Tonic Dopamine Levels Research Articles

Interplay between midbrain and dorsal anterior cingulate regions arbitrates lingering reward effects on memory encoding

Rewarding events enhance memory encoding via dopaminergic influences on hippocampal plasticity. Phasic dopamine release depends on immediate reward magnitude, but presumably also on tonic dopamine levels, which may vary as a function of the average accumulation of reward over time. Using model-based fMRI in combination with a novel associative memory task, we show that immediate reward magnitude exerts a monotonically increasing influence on the nucleus accumbens, ventral tegmental area (VTA), and hippocampal activity during encoding, and enhances memory. By contrast, average reward levels modulate feedback-related responses in the VTA and hippocampus in a non-linear (inverted U-shape) fashion, with similar effects on memory performance. Additionally, the dorsal anterior cingulate cortex (dACC) monotonically tracks average reward levels, while VTA-dACC functional connectivity is non-linearly modulated (inverted U-shape) by average reward. We propose that the dACC computes the net behavioral impact of average reward and relays this information to memory circuitry via the VTA.

CRF Release in the Nucleus Accumbens Promotes Arousal in Anticipation of Cocaine Availability: Implications for Stress‐Induced Drug‐Seeking

Dopamine signaling within the nucleus accumbens core (NAcC) is critical to the generation of motivated behaviors in both appetitive and aversive contexts. Within the accumbens, various neuropeptides influence motivational states through the modulation of dopamine release dynamics. Here, microdialysis studies show that the stress peptide corticotropin releasing factor (CRF) is released in the NAcC when rats are exposed to environmental contexts that predict either an aversive outcome (i.e. social defeat) or drug‐reward opportunity (i.e. cocaine availability), and moreover, intra‐NAcC infusion of exogenous CRF elicits a robust increase in extracellular dopamine. The present studies further interrogate accumbens‐specific CRF actions as a candidate mechanism for maladaptive arousal evoked by drug‐predictive stimuli – a hallmark feature of cocaine dependence. In order to assess the role of NAcC‐CRF on instrumental responding directed towards cocaine procurement, male Long‐Evans rats were trained to self‐administer cocaine under a heterogeneous chained schedule of reinforcement (FIFR) in order to dissociate anticipatory (‘drug‐seeking’) from consummatory (‘drug‐taking’) behavior. Completion of a fixed‐interval (10 min) was followed by a period (10 min) of continuously reinforced responding (0.32mg/kg cocaine; FR1) on another lever. Microdialysis conducted during this procedure revealed that extracellular dopamine levels within the NAcC gradually ‘ramp up’ across the fixed‐interval in parallel with lever pressing activity, as drug availability approaches. Similarly, dialysate levels of CRF were specifically and progressively elevated during the fixed‐interval component preceding drug‐access, but were unaffected by drug‐taking. Infusion of CRF into the NAc produced a rapid elevated tonic dopamine levels that was accompanied by enhanced responding during the fixed‐interval component of the procedure, but notably did not affect subsequent cocaine intake. Conversely, pharmacological blockade of CRF‐R2, dampened extracellular dopamine levels in the NAc and suppressed lever pressing behavior during the fixed‐interval. Taken together, these data suggest that in response to appetitive or aversive stimuli, CRF may be a critical mediator of motivated processes that are classically associated with dopamine transmission. To this end, stress‐evoked CRF release in the NAc may represent a candidate mechanism by which stress triggers aberrant cocaine‐seeking.Support or Funding InformationNIDA R01‐DA031734 to KAM

Cumulative Dopamine Genetic Score predicts behavioral and electrophysiological correlates of response inhibition via interactions with task demand

Functional genetic polymorphisms in the brain dopamine (DA) system have been suggested to underlie individual differences in response inhibition, namely the suppression of a prepotent or inappropriate action. However, findings on associations between single DA polymorphisms and inhibitory control often are mixed, partly due to their small effect sizes. In the present study, a cumulative genetic score (CGS) was used: alleles previously associated with both impulsive behavior and lower baseline DA level, precisely the DRD4 Exon III 7-repeat, DAT1 VNTR 10-repeat and the COMT 158val allele, each added a point to the DA-CGS. Participants (N = 128) completed a Go/No-Go task varying in difficulty and EEG recordings were made with focus on the NoGo-P3, an ERP that reflects inhibitory response processes. We found a higher DA-CGS (lower basal/tonic DA level) to be associated with better performance (lower %FA and more adaptive responding) in the very demanding/rapid than in the less demanding/rapid condition, whereas the reverse pattern was true for individuals with a lower DA-CGS. A similar interaction pattern of DA-CGS and task condition was found for NoGo-P3 amplitude. In line with assumptions of distinct optimum DA levels for different cognitive demands, a DA-CGS-dependent variation of tonic DA levels could have modulated the balance between cognitive stability and flexibility, thereby affecting the optimal DA level required for the specific task condition. Moreover, a task demand-dependent phasic DA release might have added to the DA-CGS-related basal/tonic DA levels, thereby additionally affecting the balance between flexibility and stability, in turn influencing performance and NoGo-P3.

Irritability as a Transdiagnostic Vulnerability Trait:Current Issues and Future Directions

In recent years, irritability has received increasing attention among mental health professionals given its transdiagnostic associations with diverse forms of psychopathology. In contrast to other emotional states and traits, however, literature addressing associations between irritability and related temperament and personality constructs is limited. In addition, those who study irritability have diverse perspectives on its neurobiological substrates. In this comment, we situate irritability in the literatures on child temperament and adult personality, and describe a model in which irritability derives from low tonic dopamine (DA) levels and low phasic DA reactivity in subcortical neural structures implicated in appetitive responding. We note that different findings often emerge in neuroimaging studies when irritability is assessed in circumscribed diagnostic groups versus representative samples. We conclude with directions for future research, and propose that more authors use hierarchical Bayesian modeling, which captures functional dependencies between irritability and other dispositional traits (e.g., trait anxiety) that standard regression models are insensitive too. Treatment implications are also considered.

Role of homeostatic feedback mechanisms in modulating methylphenidate actions on phasic dopamine signaling in the striatum of awake behaving rats

Methylphenidate is an established treatment for attention-deficit hyperactivity disorder that also has abuse potential. Both properties may relate to blocking dopamine and norepinephrine reuptake. We measured the effects of methylphenidate on dopamine dynamics in freely moving rats. Methylphenidate alone had no effect on the amplitude of phasic responses to cues or reward. However, when administered with the D2 receptor antagonist raclopride, methylphenidate increased dopamine responses, while raclopride alone had no effect. Using brain slices of substantia nigra or striatum, we confirmed that methylphenidate effects on firing rate of nigral dopamine neurons and dopamine release from terminals are constrained by negative feedback. A computational model using physiologically relevant parameters revealed that actions of methylphenidate on norepinephrine and dopamine transporters, and the effects of changes in tonic dopamine levels on D2 receptors, are necessary and sufficient to account for the experimental findings. In addition, non-linear fitting of the model to the data from freely moving animals revealed that methylphenidate significantly slowed the initial cue response dynamics. These results show that homeostatic regulation of dopamine release in the face of changing tonic levels of extracellular dopamine should be taken into account to understand the therapeutic benefits and abuse potential of methylphenidate.

Examining the link between reward and response inhibition in individuals with substance abuse tendencies

BackgroundSubstance use problems are often characterized by dysregulation in reward sensitivity and inhibitory control. In line with this representation, the goal of this investigation was to determine how substance abuse tendencies among university students affect incentivized response inhibition. Additionally, this study examined whether striatal dopamine moderates the impact of substance use on response inhibition performance. MethodsThe sample included ninety-eight university students. Participants completed this prospective experimental study at an on-campus laboratory. All participants completed substance abuse and disinhibition subscales of the Externalizing Spectrum Inventory-Brief Form. Using a within-subjects design, participants then performed the Stop Signal Task under both neutral (unrewarded) and reward conditions, in which correct response cancellations resulted in a monetary reward. Striatal tonic dopamine levels were operationalized using spontaneous eyeblink rate. ResultsThe outcome measures were Stop Signal Reaction Time (SSRT) performance in the unrewarded and rewarded phases of the task. A hierarchical linear regression analysis, controlling for trait disinhibition, age, gender, and cigarette smoking status, identified an interactive effect of substance use and striatal dopamine levels on incentivized SSRT. Substance abuse tendencies were associated with slower SSRT and thus poorer inhibitory control under reward conditions among individuals with low levels of striatal dopamine (F = 7.613, p = .007). ConclusionsThis work has implications for research examining advanced drug use trajectories. In situations in which rewards are at stake, drug users with low tonic dopamine may be more motivated to seek those rewards at the expense of regulating inhibitory control.

Meditation experience predicts negative reinforcement learning and is associated with attenuated FRN amplitude

Focused attention meditation (FAM) practices are cognitive control exercises where meditators learn to maintain focus and attention in the face of distracting stimuli. Previous studies have shown that FAM is both activating and causing plastic changes to the mesolimbic dopamine system and some of its target structures, particularly the anterior cingulate cortex (ACC) and striatum. Feedback-based learning also depends on these systems and is known to be modulated by tonic dopamine levels. Capitalizing on previous findings that FAM practices seem to cause dopamine release, the present study shows that FAM experience predicts learning from negative feedback on a probabilistic selection task. Furthermore, meditators exhibited attenuated feedback-related negativity (FRN) as compared with nonmeditators and this effect scales with meditation experience. Given that reinforcement learning and FRN are modulated by dopamine levels, a possible explanation for our findings is that FAM practice causes persistent increases in tonic dopamine levels which scale with amount of practice, thus altering feedback processing.

Categorization system-switching deficits in typical aging and Parkinson's disease.

Numerous studies documenting cognitive deficits in Parkinson's disease (PD) revealed impairment in a variety of tasks related to memory, learning, and attention. One ubiquitous task that has not received much attention, is categorization system-switching. Categorization system-switching is a form of task-switching requiring participants to switch between different categorization systems. In this article, we explore whether older adults and people with PD show deficits in categorization system-switching. Twenty older adults diagnosed with PD, 20 neurologically intact older adults, and 67 young adults participated in this study. Participants were first trained in rule-based (RB) and later information-integration (II) categorization separately. After training on the tasks, participants performed a block of trial-by-trial switching where the RB and II trials were randomly intermixed. Finally, the last block of trials also intermixed RB and II trials were randomly but additionally changed the location of the response buttons. Contrary to our hypothesis, the results show no difference in accuracy between older adults and people with PD during the intermixed trial block, as well as no difference in response time (RT) switch cost. However, both groups were less accurate during intermixed trial blocks and had a higher RT switch cost when compared with young adults. In addition, the proportion of participants able to switch systems was smaller in people with PD than in young adults. The results suggest that older adults and people with PD have impaired categorization system-switching ability, and that this ability may be related to a decrease in tonic dopamine (DA) levels associated with normal aging and PD. (PsycINFO Database Record

Inhibiting Basal Ganglia Regions Reduces Syllable Sequencing Errors in Parkinson's Disease: A Computer Simulation Study.

Background: Parkinson's disease affects many motor processes including speech. Besides drug treatment, deep brain stimulation (DBS) in the subthalamic nucleus (STN) and globus pallidus internus (GPi) has developed as an effective therapy.Goal: We present a neural model that simulates a syllable repetition task and evaluate its performance when varying the level of dopamine in the striatum, and the level of activity reduction in the STN or GPi.Method: The Neural Engineering Framework (NEF) is used to build a model of syllable sequencing through a cortico-basal ganglia-thalamus-cortex circuit. The model is able to simulate a failing substantia nigra pars compacta (SNc), as occurs in Parkinson's patients. We simulate syllable sequencing parameterized by (i) the tonic dopamine level in the striatum and (ii) average neural activity in STN or GPi.Results: With decreased dopamine levels, the model produces syllable sequencing errors in the form of skipping and swapping syllables, repeating the same syllable, breaking and restarting in the middle of a sequence, and cessation (“freezing”) of sequences. We also find that reducing (inhibiting) activity in either STN or GPi reduces the occurrence of syllable sequencing errors.Conclusion: The model predicts that inhibiting activity in STN or GPi can reduce syllable sequencing errors in Parkinson's patients. Since DBS also reduces syllable sequencing errors in Parkinson's patients, we therefore suggest that STN or GPi inhibition is one mechanism through which DBS reduces syllable sequencing errors in Parkinson's patients.

The opportunity cost of time modulates cognitive effort

A spate of recent work demonstrates that humans seek to avoid the expenditure of cognitive effort, much like physical effort or economic resources. Less is clear, however, about the circumstances dictating how and when people decide to expend cognitive effort. Here we adopt a popular theory of opportunity costs and response vigor and to elucidate this question. This account, grounded in Reinforcement Learning, formalizes a trade-off between two costs: the harder work assumed necessary to emit faster actions and the opportunity cost inherent in acting more slowly (i.e., the delay that results to the next reward and subsequent rewards). Recent work reveals that the opportunity cost of time—operationalized as the average reward rate per unit time, theorized to be signaled by tonic dopamine levels, modulates the speed with which a person responds in a simple discrimination tasks. We extend this framework to cognitive effort in a diverse range of cognitive tasks, for which 1) the amount of cognitive effort demanded from the task varies from trial to trial and 2) the putative expenditure of cognitive effort holds measureable consequences in terms of accuracy and response time. In the domains of cognitive control, perceptual decision-making, and task-switching, we found that subjects tuned their level of effort exertion in accordance with the experienced average reward rate: when the opportunity cost of time was high, subjects made more errors and responded more quickly, which we interpret as a withdrawal of cognitive effort. That is, expenditure of cognitive effort appeared to be modulated by the opportunity cost of time. Further, and consistent with our account, the strength of this modulation was predicted by individual differences in efficacy of cognitive control. Taken together, our results elucidate the circumstances dictating how and when people expend cognitive effort.

High reward expectancy during methylphenidate depresses the dopaminergic response to gain and loss.

Dopamine plays an important role in goal-directed behavior, through its modulatory influence on striatal neurons. It is unclear whether tonic dopamine levels, which regulate the vigor of acting, interact with the phasic dopamine response to reward that drives instrumental behavior. In a randomized placebo-controlled study in healthy volunteers, we show that methylphenidate, a drug that increases tonic dopamine levels, systematically reduced striatal phasic BOLD responses to gain and loss in a gambling task as measured with fMRI. It also increased response vigor and reward expectancy-related BOLD signals in the ventral striatum. These findings suggest that striatal tonic dopamine levels constitute an average reward expectation signal that modulates the phasic dopaminergic response to reward. This offers opportunities for treatment of behavioral disorders associated with abnormal reward sensitivity.

Striatal Dopamine, Externalizing Proneness, and Substance Abuse: Effects on Wanting and Learning during Reward-Based Decision Making.

We examined whether striatal dopamine moderates the impact of externalizing proneness (disinhibition) on reward-based decision-making. Participants completed disinhibition and substance abuse subscales of the brief form Externalizing Spectrum Inventory, and then performed a delay discounting task to assess preference for immediate rewards along with a dynamic decision-making task that assessed long-term reward learning (i.e., inclination to choose larger delayed versus smaller immediate rewards). Striatal tonic dopamine levels were operationalized using spontaneous eyeblink rate. Regression analyses revealed that high disinhibition predicted greater delay discounting among participants with lower levels of striatal dopamine only, while substance abuse was associated with poorer long-term learning among individuals with lower levels of striatal dopamine, but better long-term learning in those with higher levels of striatal dopamine. These results suggest that disinhibition is more strongly associated with the wanting component of reward-based decision-making, whereas substance abuse behavior is associated more with learning of long-term action-reward contingencies.

Reversal of Alcohol-Induced Dysregulation in Dopamine Network Dynamics May Rescue Maladaptive Decision-making.

One of the primary problems resulting from chronic alcohol use is persistent, maladaptive decision-making that is associated with ongoing addiction vulnerability and relapse. Indeed, studies with the Iowa Gambling Task, a standard measure of risk-based decision-making, have reliably shown that alcohol-dependent individuals make riskier, more maladaptive choices than nondependent individuals, even after periods of prolonged abstinence. Using a preclinical model, in the current work, we identify a selective disruption in dopamine network dynamics that may promote maladaptive decision-making after chronic adolescent alcohol use and demonstrate its pharmacological reversal in adulthood. Together, these results highlight a novel neural mechanism underlying heightened risk-taking behavior in alcohol-dependent individuals and provide a potential therapeutic target for further investigation.

A novel electrochemical approach for prolonged measurement of absolute levels of extracellular dopamine in brain slices.

Tonic dopamine (DA) levels influence the activity of dopaminergic neurons and the dynamics of fast dopaminergic transmission. Although carbon fiber microelectrodes and fast-scan cyclic voltammetry (FSCV) have been extensively used to quantify stimulus-induced release and uptake of DA in vivo and in vitro, this technique relies on background subtraction and thus cannot provide information about absolute extracellular concentrations. It is also generally not suitable for prolonged (>90 s) recordings due to drift of the background current. A recently reported, modified FSCV approach called fast-scan controlled-adsorption voltammetry (FSCAV) has been used to assess tonic DA levels in solution and in the anesthetized mouse brain. Here we describe a novel extension of FSCAV to investigate pharmacologically induced, slowly occurring changes in tonic (background) extracellular DA concentration, and phasic (stimulated) DA release in brain slices. FSCAV was used to measure adsorption dynamics and changes in DA concentration (for up to 1.5 h, sampling interval 30 s, detection threshold < 10 nM) evoked by drugs affecting DA release and uptake (amphetamine, l-DOPA, pargyline, cocaine, Ro4-1284) in submerged striatal slices obtained from rats. We also show that combined FSCAV-FSCV recordings can be used for concurrent study of stimulated release and changes in tonic DA concentration. Our results demonstrate that FSCAV can be effectively used in brain slices to measure prolonged changes in extracellular level of endogenous DA expressed as absolute values, complementing studies conducted in vivo with microdialysis.

Spontaneous eye blink rate predicts learning from negative, but not positive, outcomes

A large body of research shows that striatal dopamine critically affects the extent to which we learn from the positive and negative outcomes of our decisions. In this study, we examined the relationship between reinforcement learning and spontaneous eye blink rate (sEBR), a cheap, non-invasive, and easy to obtain marker of striatal dopaminergic activity. Based on previous findings from pharmacological and patient studies, our main prediction was that in healthy individuals, low blink rates (and concomitant lower striatal dopamine levels) would be associated with better learning from negative choices, while high blink rates (and concomitant higher striatal dopamine levels) would be associated with learning from positive choices. Behavioral analyses showed that in healthy individuals, lower blink rates were indeed associated with greater learning from negative outcomes, indicating that lower dopamine levels per se may enhance avoidance learning. Yet, higher EBR was not associated with better learning from positive outcomes. These observations support the notion that sEBR reflects tonic dopamine levels, and suggest that sEBR may specifically relate to dopamine D2 receptor function, given the importance of the dopaminergic D2 pathway in avoidance learning. More generally, these findings highlight the usefulness of sEBR as a non-invasive and cheap method for assessing the relationship between striatal dopaminergic function and behavior.

The role of dopamine in motor flexibility.

Humans carry out many daily tasks in a seemingly automatic fashion. However, when unexpected changes in the environment occur, we have the capacity to inhibit prepotent behavior and replace it with an alternative one. Such behavioral flexibility is a hallmark of executive functions. The neurotransmitter dopamine is known to be crucial for fast, efficient, and accurate cognitive flexibility. Despite the perceived similarities between cognitive and motor flexibility, less is known regarding the role of dopamine within the motor domain. Therefore, the aim of this study was to determine the role of dopamine in motor flexibility. In a double-blind, five-session, within-subject pharmacological experiment, human participants performed an RT task within a probabilistic context that was either predictable or unpredictable. The probabilistic nature of the predictable context resulted in prediction errors. This required participants to replace the prepotent or prepared action with an unprepared action (motor flexibility). The task was overlearned, and changes in context were explicitly instructed, thus controlling for contributions from other dopamine-related processes such as probabilistic or reversal learning and interactions with other types of uncertainty. We found that dopamine receptor blockade by high-dose haloperidol (D1/D2 dopamine receptors) impaired participants' ability to react to unexpected events occurring in a predictable context, which elicit large prediction errors and necessitate motor flexibility. This effect was not observed with selective D2 receptor blockade (sulpiride), with a general increase in tonic dopamine levels (levodopa), or during an unpredictable context, which evoked minimal prediction error. We propose that dopamine is vital in responding to low-level prediction errors about stimulus outcome that requires motor flexibility.

State-dependent value representation: evidence from the striatum.

State-dependent value representation: evidence from the striatum.

Orbitofrontal dopamine depletion upregulates caudate dopamine and alters behavior via changes in reinforcement sensitivity.

Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.

Scaling and coordination deficits during dynamic object manipulation in Parkinson's disease

The ability to reach for and dynamically manipulate objects in a dexterous fashion requires scaling and coordination of arm, hand, and fingertip forces during reach and grasp components of this behavior. The neural substrates underlying dynamic object manipulation are not well understood. Insight into the role of basal ganglia-thalamocortical circuits in object manipulation can come from the study of patients with Parkinson's disease (PD). We hypothesized that scaling and coordination aspects of motor control are differentially affected by this disorder. We asked 20 PD patients and 23 age-matched control subjects to reach for, grasp, and lift virtual objects along prescribed paths. The movements were subdivided into two types, intensive (scaling) and coordinative, by detecting their underlying self-similarity. PD patients off medication were significantly impaired relative to control subjects for both aspects of movement. Intensive deficits, reduced peak speed and aperture, were seen during the reach. Coordinative deficits were observed during the reach, namely, the relative position along the trajectory at which peak speed and aperture were achieved, and during the lift, when objects tilted with respect to the gravitational axis. These results suggest that basal ganglia-thalamocortical circuits may play an important role in fine motor coordination. Dopaminergic therapy significantly improved intensive but not coordinative aspects of movements. These findings are consistent with a framework in which tonic levels of dopamine in the dorsal striatum encode the energetic cost of a movement, thereby improving intensive or scaling aspects of movement. However, repletion of brain dopamine levels does not restore finely coordinated movement.

Dopamine Function and the Efficiency of Human Movement

To sustain successful behavior in dynamic environments, active organisms must be able to learn from the consequences of their actions and predict action outcomes. One of the most important discoveries in systems neuroscience over the last 15 years has been about the key role of the neurotransmitter dopamine in mediating such active behavior. Dopamine cell firing was found to encode differences between the expected and obtained outcomes of actions. Although activity of dopamine cells does not specify movements themselves, a recent study in humans has suggested that tonic levels of dopamine in the dorsal striatum may in part enable normal movement by encoding sensitivity to the energy cost of a movement, providing an implicit "motor motivational" signal for movement. We investigated the motivational hypothesis of dopamine by studying motor performance of patients with Parkinson disease who have marked dopamine depletion in the dorsal striatum and compared their performance with that of elderly healthy adults. All participants performed rapid sequential movements to visual targets associated with different risk and different energy costs, countered or assisted by gravity. In conditions of low energy cost, patients performed surprisingly well, similar to prescriptions of an ideal planner and healthy participants. As energy costs increased, however, performance of patients with Parkinson disease dropped markedly below the prescriptions for action by an ideal planner and below performance of healthy elderly participants. The results indicate that the ability for efficient planning depends on the energy cost of action and that the effect of energy cost on action is mediated by dopamine.