Tonic Dopamine Signaling Research Articles

Abundance Compensates Kinetics: Similar Effect of Dopamine Signals on D1 and D2 Receptor Populations.

The neuromodulator dopamine plays a key role in motivation, reward-related learning, and normal motor function. The different affinity of striatal D1 and D2 dopamine receptor types has been argued to constrain the D1 and D2 signaling pathways to phasic and tonic dopamine signals, respectively. However, this view assumes that dopamine receptor kinetics are instantaneous so that the time courses of changes in dopamine concentration and changes in receptor occupation are basically identical. Here we developed a neurochemical model of dopamine receptor binding taking into account the different kinetics and abundance of D1 and D2 receptors in the striatum. Testing a large range of behaviorally-relevant dopamine signals, we found that the D1 and D2 dopamine receptor populations responded very similarly to tonic and phasic dopamine signals. Furthermore, because of slow unbinding rates, both receptor populations integrated dopamine signals over a timescale of minutes. Our model provides a description of how physiological dopamine signals translate into changes in dopamine receptor occupation in the striatum, and explains why dopamine ramps are an effective signal to occupy dopamine receptors. Overall, our model points to the importance of taking into account receptor kinetics for functional considerations of dopamine signaling.SIGNIFICANCE STATEMENT Current models of basal ganglia function are often based on a distinction of two types of dopamine receptors, D1 and D2, with low and high affinity, respectively. Thereby, phasic dopamine signals are believed to mostly affect striatal neurons with D1 receptors, and tonic dopamine signals are believed to mostly affect striatal neurons with D2 receptors. This view does not take into account the rates for the binding and unbinding of dopamine to D1 and D2 receptors. By incorporating these kinetics into a computational model we show that D1 and D2 receptors both respond to phasic and tonic dopamine signals. This has implications for the processing of reward-related and motivational signals in the basal ganglia.

Dopamine dysregulation hypothesis: the common basis for motivational anhedonia in major depressive disorder and schizophrenia?

Abnormalities in reward processing are crucial symptoms of major depressive disorder (MDD) and schizophrenia (SCH). Recent neuroscientific findings regarding MDD have led to conclusions about two different symptoms related to reward processing: motivational and consummatory anhedonia, corresponding, respectively, to impaired motivation to obtain rewards ('wanting'), and diminished satisfaction from consuming them ('liking'). One can ask: which of these is common for MDD and SCH. In our review of the latest neuroscientific studies, we show that MDD and SCH do not share consummatory anhedonia, as SCH patients usually have unaltered liking. Therefore, we investigated whether motivational anhedonia is the common symptom across MDD and SCH. With regard to the similarities and differences between the neural mechanisms of MDD and SCH, here we expand the current knowledge of motivation deficits and present the common underlying mechanism of motivational anhedonia - the dopamine dysregulation hypothesis - stating that any prolonged dysregulation in tonic dopamine signaling that exceeds the given equilibrium can lead to striatal dysfunction and motivational anhedonia. The implications for further research and treatment of MDD and SCH are also discussed.

Modafinil increases reward salience in a slot machine game in low and high impulsivity pathological gamblers

This study examined the effects of modafinil (200 mg) on slot machine betting profiles from a previous sample of low and high impulsivity (LI/HI) pathological gamblers (10/Group; Zack and Poulos, 2009). Hierarchical regression assessed the prospective relationship between Payoff and Bet Size on consecutive trials, along with moderating effects of Group, Cumulative Winnings (low/high) and Phase of game (early/late) under drug and placebo. Y intercepts for the simple regressions of Bet Size on Payoff indexed overall motivation to bet. Under placebo, both groups gauged their bets less closely to the preceding Payoff as trials continued when Winnings were low but not high. Under modafinil, both groups gauged their bets more closely to the preceding Payoff when Winnings were low but gauged their bets less closely to the previous Payoff when Winnings were high. The tendency to gauge bets closely to the previous Payoff coincided with a bias toward low overall Bet Size, and modafinil accentuated this relationship, in LI but not HI subjects. Results suggest that modafinil increases the salience of environmental rewards, leading to more tightly calibrated responses to individual rewards when resources are low, but progressively loosens reward-response calibration when resources are high. Increased relative impact of phasic vs. tonic dopamine signals may account for patterns seen at low vs. high Winnings, respectively, under the drug. Clinically, modafinil may deter pathological gamblers from chasing losses but also encourage them to continue betting rather than quit while they are ahead. Whether low-dose modafinil confers more uniform benefits deserves investigation.

Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine.

Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties.

GABAB receptor activation attenuates the stimulant but not mesolimbic dopamine response to ethanol in FAST mice

Neural processes influenced by γ-aminobutyric acid B (GABAB) receptors appear to contribute to acute ethanol sensitivity, including the difference between lines of mice bred for extreme sensitivity (FAST) or insensitivity (SLOW) to the locomotor stimulant effect of ethanol. One goal of the current study was to determine whether selection of the FAST and SLOW lines resulted in changes in GABAB receptor function, since the lines differ in sensitivity to the GABAB receptor agonist baclofen and baclofen attenuates the stimulant response to ethanol in FAST mice. A second goal was to determine whether the baclofen-induced reduction in ethanol stimulation in FAST mice is associated with an attenuation of the mesolimbic dopamine response to ethanol. In Experiment 1, the FAST and SLOW lines were found to not differ in GABAB receptor function (measured by baclofen-stimulated [35S]GTPγS binding) in whole brain or in several regional preparations, except in the striatum in one of the two replicate sets of selected lines. In Experiment 2, baclofen-induced attenuation of the locomotor stimulant response to ethanol in FAST mice was not accompanied by a reduction in dopamine levels in the nucleus accumbens, as measured by microdialysis. These data suggest that, overall, GABAB receptor function does not play an integral role in the genetic difference in ethanol sensitivity between the FAST and SLOW lines. Further, although GABAB receptors do modulate the locomotor stimulant response to ethanol in FAST mice, this effect does not appear to be due to a reduction in tonic dopamine signaling in the nucleus accumbens.

Withdrawal from Chronic Nicotine Exposure Alters Dopamine Signaling Dynamics in the Nucleus Accumbens

Unaided attempts to quit smoking commonly fail during the first 2 weeks of the nicotine withdrawal syndrome. Alterations in dopamine (DA) signaling correlate with withdrawal from chronic nicotine exposure, but those changes have not been well-characterized. Mice were administered nicotine in their drinking water for 4 or 12 weeks. Then nicotine was withheld for 1 to 10 days while DA signaling was characterized with in vivo microdialysis or fast-scan cyclic voltammetry. Upon withdrawal of nicotine, the basal DA concentration in the nucleus accumbens decreased as measured by microdialysis. The length of time that the low basal DA state lasted depended on the length of the chronic nicotine treatment. Microdialysis indicated that acute re-exposure to nicotine during withdrawal temporarily reversed this hypodopaminergic state. Voltammetry measurements supported the microdialysis results by showing that nicotine withdrawal decreased tonic and phasic DA release. The basal DA concentration and tonic DA signals, however, were disproportionately lower than the phasic DA signals. Therefore, the phasic/tonic DA signaling ratio was increased during the withdrawal period. The relative increase in the sensitivity of DA release to phasic stimulation suggests an increase in the signal-to-noise relationship of DA signaling during the withdrawal period. Therefore, the DA signal produced by acute nicotine re-exposure produces a DA response that might reinforce relapse to drug use (i.e., smoking). Because the basal DA concentration is low during withdrawal, therapies aimed at elevating the background DA signal represent a reasonable treatment strategy for nicotine-dependent individuals attempting to quit.

Dopamine Release in the Prefrontal Cortex and Striatum: Temporal and Behavioural Aspects

Dopamine (DA) neurons originating in the substantia nigra and ventral tegmental area project to a variety of forebrain structures thereby forming a complex neuromodulatory system that is essential for numerous motor, cognitive and motivational processes. DA neurons can operate in distinct temporal modes, i. e. they display responses across varying timescales including fast phasic changes of DA release on a seconds time scale and slower phasic changes in a minutes to hour range. Furthermore, tonic levels of DA provide a DA receptor 'tone'. Here we briefly highlight findings indicating that temporally distinct responses of DA neurons in the prefrontal cortex and striatum are related to different kinds of information and may serve dissociable behavioural functions. Furthermore we consider how DA neuronal activity and temporarily distinct patterns of DA release are regulated and summarize some relevant findings on the basic neuroanatomy of ascending DA systems. A better understanding of the specific functions of phasic and tonic DA signals will be critical for determining the role of DA in behaviour in detail.

Controls of Tonic and Phasic Dopamine Transmission in the Dorsal and Ventral Striatum

Dopamine (DA) release varies within subregions and local environments of the striatum, suggesting that controls intrinsic and extrinsic to the DA fibers and terminals regulate release. While applying fast-scan cyclic voltammetry and using tonic and phasic stimulus trains, we investigated the regulation of DA release in the dorsolateral to ventral striatum. The ratio of phasic-to-tonic-evoked DA signals varied with the average ongoing firing frequency, and the ratio was generally higher in the nucleus accumbens (NAc) compared with the dorsolateral striatum. At the normal average firing frequency, burst stimulation produces a larger increase in the DA response in the NAc than the dorsolateral striatum. This finding was comparable whether the DA measurements were made using in vitro brain slices or were recorded in vivo from freely moving rodents. Blockade of the dopamine transporters and dopamine D(2) receptors particularly enhanced the tonic DA signals. Conversely, blockade of nicotinic acetylcholine receptors (nAChRs) containing the beta(2) subunit (beta(2)(*)) predominantly suppressed tonic DA signals. The suppression of tonic DA release increased the contrast between phasic and tonic DA signals, and that made the frequency-dependent DA dynamics between the dorsolateral striatum and NAc more similar. The results indicate that intrinsic differences in the DA fibers that innervate specific regions of the striatum combine with (at least) DA transporters, DA receptors, and nAChRs to regulate the frequency dependence of DA release. A combination of mechanisms provides specific local control of DA release that underlies pathway-specific information associated with motor and reward-related functions.

Dopamine tone increases similarly during predictable and unpredictable administration of rewarding brain stimulation at short inter-train intervals

Unpredicted rewards, but not predicted ones, trigger strong phasic changes in the firing rates of midbrain dopamine (DA). In contrast, neurochemical measurements of DA tone have failed to reveal an influence of reward predictability. However, the subjects of the neurochemical experiments were asked to predict reward onset over longer intervals (12 s, on average) than the subjects of the electrophysiological studies (typically, 2 s). Thus, the contrasting effects of reward predictability could reflect the difference in the duration of the interval separating the predictor from the reward rather than a difference in the influence of reward predictability on phasic and tonic DA signaling. This hypothesis was tested in rats receiving trains of rewarding electrical brain stimulation with either a predictable or unpredictable onset. The mean inter-train interval was 1.5 s, a value close to the 2-s CS–US interval that has been used in electrophysiological studies demonstrating the dependence of phasic DA responses on reward predictability. Despite the shortened inter-train interval, the time courses of the observed stimulation-induced elevations in DA levels were very similar, regardless of whether train onset was predictable. This finding is consistent with the idea that tonic DA signaling is insensitive to the predictability of rewards.

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.