Tonic Dopamine Levels Research Articles

Cost, Benefit, Tonic, Phasic

The role of dopamine in decision making has received much attention from both the experimental and computational communities. However, because reinforcement learning models concentrate on discrete action selection and on phasic dopamine signals, they are silent as to how animals decide upon the rate of their actions, and they fail to account for the prominent effects of dopamine on response rates. We suggest an extension to reinforcement learning models in which response rates are optimally determined by balancing the tradeoff between the cost of fast responding and the benefit of rapid reward acquisition. The resulting behavior conforms well with numerous characteristics of free-operant responding. More importantly, this framework highlights a role for a tonic signal corresponding to the net rate of rewards, in determining the optimal rate of responding. We hypothesize that this critical quantity is conveyed by tonic levels of dopamine, explaining why dopaminergic manipulations exert a global affect on response rates. We further suggest that the effects of motivation on instrumental rates of responding are mediated through its influence on the net reward rate, implying a tight coupling between motivational states and tonic dopamine. The relationships between phasic and tonic dopamine signaling, and between directing and energizing effects of motivation, as well as the implications for motivational control of habitual and goal-directed instrumental action selection, are discussed.

What do Dopamine Transporter and Catechol-O-Methyltransferase Tell us About Attention Deficit–Hyperactivity Disorder? Pharmacogenomic Implications

The purpose of the present paper was to review studies of two candidate genes for attention deficit-hyperactivity disorder (ADHD) and to separate aetiological from therapeutic effects. Genomic studies of ADHD were reviewed for candidate dopamine genes and studies selected to distinguish catechol-o-methyltransferase (COMT) and dopamine transporter (DAT-1) effects. Pharmacogenomic findings for the COMT gene were in agreement with the 1977 observations of Sprague and Sleator, who reported that at low psychostimulant doses, children with ADHD showed a remarkable improvement on a short-term memory test at all levels of task load, whereas at higher doses, there was a significant decrement in performance on the more difficult versions of the task, corresponding to an 'inverted 'U' shaped curve'. Recent studies show that individuals with the homozygous COMT (valine/valine) genotype demonstrated improvement following psychostimulant treatment, because their tonic dopamine (DA) levels were low, whereas the homozygous COMT (methionine/methionine) individuals, who already have high initial prefrontal cortex (PFC) dopamine levels performed more poorly after medication, in tasks with high working memory load. On the other hand aetiological findings for DAT-1 gene were heterogenous, but more often positive than for COMT. Contrasting findings for COMT and DAT-1 may best be considered in terms of prediction of medication response in ADHD in the case of COMT, but in aetiological terms in the case of DAT-1, which is abundant in the striatum and possibly plays a greater role in determining hyperactivity and impulsivity, than working memory deficiencies.

A Large-scale Neurocomputational Model of Task-oriented Behavior Selection and Working Memory in Prefrontal Cortex

The prefrontal cortex (PFC) is crucially involved in the executive component of working memory, representation of task state, and behavior selection. This article presents a large-scale computational model of the PFC and associated brain regions designed to investigate the mechanisms by which working memory and task state interact to select adaptive behaviors from a behavioral repertoire. The model consists of multiple brain regions containing neuronal populations with realistic physiological and anatomical properties, including extrastriate visual cortical regions, the inferotemporal cortex, the PFC, the striatum, and midbrain dopamine (DA) neurons. The onset of a delayed match-to-sample or delayed nonmatch-to-sample task triggers tonic DA release in the PFC causing a switch into a persistent, stimulus-insensitive dynamic state that promotes the maintenance of stimulus representations within prefrontal networks. Other modeled prefrontal and striatal units select cognitive acceptance or rejection behaviors according to which task is active and whether prefrontal working memory representations match the current stimulus. Working memory task performance and memory fields of prefrontal delay units are degraded by extreme elevation or depletion of tonic DA levels. Analyses of cellular and synaptic activity suggest that hyponormal DA levels result in increased prefrontal activation, whereas hypernormal DA levels lead to decreased activation. Our simulation results suggest a range of predictions for behavioral, single-cell, and neuroimaging response data under the proposed task set and under manipulations of DA concentration.

A Large-scale Neurocomputational Model of Task-oriented Behavior Selection and Working Memory in Prefrontal Cortex

Abstract The prefrontal cortex (PFC) is crucially involved in the executive component of working memory, representation of task state, and behavior selection. This article presents a large-scale computational model of the PFC and associated brain regions designed to investigate the mechanisms by which working memory and task state interact to select adaptive behaviors from a behavioral repertoire. The model consists of multiple brain regions containing neuronal populations with realistic physiological and anatomical properties, including extrastriate visual cortical regions, the inferotemporal cortex, the PFC, the striatum, and midbrain dopamine (DA) neurons. The onset of a delayed match-to-sample or delayed nonmatch-to-sample task triggers tonic DA release in the PFC causing a switch into a persistent, stimulus-insensitive dynamic state that promotes the maintenance of stimulus representations within prefrontal networks. Other modeled prefrontal and striatal units select cognitive acceptance or rejection behaviors according to which task is active and whether prefrontal working memory representations match the current stimulus. Working memory task performance and memory fields of prefrontal delay units are degraded by extreme elevation or depletion of tonic DA levels. Analyses of cellular and synaptic activity suggest that hyponormal DA levels result in increased prefrontal activation, whereas hypernormal DA levels lead to decreased activation. Our simulation results suggest a range of predictions for behavioral, single-cell, and neuroimaging response data under the proposed task set and under manipulations of DA concentration.

Extinction of Cocaine Self-Administration Reveals Functionally and Temporally Distinct Dopaminergic Signals in the Nucleus Accumbens

While Pavlovian and operant conditioning influence drug-seeking behavior, the role of rapid dopamine signaling in modulating these processes is unknown. During self-administration of cocaine, two dopaminergic signals, measured with 100 ms resolution, occurred immediately before and after the lever press (termed pre- and post-response dopamine transients). Extinction of self-administration revealed that these two signals were functionally distinct. Pre-response transients, which could reflect the motivation to obtain the drug, did not decline during extinction. Remarkably, post-response dopamine transients attenuated as extinction progressed, suggesting that they encode the learned association between environmental cues and cocaine. A third type of dopamine transient, not time locked to overt stimuli, decreased in frequency during extinction and correlated with calculated cocaine concentrations. These results show that dopamine release transients involved in different aspects of cocaine self-administration are highly plastic--differentially governed by motivation, learned associations linked with environmental stimuli, and the pharmacological actions of cocaine.

The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving.

All drugs of abuse have been shown to act either directly or indirectly by increasing dopamine neurotransmission within the limbic system. Thus, alcohol has been shown to increase dopamine transmission primarily by activating dopamine cell spike activity, whereas psychostimulants increase dopamine transmission by inhibiting the removal of dopamine from the synaptic space after its release. The spike-dependent release of dopamine that is modulated by drugs of abuse to lead to their rewarding actions has been termed the phasic dopamine response. In contrast, with repeated drug administration, dopamine will also accumulate in the extracellular space of the nucleus accumbens in concentrations too low to stimulate postsynaptic receptors, but of sufficient magnitude to activate dopamine release-inhibiting autoreceptors. In addition, the level of extracellular dopamine is proposed to be under the regulatory influence of cortico-accumbens afferents. This steady-state level of extrasynaptic dopamine has been termed the tonic dopamine response. In this paper it is proposed that several of the aspects of drug addiction, withdrawal and craving associated with the continued use of these drugs can be explained on the basis of their effects on tonic versus phasic dopamine system function. Thus, the increase in tonic dopamine levels that occurs with repeated drug administration would serve to oppose phasic dopamine release via stimulation of dopamine terminal autoreceptors, causing the subject to increase drug administration to restore the phasic response. Moreover, after withdrawal from the drugs, exposure to priming doses of drug or to drug-related stimuli are proposed to increase tonic dopamine levels, again triggering drug-seeking behavior in order to restore balance between the tonic and phasic dopamine systems. Therefore, one consequence of continued drug use is that these parameters of dopamine system function that normally serve to keep the system stable will enter into a new steady-state homeostasis, from which the system is particularly susceptible to destabilizing influences that may precipitate relapse.

The tonic/phasic model of dopamine system regulation and its implications for understanding alcohol and psychostimulant craving

All drugs of abuse have been shown to act either directly or indirectly by increasing dopamine neurotransmission within the limbic system. Thus, alcohol has been shown to increase dopamine transmission primarily by activating dopamine cell spike activity, whereas psychostimulants increase dopamine transmission by inhibiting the removal of dopamine from the synaptic space after its release. The spike‐dependent release of dopamine that is modulated by drugs of abuse to lead to their rewarding actions has been termed the phasic dopamine response. In contrast, with repeated drug administration, dopamine will also accumulate in the extracellular space of the nucleus accumbens in concentrations too low to stimulate postsynaptic receptors, but of sufficient magnitude to activate dopamine release‐inhibiting autoreceptors. In addition, the level of extracellular dopamine is proposed to be under the regulatory influence of cortico‐accumbens afferents. This steady‐state level of extrasynaptic dopamine has been termed the tonic dopamine response. In this paper it is proposed that several of the aspects of drug addiction, withdrawal and craving associated with the continued use of these drugs can be explained on the basis of their effects on tonic versus phasic dopamine system function. Thus, the increase in tonic dopamine levels that occurs with repeated drug administration would serve to oppose phasic dopamine release via stimulation of dopamine terminal autoreceptors, causing the subject to increase drug administration to restore the phasic response. Moreover, after withdrawal from the drugs, exposure to priming doses of drug or to drug‐related stimuli are proposed to increase tonic dopamine levels, again triggering drug‐seeking behavior in order to restore balance between the tonic and phasic dopamine systems. Therefore, one consequence of continued drug use is that these parameters of dopamine system function that normally serve to keep the system stable will enter into a new steady‐state homeostasis, from which the system is particularly susceptible to destabilizing influences that may precipitate relapse.

Predictive reward signal of dopamine neurons.

The effects of lesions, receptor blocking, electrical self-stimulation, and drugs of abuse suggest that midbrain dopamine systems are involved in processing reward information and learning approach behavior. Most dopamine neurons show phasic activations after primary liquid and food rewards and conditioned, reward-predicting visual and auditory stimuli. They show biphasic, activation-depression responses after stimuli that resemble reward-predicting stimuli or are novel or particularly salient. However, only few phasic activations follow aversive stimuli. Thus dopamine neurons label environmental stimuli with appetitive value, predict and detect rewards and signal alerting and motivating events. By failing to discriminate between different rewards, dopamine neurons appear to emit an alerting message about the surprising presence or absence of rewards. All responses to rewards and reward-predicting stimuli depend on event predictability. Dopamine neurons are activated by rewarding events that are better than predicted, remain uninfluenced by events that are as good as predicted, and are depressed by events that are worse than predicted. By signaling rewards according to a prediction error, dopamine responses have the formal characteristics of a teaching signal postulated by reinforcement learning theories. Dopamine responses transfer during learning from primary rewards to reward-predicting stimuli. This may contribute to neuronal mechanisms underlying the retrograde action of rewards, one of the main puzzles in reinforcement learning. The impulse response releases a short pulse of dopamine onto many dendrites, thus broadcasting a rather global reinforcement signal to postsynaptic neurons. This signal may improve approach behavior by providing advance reward information before the behavior occurs, and may contribute to learning by modifying synaptic transmission. The dopamine reward signal is supplemented by activity in neurons in striatum, frontal cortex, and amygdala, which process specific reward information but do not emit a global reward prediction error signal. A cooperation between the different reward signals may assure the use of specific rewards for selectively reinforcing behaviors. Among the other projection systems, noradrenaline neurons predominantly serve attentional mechanisms and nucleus basalis neurons code rewards heterogeneously. Cerebellar climbing fibers signal errors in motor performance or errors in the prediction of aversive events to cerebellar Purkinje cells. Most deficits following dopamine-depleting lesions are not easily explained by a defective reward signal but may reflect the absence of a general enabling function of tonic levels of extracellular dopamine. Thus dopamine systems may have two functions, the phasic transmission of reward information and the tonic enabling of postsynaptic neurons.

Dynamic regulation of striatal dopaminergic grafts during locomotor activity

The present experiment was designed to estimate the neurochemical activity of dopaminergic grafts in hemiparkinsonian model rats during locomotion and to examine the functional importance of dynamic regulation of the grafted neurons in the host brain. Rats were trained to run on a straight treadmill at various speeds (300, 660, 1200, 1800 cm/min), and extracellular dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis during and after running. Grafted rats were divided into two groups depending on their running ability and data were compared with those of normal and lesioned controls. Although the tonic level of extracellular DA in grafted rats recovered to 70% of control, levels of DOPAC and HVA remained 15–20% of controls. A small number of grafted rats showed full recovery in treadmill running tasks. In these animals, the percentage increase in DOPAC and HVA showed similar time courses and magnitudes as those in normal rats. Most grafted rats showed partial recovery in locomotor ability. The percentage increase in DOPAC and HVA in these animals remained at a lower level than that in normal rats, though the tonic levels of DA, DOPAC and HVA were not lower than those of fully recovered rats. Data suggest that grafted DAergic cells in functionally well recovered rats were dynamically regulated in the host brain in an actual behavior and that well-controlled release of DA might be involved in the recovery of complex motor behavior, such as high speed locomotion.