Enhanced Risky Choice in Male Rats Elicited by the Acute Pharmacological Stressor Yohimbine Involves Prefrontal Dopamine D1 Receptor Activation.

BACKGROUND: Acute stress alters risk-based decision-making; however, the underlying neural and neurochemical substrates are underexplored. Given their well-documented stress-inducing effects in humans and laboratory animals, glucocorticoids such as cortisol and corticosterone and the α2-adrenoceptor antagonist yohimbine represent potent pharmacological tools to mimic some characteristics of acute stress. METHODS: Here, we analyzed the effects of the pharmacological stressors corticosterone and yohimbine given systemically on risk-based decision-making in male rats. Moreover, we investigated whether pharmacological stressor effects on risk-based decision-making involve dopamine D1 receptor stimulation in the dorsal prelimbic cortex (PL). We used a risk discounting task that requires choosing between a certain/small reward lever that always delivered 1 pellet and a risky/large reward lever that delivered 4 pellets with a decreasing probability across subsequent trials. RESULTS: Systemic administration of yohimbine increased the preference for the risky/large reward lever. By contrast, systemic single administration of corticosterone did not significantly promote risky choice. Moreover, co-administration of corticosterone did not enhance the effects of yohimbine on risky choice. The data further show that the increased preference for the risky/large reward lever under systemic yohimbine was lowered by a concurrent pharmacological blockade of dopamine D1 receptors in the PL. CONCLUSIONS: Our rodent data provide causal evidence that stimulation of PL D1 receptors may represent a neurochemical mechanism by which the acute pharmacological stressor yohimbine, and possibly nonpharmacological stressors as well, promote risky choice.

Effects of Motivational Downshifts on Specific Pavlovian-Instrumental Transfer in Rats.

BACKGROUND: Pavlovian stimuli predictive of appetitive outcomes can exert a powerful influence on the selection and initiation of action, a phenomenon termed outcome-selective Pavlovian-instrumental transfer (sPIT). Rodent studies suggest that sPIT is insensitive to motivational downshift induced by outcome devaluation, an effect that is, however, relatively underexplored. METHODS: Here we examined in detail the effects of distinct shifts in motivation from hunger to a state of relative satiety on sPIT in rats. RESULTS: A motivational downshift by outcome-specific devaluation immediately prior to testing markedly reduced overall lever responding and magazine entries but left intact the sPIT effect. A motivational downshift prior testing by (1) giving ad libitum rather than restricted access to maintenance diet in the home cage for 24 hours or by (2) a systemic blockade of hormone secretagogue receptor subtype 1A receptors to inhibit orexigenic actions of ghrelin both reduced overall lever responding and magazine entries. Moreover, these latter motivational downshifts reduced the sPIT effect; however, the sizes of the sPIT effects were still large. CONCLUSIONS: Collectively, our rodent findings indicate that major effects of various motivational downshifts are overall inhibition of lever pressing and magazine approach, possibly reflecting reduced general motivation. The observed effects of motivational downshifts on sPIT have implications with regard to the role of general motivating effects in sPIT and to the contribution of Pavlovian-instrumental interactions to excessive food seeking as well as obesity in humans.

Medial Orbitofrontal Cortex Mediates Effort-related Responding in Rats.

The medial orbitofrontal cortex (mOFC) is known to support flexible control of goal-directed behavior. However, limited evidence suggests that the mOFC also mediates the ability of organisms to work with vigor towards a selected goal, a hypothesis that received little consideration to date. Here we show that excitotoxic mOFC lesion increased responding under a progressive ratio (PR) schedule of reinforcement, that is, the highest ratio achieved, and increased the preference for the high effort-high reward option in an effort-related decision-making task, but left intact outcome-selective Pavlovian-instrumental transfer and outcome-specific devaluation. Moreover, pharmacological inhibition of the mOFC increased, while pharmacological stimulation reduced PR responding. In addition, pharmacological mOFC stimulation attenuated methylphenidate-induced increase of PR responding. Intact rats tested for PR responding displayed higher numbers of c-Fos positive mOFC neurons than appropriate controls; however, mOFC neurons projecting to the nucleus accumbens did not show a selective increase in neuronal activation implying that they may not play a major role in regulating PR responding. Collectively, these results suggest that the mOFC plays a major role in mediating effort-related motivational functions. Moreover, our data demonstrate for the first time that the mOFC modulates effort-related effects of psychostimulant drugs.

Stimulant drug effects on touchscreen automated paired-associates learning (PAL) in rats.

Here we tested in rats effects of the procognitive drugs modafinil and methylphenidate on post-acquisition performance in an object-location paired-associates learning (PAL) task. Modafinil (32; 64 mg/kg) was without effect, while higher (9 mg/kg) but not lower (4.5 mg/kg) doses of methylphenidate impaired PAL performance. Likewise, higher but not lower doses of amphetamine (0.4; 0.8 mg/kg) and MK-801 (0.08; 0.12 mg/kg) decreased PAL performance. Impaired PAL performance induced by methylphenidate, amphetamine, and MK801 most likely reflects compromised cognitive function, e.g., retrieval of learned paired associates. Our data suggest that stimulant drugs such as methylphenidate and modafinil might not facilitate performance in hippocampus-related cognitive tasks.

Ghrelin receptor activation in the ventral tegmental area amplified instrumental responding but not the excitatory influence of Pavlovian stimuli on instrumental responding.

Pavlovian stimuli predictive of food are able to amplify instrumental responding for food. This phenomenon termed Pavlovian-instrumental transfer (PIT) critically depends on intact VTA function and mesoaccumbens dopamine transmission. Considerable evidence suggests that food-predictive stimuli can enhance the release of ghrelin, an orexigen hormone that promotes food-directed responding. The ventral tegmental area (VTA) appears to be a key region through which stimulation of ghrelin receptors (GHS-R1A) invigorates food-directed responding, in part by activating the mesoaccumbens dopamine system. Thus, it is conceivable that stimulation of GHS-R1A in the VTA can amplify PIT, i.e. stimulus-elicited increase in lever pressing for food. Here we examined in rats the effects of VTA ghrelin microinfusion on PIT. Our results demonstrate that ghrelin microinfusion into the VTA failed to enhance PIT suggesting that VTA GHS-R1A stimulation was unable to enhance the motivational significance of food-predictive stimuli. Consistent with previous studies, our results further indicate that intra-VTA ghrelin microinfusion invigorated instrumental responding under a progressive ratio schedule. These data provide support to the notion that VTA GHS-R1A stimulation increases the tendency to work for food.

Orbitofrontal or accumbens dopamine depletion does not affect risk-based decision making in rats.

Considerable evidence has implicated dopamine (DA) signals in target regions of midbrain DA neurons such as the medial prefrontal cortex or the core region of the nucleus accumbens in controlling risk-based decision-making. However, to date little is known about the contribution of DA in the orbitofrontal cortex (OFC) and the medial shell region of the nucleus accumbens (AcbS) to risk-based decision-making. Here we examined in rats the effects of 6-hydroxydopamine-induced DA depletions of the OFC and AcbS on risky choice using an instrumental two-lever choice task that requires the assessment of fixed within-session reward probabilities that were shifted across subsequent sessions, i.e., rats had to choose between two levers, a small/certain lever that delivered one certain food reward (one pellet at p = 1) and a large/risky lever that delivered a larger uncertain food reward with decreasing probabilities across subsequent sessions (four pellets at p = 0.75, 0.5, 0.25, 0.125, 0.0625). Results show that systemic administration of amphetamine or cocaine increased the preference for the large/risky lever. Results further demonstrate that, like sham controls, rats with OFC or AcbS DA depletion were sensitive to changes in probabilities for obtaining the large/risky reward across sessions and displayed probabilistic discounting. These findings point to the view that the basal capacity to evaluate the magnitude and likelihood of rewards associated with alternative courses of action as well as long-term changes of reward probabilities does not rely on DA input to the AcbS or OFC.

Dopamine D1/D2 Receptor Activity in the Nucleus Accumbens Core But Not in the Nucleus Accumbens Shell and Orbitofrontal Cortex Modulates Risk-Based Decision Making.

BACKGROUND: It is well known that brain dopamine (DA) signals support risk-based decision making; however, the specific terminal regions of midbrain DA neurons through which DA signals mediate risk-based decision making are unknown. METHODS: Using microinfusions of the D1/D2 receptor antagonist flupenthixol, we sought to explore the role of D1/D2 receptor activity in the rat orbitofrontal cortex (OFC) and core and shell regions of the nucleus accumbens (AcbC and AcbS, respectively) in the regulation of risky choices. A risk-discounting task was used that involves choices between a certain small-reward lever that always delivered 1 pellet or a risky large-reward lever which delivered 4 pellets but had a decreasing probability of receiving the reward across 4 subsequent within-session trial blocks (100%, 50%, 25%, 12.5%). To validate task sensitivity to experimental manipulations of DA activity, we also examined the effects of systemic amphetamine and flupenthixol. RESULTS: Systemic amphetamine increased while systemic flupenthixol reduced risky choices. Results further demonstrate that rats that received intra-AcbC flupenthixol were able to track increasing risk associated with the risky lever but displayed a generally reduced preference for the risky lever across all trial blocks, including in the initial trial block (large reward at 100%). Microinfusions of flupenthixol into the AcbS or OFC did not alter risk-based decision making. CONCLUSIONS: Our data suggest that intra-AcbC D1/D2 receptor signaling does not support the ability to track shifts in reward probabilities but does bias risk-based decision making. That is, it increased the rats' preference for the response option known to be associated with higher risk-related costs.

Dopamine D1/D2 receptors do not mediate the expression of conditioned place preference induced by the aftereffect of wheel running.

BACKGROUND: Rats lever-press for access to running wheels suggesting that wheel running by itself is reinforcing. Furthermore, pairings of an episode of wheel running and subsequent confinement in a specific environment can establish a conditioned place preference (CPP). This finding implies that the reinforcing effects of wheel running outlast the actual occurrence of physical activity, a phenomenon referred to as aftereffect of wheel running. Aftereffect-induced CPP involves Pavlovian conditioning, i.e. repeated pairings of the aftereffect of wheel running with a specific environment creates a learned association between aftereffect and environment and, in turn, a preference for that environment. Given the involvement of dopamine systems in mediating effects of Pavlovian stimuli on appetitive behavior, a role of dopamine in mediating aftereffect-induced CPP seems plausible. Here we assessed whether the mixed D1/D2 receptor antagonist flupenthixol (0.25 mg/kg, i.p.) can block the expression of an aftereffect-induced CPP. RESULTS: In line with earlier studies, our results demonstrate that rats displayed a conditioned preference for environments paired with the aftereffect of wheel running and further show that the magnitude of CPP was not related to the wheel running rate. Furthermore, we found that flupenthixol (0.25 mg/kg, i.p.) reduced locomotor activity but did not attenuate the expression of an aftereffect-induced CPP. CONCLUSION: The expression of a CPP produced by the aftereffect of wheel running seems not to depend on dopamine D1/D2 receptor activation.

Acute stressor effects on goal-directed action in rats.

Here we examined effects of acute stressors that involve either systemic coadministration of corticosterone/yohimbine (3 mg/kg each) to increase glucocorticoid/noradrenaline activity (denoted as "pharmacological" stressor) or one or several distinct restraint stressors (denoted as "single" vs. "multiple" stressor) on performance of goal-directed actions. Rats were trained over 11 d to perform two instrumental actions, one for food pellets the other for sucrose solution, followed by two consecutive tests days. On each test day, rats were first sated in a counterbalanced manner on one of the two outcomes by prefeeding (selective outcome devaluation), then subjected to an acute stressor, and tested afterward in a two-lever choice task in extinction to assess whether instrumental performance is goal-directed, i.e., sensitive to changes in outcome value. Like in control rats, in rats subjected to the pharmacological or single restraint stressor prior to the choice test, performance of instrumental action was goal-directed, i.e., sensitive to outcome devaluation. By contrast, in rats exposed to the multiple stressor prior to the choice test, performance of instrumental action was habitual, i.e., insensitive to outcome devaluation. Pretreatment with diazepam (1 and 2 mg/kg) did not alleviate (or only marginally) this multiple stressor-induced effect. Thus, an intense acute stressor can render performance of previously acquired instrumental action habitual, possibly due to a compromised retrieval of encoded relationships between actions and their outcome value. Our observation in rats that an acute stressor can shift instrumental responding from goal-directed to habitual control is consistent with similar findings in humans.

The effects of acute stress on Pavlovian-instrumental transfer in rats.

Pavlovian stimuli invigorate ongoing instrumental action, a phenomenon termed the Pavlovian-instrumental transfer (PIT) effect. Acute stressors can markedly enhance the release of corticotropin-releasing factor (CRF), and CRF injection into the nucleus accumbens increases the PIT effect. However, it is unknown whether acute stressors by themselves would amplify the PIT effect. Here, we examined the effects of acute stressors on PIT. Rats first received Pavlovian and instrumental training, and then the impact of the Pavlovian stimuli on instrumental responding was analyzed in the subsequent PIT test. Acute stressors were applied prior to the PIT test. Because the effects of acute stressors critically depend on stressor type and time of day, we used two acute stressors that involved one or several distinct stressors (denoted here as "single" vs. "multiple" stressors) applied either in the light or the dark period of the light:dark cycle. The results revealed that single and multiple stressors applied in the light period did not alter the PIT effect--that is, the ability of an appetitive Pavlovian stimulus to enhance leverpressing--or the basal leverpress rate. When applied in the dark period, single and multiple stressors also did not alter the PIT effect, but they did markedly reduce the basal leverpress rate. Diazepam pretreatment did not counteract the declines in basal instrumental responding in the PIT test that were induced by either a single or multiple stressors. Our findings suggest that acute stressors were unable to amplify the incentive salience of reward-predictive Pavlovian stimuli to activate instrumental responding, but, depending on the time of day of stressor exposure, they did reduce basal instrumental responding.

Striatal dopamine depletion in rats produces variable effects on contingency detection: task-related influences.

Dopamine (DA) depletion of the posterior dorsomedial striatum (pDMS) can impair the capability of rats to detect changes in the causal efficacy of actions. Here we sought to characterize in more detail the effects of pDMS DA depletions on contingency detection as a function of different contingency degradation training protocols. In experiment 1, sham controls and rats with pDMS DA depletions received limited contingency degradation training (4 days) that involved an invariable and high degree of degradation to one of two contingencies controlling instrumental choice behaviour. The results demonstrated that lesioned rats were insensitive to contingency manipulations both during contingency degradation training and in the subsequent extinction test. Experiment 2 further indicated that rats with pDMS DA depletion subjected to extended contingency degradation training (12 days) became sensitive to contingency manipulations during the training phase but not in the subsequent extinction test. In experiment 3, an extended but more complex contingency degradation training protocol (12 days) was used that involved a gradual shift from a low to an intermediate and a high degree of contingency degradation rather than a high and invariable degree of contingency degradation as in experiments 1 and 2. Notably, lesioned rats were sensitive to contingency manipulations both during the contingency degradation training phase and in the subsequent extinction test. Thus, pDMS DA depletions can impair the capability to detect changes in the causal efficacy of actions; however, the occurrence and pattern of impairments depend on the contingency degradation training protocol being used.

Intact risk-based decision making in rats with prefrontal or accumbens dopamine depletion.

The medial prefrontal cortex (mPFC) and the core region of the nucleus accumbens (AcbC) are key regions of a neural system that subserves risk-based decision making. Here, we examined whether dopamine (DA) signals conveyed to the mPFC and AcbC are critical for risk-based decision making. Rats with 6-hydroxydopamine or vehicle infusions into the mPFC or AcbC were examined in an instrumental task demanding probabilistic choice. In each session, probabilities of reward delivery after pressing one of two available levers were signaled in advance in forced trials followed by choice trials that assessed the animal's preference. The probabilities of reward delivery associated with the large/risky lever declined systematically across four consecutive blocks but were kept constant within four subsequent daily sessions of a particular block. Thus, in a given session, rats need to assess the current value associated with the large/risky versus small/certain lever and adapt their lever preference accordingly. Results demonstrate that the assessment of within-session reward probabilities and probability discounting across blocks were not altered in rats with mPFC and AcbC DA depletions, relative to sham controls. These findings suggest that the capacity to evaluate the magnitude and likelihood of rewards associated with alternative courses of action seems not to rely on intact DA transmission in the mPFC or AcbC.

Motivational states influence effort-based decision making in rats: the role of dopamine in the nucleus accumbens.

Decision-making policies are subject to modulation by changing motivational states. However, so far, little is known about the neurochemical mechanisms that bridge motivational states with decision making. Here we examined whether dopamine (DA) in the nucleus accumbens core (AcbC) modulates the effects of motivational states on effort-based decision making. Using a cost-benefit T-maze task in rats, we examined the effects of AcbC DA depletions on effort-based decision making, in particular on the sensitivity of effort-based decision making to a shift from a hungry to a sated state. The results demonstrated that, relative to sham controls, rats with AcbC DA depletion in a hungry as well as in a sated state had a reduced preference for effortful but large-reward action. This finding provides further support for the notion that AcbC DA regulates how much effort to invest for rewards. Importantly, our results further revealed that effort-based decision making in lesioned rats, as in sham controls, was still sensitive to a shift from a hungry to a sated state; that is, their preferences for effortful large-reward actions became lower after a shift from a restricted to a free-feeding regimen. These finding indicate that AcbC DA is not necessarily involved in mediating the effects of a shift in motivational state on decision-making policies.

Pro-cognitive effects of the GlyT1 inhibitor Bitopertin in rodents.

N-methyl-D-aspartate-receptor (NMDAR) hypofunction contributes to cognitive impairments in neuropsychiatric disorders such as schizophrenia. Reduced NMDAR signalling can be enhanced by increasing extracellular levels of the NMDAR co-agonist glycine through inhibition of its transporter (GlyT1). This may be one option to improve cognitive deficits or negative symptoms of schizophrenia. In this preclinical study, we aimed at investigating effects of the GlyT1-inhibitor Bitopertin on cognition, social function and motivation. Central target engagement was assessed by Bitopertin-induced changes in glycine levels in rats' cerebrospinal fluid (CSF) and prefrontal cortex (PFC). Behavioural effects of Bitopertin on recognition memory were evaluated using a social-recognition test in rats, while its effects on working memory were tested in a spontaneous alternation task in mice pre-treated with the NMDAR antagonist MK-801. Bitopertin was further investigated using a social interaction test in rats pre-treated with the NMDAR antagonist phencyclidine, and the effects on effortful motivation were explored in progressive ratio tasks in rats. Results show that Bitopertin increased glycine levels in CSF and PFC. Moreover, it enhanced recognition memory and reduced MK-801-induced working memory deficits. By contrast, Bitopertin had no significant effects on PCP-induced social interaction deficits, and it did not alter effort-related responding. Collectively, our data demonstrate that GlyT1 inhibition by Bitopertin increased CSF and extracellular glycine levels and advocated for pro-cognitive effects of GlyT1 inhibition both in intact and NMDAR antagonists-pre-treated rodents. Together, these findings support the use of GlyT1-inhibitors for the treatment of cognitive symptoms in pathologies characterized by NMDR hypofunction, such as schizophrenia.

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.

Effort-based decision making in the rat: an [18F]fluorodeoxyglucose micro positron emission tomography study.

Decision making refers to the process by which subjects choose between competing courses of action based on the expected costs and benefits of their consequences. Lesion studies in rats suggest that the anterior cingulate cortex and the nucleus accumbens are key structures of a neural system that subserves effort-based decision making. Little is known about brain activation associated with effort-based decisions in intact rats. Using an open hypothesis approach, we used 2-deoxy-2[(18)F]fluoro-D-glucose positron emission tomography (FDG-PET) to assess regional metabolic changes in two conditions of an effort-based decision making task. In the "same effort" condition, male rats could choose between two response options associated with the same effort but different reward sizes, i.e., decision making was simply a function of reward size. By contrast, in the "different effort" condition, an integration of different efforts and reward sizes associated with the two response options was necessary before making a decision. Separate PET scans were performed from each condition. Subtractive analysis revealed that metabolic activity was increased in the different effort relative to the same effort condition in the left anterior cingulate, left orbitofrontal and prelimbic cortex region. Metabolic activity was decreased in the infralimbic cortex and septum region. Our findings suggest that making decisions on how much effort to invest to obtain greater rewards evokes changes of metabolic activity in multiple brain areas associated with cognitive, limbic, motor and autonomic functions. This study demonstrates that FDG-PET provides a tool to determine in rats regional brain metabolic activity in cognitive tasks.

The role of dopamine in the dorsomedial striatum in general and outcome-selective Pavlovian-instrumental transfer.

Pavlovian stimuli predictive of appetitive outcomes can influence the selection and initiation of instrumental behaviour. For instance, Pavlovian stimuli can act to enhance those actions with which they share an outcome, but not others with which they do not share an outcome, a phenomenon termed outcome-selective Pavlovian-instrumental transfer (PIT). Furthermore, Pavlovian stimuli can invigorate an action by inducing a general appetitive arousal that elevates instrumental responding, a phenomenon termed general PIT. The dorsomedial striatum has been implicated in outcome-selective, but not general PIT. However, the role of dopamine (DA) signals in this subregion in mediating PIT is unknown. Here we examined in rats the effects of a 6-hydroxydopamine-induced DA depletion of the anterior (aDMS) or posterior (pDMS) subregion of the dorsomedial striatum on outcome-selective and general PIT as well as on instrumental performance on a FR-5 schedule (five lever presses earned one pellet). Results demonstrate that aDMS and pDMS DA depletions compromised the rate of responding on a FR-5 schedule, suggesting that DA signals in the dorsomedial striatum are necessary to maintain high rates of instrumental responding. By contrast, aDMS and pDMS DA depletions did not affect general PIT, suggesting that DA signals in the dorsomedial striatum do not mediate general activating effects of reward-predictive stimuli to invigorate instrumental responding. Furthermore, aDMS DA depletions did not impair outcome-selective PIT, while pDMS DA depletions had no or only minor effects. Thus, DA signals in the DMS may not be involved in mediating the specific cueing effects of reward-predictive stimuli.

The role of dopamine in the prelimbic cortex and the dorsomedial striatum in instrumental conditioning.

The prelimbic (PL) region of the prefrontal cortex and the posterior subregion of the dorsomedial striatum (pDMS) are components of a corticostriatal circuit subserving instrumental learning. Here, we examined whether dopamine (DA) signals conveyed to the PL and pDMS are critical for instrumental learning. Rats with 6-hydroxydopamine or vehicle infusion into the PL and pDMS were trained to press 2 levers, either for food pellets or a sucrose solution. Thereafter, we tested whether the animals were sensitive 1) to a selective degradation of 1 of 2 outcomes using a specific satiety procedure and 2) to a selective degradation of 1 of 2 contingencies controlling instrumental behavior. Rats with PL DA depletion displayed a reduced rate of lever presses but appeared to be sensitive to outcome devaluation and contingency degradation. Thus, PL DA seems to modulate lever pressing but does not support instrumental conditioning. In contrast, rats with pDMS DA depletion had intact response rates and were sensitive to selective outcome devaluation; however, they showed a reduced sensitivity to contingency degradation. Therefore, pDMS DA signaling seems not to be involved in maintaining lever pressing but instead contributes to instrumental conditioning by supporting the detection of causal relationships between an action and its consequences.

The role of nucleus accumbens dopamine in outcome encoding in instrumental and Pavlovian conditioning.

Considerable evidence suggests that dopamine in the core subregion of the nucleus accumbens is not only involved in Pavlovian conditioning but also supports instrumental performance. However, it is largely unknown whether NAc dopamine is required for outcome encoding which plays an important role both in Pavlovian stimulus-outcome learning and instrumental action-outcome learning. Therefore, we tested rats with 6-hydroxydopamine (6-OHDA) induced dopamine depletion of the NAc core for their sensitivity to outcome devaluation in a Pavlovian and an instrumental task. Results indicate that 6-OHDA-lesioned animals were sensitive to outcome devaluation in an instrumental task. This finding provides support to the notion that NAc core dopamine may not be crucial in encoding action-outcome associations. However, during instrumental conditioning lever pressing rates in 6-OHDA-lesioned animals were markedly lower which could reflect an impaired behavioral activation. By contrast, after outcome-specific devaluation in a Pavlovian task, performance in 6-OHDA-lesioned animals was impaired, i.e. their magazine-directed responding was non-selectively reduced. One possibility to explain non-selective responding is that NAc core DA depletion impaired the ability of conditioned stimuli to activate the memory of the current value of the reinforcer.

Prefrontostriatal circuitry regulates effort-related decision making.

The anterior cingulate cortex (ACC), the basolateral amygdala (BLA), and the dopamine in the nucleus accumbens (NAc) are part of a neural system that is critically involved in making decisions on how much effort to invest for rewards. In the present study, we sought to identify functional interactions between ACC and NAc regulating effort-based decision making. Rats were tested in a T-maze cost-benefit task in which they could either choose to climb a barrier to obtain a large reward (LR) in one arm or a small reward in the other arm without a barrier. Experiment 1 revealed that bilateral excitotoxic lesions of the core subregion of the NAc impaired effort-based decision making, that is, reduced the preference for the high effort-LR option when having the choice to obtain a low reward with little effort. Experiment 2 showed that disconnection of the ACC and NAc core using an asymmetrical excitotoxic lesion procedure impaired effort-based decision making. The present data provide evidence that effort-based decision making is governed by an interconnected neural system that requires serial information transfer between ACC and NAc core.