We conclude that an increase in striatal D2R reduces FAA by modulating motivation and not by acting on a clock mechanism.

Evidence for a Mixed Timing and Counting Strategy in Mice Performing a Mechner Counting Task.

Numerosity, or the ability to understand and distinguish between discrete quantities, was first formalized for study in animals by Mechner (1958a). Rats had to press one lever (the counting lever) n times to arm food release from pressing a second lever (the reward lever). The only cue that n presses had been made to the counting lever was the animal's representation of how many times it had pressed it. In the years that have passed since, many researchers have modified the task in meaningful ways to attempt to tease apart timing-based and count-based strategies. Strong evidence has amassed that the two are fundamentally different and separable skills but, to date, no study has effectively examined the differential contributions of the two strategies in Mechner's original task. By examining performance mid-trial and correlating it with whole-trial performance, we were able to identify patterns of correlation consistent with counting and timing strategies. Due to the independent nature of these correlation patterns, this technique was uniquely able to provide evidence for strategies that combined both timing and counting components. The results show that most mice demonstrated this combined strategy. This provides direct evidence that mice can and do use numerosity to complete Mechner's original task. A rational agent with fallible estimates of both counts made and time elapsed in making them should use both estimates when deciding when to switch to the second lever.

Time-scale-invariant information-theoretic contingencies in discrimination learning.

Animals optimize their behavior to maximize rewards by utilizing cues from the environment. In discrimination learning, cues signal when rewards can and cannot be earned by making a particular response. In our experiment, we trained male mice to press a lever to receive a reward on a random interval schedule. We then introduced a prolonged tone (20, 40, or 80 sec), during which no rewards could be earned. We sought to test our hypothesis that the duration of the tone and frequency of reward during the inter-tone-intervals affect the informativeness of cues and led to differences in discriminative behavior. Learning was expressed as an increase in lever pressing during the intertrial interval (ITI) and, when the informativeness of the cue was high, animals also reduced their lever pressing during the tone. Additionally, we found that the depth of discriminative learning was linearly related to the informativeness of the cues. Our results show that the time-scale invariant information-theoretic definition of contingency applied to excitatory conditioning can also be applied to inhibitory conditioning. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Striatal dopamine D2 receptors regulate effort but not value-based decision making and alter the dopaminergic encoding of cost.

Deficits in goal-directed motivation represent a debilitating symptom for many patients with schizophrenia. Impairments in motivation can arise from deficits in processing information about effort and or value, disrupting effective cost-benefit decision making. We have previously shown that upregulated dopamine D2 receptor expression within the striatum (D2R-OE mice) decreases goal-directed motivation. Here, we determine the behavioral and neurochemical mechanisms behind this deficit. Female D2R-OE mice were tested in several behavioral paradigms including recently developed tasks that independently assess the impact of Value or Effort manipulations on cost-benefit decision making. In vivo microdialysis was used to measure extracellular dopamine in the striatum during behavior. In a value-based choice task, D2R-OE mice show normal sensitivity to changes in reward value and used reward value to guide their actions. In an effort-based choice task, D2R-OE mice evaluate the cost of increasing the number of responses greater relative to the effort cost of longer duration responses compared to controls. This shift away from choosing to repeatedly execute a response is accompanied by a dampening of extracellular dopamine in the striatum during goal-directed behavior. In the ventral striatum, extracellular dopamine level negatively correlates with response cost in controls, but this relationship is lost in D2R-OE mice. These results show that D2R signaling in the striatum, as observed in some patients with schizophrenia, alters the relationship between effort expenditure and extracellular dopamine. This dysregulation produces motivation deficits that are specific to effort but not value-based decision making, paralleling the effort-based motivational deficits observed in schizophrenia.

A Perceptual Inference Mechanism for Hallucinations Linked to Striatal Dopamine.

Hallucinations, a cardinal feature of psychotic disorders such as schizophrenia, are known to depend on excessive striatal dopamine. However, an underlying cognitive mechanism linking dopamine dysregulation and the experience of hallucinatory percepts remains elusive. Bayesian models explain perception as an optimal combination of prior expectations and new sensory evidence, where perceptual distortions such as illusions and hallucinations may occur if prior expectations are afforded excessive weight. Such excessive weight of prior expectations, in turn, could stem from a gain-control process controlled by neuromodulators such as dopamine. To test for such a dopamine-dependent gain-control mechanism of hallucinations, we studied unmedicated patients with schizophrenia with varying degrees of hallucination severity and healthy individuals using molecular imaging with a pharmacological manipulation of dopamine, structural imaging, and a novel task designed to measure illusory changes in the perceived duration of auditory stimuli under different levels of uncertainty. Hallucinations correlated with a perceptual bias, reflecting disproportional gain on expectations under uncertainty. This bias could be pharmacologically induced by amphetamine, strongly correlated with striatal dopamine release, and related to cortical volume of the dorsal anterior cingulate, a brain region involved in tracking environmental uncertainty. These findings outline a novel dopamine-dependent mechanism for perceptual modulation in physiological conditions and further suggest that this mechanism may confer vulnerability to hallucinations in hyper-dopaminergic states underlying psychosis.

An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice.

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.

Dopamine D2 Receptors in the Paraventricular Thalamus Attenuate Cocaine Locomotor Sensitization.

Alterations in thalamic dopamine (DA) or DA D2 receptors (D2Rs) have been measured in drug addiction and schizophrenia, but the relevance of thalamic D2Rs for behavior is largely unknown. Using in situ hybridization and mice expressing green fluorescent protein (GFP) under the Drd2 promoter, we found that D2R expression within the thalamus is enriched in the paraventricular nucleus (PVT) as well as in more ventral midline thalamic nuclei. Within the PVT, D2Rs are inhibitory as their activation inhibits neuronal action potentials in brain slices. Using Cre-dependent anterograde and retrograde viral tracers, we further determined that PVT neurons are reciprocally interconnected with multiple areas of the limbic system including the amygdala and the nucleus accumbens (NAc). Based on these anatomical findings, we analyzed the role of D2Rs in the PVT in behaviors that are supported by these areas and that also have relevance for schizophrenia and drug addiction. Male and female mice with selective overexpression of D2Rs in the PVT showed attenuated cocaine locomotor sensitization, whereas anxiety levels, fear conditioning, sensorimotor gating, and food-motivated behaviors were not affected. These findings suggest the importance of PVT inhibition by D2Rs in modulating the sensitivity to cocaine, a finding that may have novel implications for human drug use.