Tonic Dopamine Levels Research Articles

Tonic and Phasic Dopamine Fluctuations as Reflected in Beta-power Predict Interval Timing Behavior

It has been repeatedly shown that dopamine impacts interval timing in humans and animals (for a review, see Coull, Cheng, & Meck, 2012). Particularly, administration of dopamine agonists or antagonists speeds-up or slows down internal passage of time, respectively (Meck, 1996). This co-variations in the dopamine level and clock speed has been typically induced by pharmacological manipulations (e.g., Lustig & Meck, 2005). However, it has not been assessed whether naturally occurring fluctuations in dopamine level are sufficient for altering interval timing performance. Recent advances in neurophysiology suggest that tonic and phasic changes of dopamine level in cortical-basal ganglia loop can be traced by fluctuations of beta power (Jenkinson & Brown, 2011). We assessed dopamine levels by measuring the beta power while participants were asked to produce time intervals by two key presses. Both tonic levels of dopamine as measured by the beta power before interval initiation and phasic level of dopamine as measured after the first key-press predict timing performance. These positive correlations between beta power and length of produced intervals support the notion that dopamine plays an important role in interval timing, even in the range of naturally occurring fluctuations.

A model of reversal learning and working memory in medicated and unmedicated patients with Parkinson’s disease

We present a neural network model of cognition in medicated and unmedicated patients with Parkinson’s disease (PD) in various learning and memory tasks. The model extends our prior models of the basal ganglia and PD with further modeling of the role of prefrontal cortex (PFC) dopamine in stimulus–response learning, reversal, and working memory. In our model, PD is associated with decreased dopamine levels in the basal ganglia and PFC, whereas dopamine medications increase dopamine levels in both brain structures. Simulation results suggest that dopamine medications impair stimulus–response learning in agreement with experimental data (Breitenstein et al., 2006; Gotham, Brown, & Marsden, 1988). We show how decreased dopamine levels in the PFC in unmedicated PD patients are associated with impaired working memory performance, as seen experimentally (Costa et al., 2003; Lange et al., 1992; Moustafa, Sherman, & Frank, 2008; Owen, Sahakian, Hodges, Summers, & Polkey, 1995). Further, our model simulations illustrate how increases in tonic dopamine levels in the PFC due to dopamine medications will enhance working memory, in accord with previous modeling and experimental results (Cohen, Braver, & Brown, 2002; Durstewitz, Seamans, & Sejnowski, 2000; Wang, Vijayraghavan, & Goldman-Rakic, 2004). The model is also consistent with data reported in Cools, Barker, Sahakian, and Robbins (2001), who showed that dopamine medications impair reversal learning. In addition, our model shows that extended training of the reversal phase leads to enhanced reversal performance in medicated PD patients, which is a new, and as yet untested, prediction of the model. Overall, our model provides a unified account for performance in various behavioral tasks using common computational principles.

Parkinson’s disease patients show impaired corrective grasp control and eye–hand coupling when reaching to grasp virtual objects

The effect of Parkinson’s disease (PD) on hand–eye coordination and corrective response control during reach-to-grasp tasks remains unclear. Moderately impaired PD patients (n=9) and age-matched controls (n=12) reached to and grasped a virtual rectangular object, with haptic feedback provided to the thumb and index fingertip by two 3-degree of freedom manipulanda. The object rotated unexpectedly on a minority of trials, requiring subjects to adjust their grasp aperture. On half the trials, visual feedback of finger positions disappeared during the initial phase of the reach, when feedforward mechanisms are known to guide movement. PD patients were tested without (OFF) and with (ON) medication to investigate the effects of dopamine depletion and repletion on eye–hand coordination online corrective response control. We quantified eye–hand coordination by monitoring hand kinematics and eye position during the reach. We hypothesized that if the basal ganglia are important for eye–hand coordination and online corrections to object perturbations, then PD patients tested OFF medication would show reduced eye–hand spans and impoverished arm-hand coordination responses to the perturbation, which would be further exasperated when visual feedback of the hand was removed. Strikingly, PD patients tracked their hands with their gaze, and their movements became destabilized when having to make online corrective responses to object perturbations exhibiting pauses and changes in movement direction. These impairments largely remained even when tested in the ON state, despite significant improvement on the Unified Parkinson’s Disease Rating Scale. Our findings suggest that basal ganglia-cortical loops are essential for mediating eye–hand coordination and adaptive online responses for reach-to-grasp movements, and that restoration of tonic levels of dopamine may not be adequate to remediate this coordinative nature of basal ganglia-modulated function.

A preliminary study suggests that nicotine and prefrontal dopamine affect cortico-striatal areas in smokers with performance feedback.

Nicotine and tonic dopamine (DA) levels [as inferred by catechol-O-methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico-striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy.

How Does Tonic Dopamine Level Affect Decision-Making in Dual Tasks in Parkinson’s Disease?

How Does Tonic Dopamine Level Affect Decision-Making in Dual Tasks in Parkinson’s Disease?

Dynamic Fluctuations in Dopamine Efflux in the Prefrontal Cortex and Nucleus Accumbens during Risk-Based Decision Making

Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies.

More creative through positive mood? Not everyone!

It is commonly assumed that positive mood improves human creativity and that the neurotransmitter dopamine might mediate this association. However, given the non-linear relation between dopamine and flexibility in divergent thinking (Akbari Chermahini and Hommel, 2010), the impact of mood on divergent kinds of creativity might depend on a given individual's tonic dopamine level. We tested this possibility in adults by assessing mood, performance in a divergent thinking task [the Alternate Uses Task (AUT)], and eye blink rates (EBRs), a well-established clinical marker of the individual dopamine level, before and after positive mood or negative mood induction. As expected, the association between flexibility in divergent thinking performance and EBR followed an inverted U-shape function (with best performance for medium levels), positive mood induction raised EBRs and only individuals with below-median EBRs, but not those with above-median EBRs, benefited from positive mood. These observations provide support for dopamine-based approaches to the impact of mood on creativity and challenge the generality of the widely held view that positive mood facilitates creativity.

The COMT Val158 allele is associated with impaired delayed-match-to-sample performance in ADHD

BackgroundThis study explored the association between three measures of working memory ability and genetic variation in a range of catecholamine genes in a sample of children with ADHD.MethodsOne hundred and eighteen children with ADHD performed three working memory measures taken from the CANTAB battery (Spatial Span, Delayed-match-to-sample, and Spatial Working Memory). Associations between performance on working memory measures and allelic variation in catecholamine genes (including those for the noradrenaline transporter [NET1], the dopamine D4 and D2 receptor genes [DRD4; DRD2], the gene encoding dopamine beta hydroxylase [DBH] and catechol-O-methyl transferase [COMT]) were investigated using regression models that controlled for age, IQ, gender and medication status on the day of test.ResultsSignificant associations were found between performance on the delayed-match-to-sample task and COMT genotype. More specifically, val/val homozygotes produced significantly more errors than did children who carried a least one met allele. There were no further associations between allelic variants and performance across the other working memory tasks.ConclusionsThe working memory measures employed in the present study differed in the degree to which accurate task performance depended upon either the dynamic updating and/or manipulation of items in working memory, as in the spatial span and spatial working memory tasks, or upon the stable maintenance of representations, as in the delay-match–to-sample task. The results are interpreted as evidence of a relationship between tonic dopamine levels associated with the met COMT allele and the maintenance of stable working memory representations required to perform the delayed-match-to-sample-task.

Vigor in the Face of Fluctuating Rates of Reward: An Experimental Examination

Two fundamental questions underlie the expression of behavior, namely what to do and how vigorously to do it. The former is the topic of an overwhelming wealth of theoretical and empirical work particularly in the fields of reinforcement learning and decision-making, with various forms of affective prediction error playing key roles. Although vigor concerns motivation, and so is the subject of many empirical studies in diverse fields, it has suffered a dearth of computational models. Recently, Niv et al. [Niv, Y., Daw, N. D., Joel, D., & Dayan, P. Tonic dopamine: Opportunity costs and the control of response vigor. Psychopharmacology (Berlin), 191, 507-520, 2007] suggested that vigor should be controlled by the opportunity cost of time, which is itself determined by the average rate of reward. This coupling of reward rate and vigor can be shown to be optimal under the theory of average return reinforcement learning for a particular class of tasks but may also be a more general, perhaps hard-wired, characteristic of the architecture of control. We, therefore, tested the hypothesis that healthy human participants would adjust their RTs on the basis of the average rate of reward. We measured RTs in an odd-ball discrimination task for rewards whose magnitudes varied slowly but systematically. Linear regression on the subjects' individual RTs using the time varying average rate of reward as the regressor of interest, and including nuisance regressors such as the immediate reward in a round and in the preceding round, showed that a significant fraction of the variance in subjects' RTs could indeed be explained by the rate of experienced reward. This validates one of the key proposals associated with the model, illuminating an apparently mandatory form of coupling that may involve tonic levels of dopamine.

Rapid Target-Specific Remodeling of Fast-Spiking Inhibitory Circuits after Loss of Dopamine

In Parkinson's disease (PD), dopamine depletion alters neuronal activity in the direct and indirect pathways and leads to increased synchrony in the basal ganglia network. However, the origins of thesechanges remain elusive. Because GABAergic interneurons regulate activity of projection neurons andpromote neuronal synchrony, we recorded from pairs of striatal fast-spiking (FS) interneurons and direct- or indirect-pathway MSNs after dopamine depletion with 6-OHDA. Synaptic properties ofFS-MSN connections remained similar, yet within 3days of dopamine depletion, individual FS cells doubled their connectivity to indirect-pathway MSNs, whereas connections to direct-pathway MSNs remained unchanged. A model of the striatal microcircuit revealed that such increases in FS innervation were effective at enhancing synchrony within targeted cell populations. These data suggest that after dopamine depletion, rapid target-specific microcircuit organization in the striatum may lead to increased synchrony of indirect-pathway MSNs that contributes to pathological network oscillations and motor symptoms of PD.

A Neurocomputational Model of Dopamine and Prefrontal–Striatal Interactions during Multicue Category Learning by Parkinson Patients

Most existing models of dopamine and learning in Parkinson disease (PD) focus on simulating the role of basal ganglia dopamine in reinforcement learning. Much data argue, however, for a critical role for prefrontal cortex (PFC) dopamine in stimulus selection in attentional learning. Here, we present a new computational model that simulates performance in multicue category learning, such as the "weather prediction" task. The model addresses how PD and dopamine medications affect stimulus selection processes, which mediate reinforcement learning. In this model, PFC dopamine is key for attentional learning, whereas basal ganglia dopamine, consistent with other models, is key for reinforcement and motor learning. The model assumes that competitive dynamics among PFC neurons is the neural mechanism underlying stimulus selection with limited attentional resources, whereas competitive dynamics among striatal neurons is the neural mechanism underlying action selection. According to our model, PD is associated with decreased phasic and tonic dopamine levels in both PFC and basal ganglia. We assume that dopamine medications increase dopamine levels in both the basal ganglia and PFC, which, in turn, increase tonic dopamine levels but decrease the magnitude of phasic dopamine signaling in these brain structures. Increase of tonic dopamine levels in the simulated PFC enhances attentional shifting performance. The model provides a mechanistic account for several phenomena, including (a) medicated PD patients are more impaired at multicue probabilistic category learning than unmedicated patients and (b) medicated PD patients opt out of reversal when there are alternative and redundant cue dimensions.

Dopaminergic Presynaptic Modulation of Nigral Afferents: Its Role in the Generation of Recurrent Bursting in Substantia Nigra Pars Reticulata Neurons

Previous work has shown the functions associated with activation of dopamine presynaptic receptors in some substantia nigra pars reticulata (SNr) afferents: (i) striatonigral terminals (direct pathway) posses presynaptic dopamine D1-class receptors whose action is to enhance inhibitory postsynaptic currents (IPSCs) and GABA transmission. (ii) Subthalamonigral terminals posses D1- and D2-class receptors where D1-class receptor activation enhances and D2-class receptor activation decreases excitatory postsynaptic currents. Here we report that pallidonigral afferents posses D2-class receptors (D3 and D4 types) that decrease inhibitory synaptic transmission via presynaptic modulation. No action of D1-class agonists was found on pallidonigral synapses. In contrast, administration of D1-receptor antagonists greatly decreased striatonigral IPSCs in the same preparation, suggesting that tonic dopamine levels help in maintaining the function of the striatonigral (direct) pathway. When both D3 and D4 type receptors were blocked, pallidonigral IPSCs increased in amplitude while striatonigral connections had no significant change, suggesting that tonic dopamine levels are repressing a powerful inhibition conveyed by pallidonigral synapses (a branch of the indirect pathway). We then blocked both D1- and D2-class receptors to acutely decrease direct pathway (striatonigral) and enhance indirect pathways (subthalamonigral and pallidonigral) synaptic force. The result was that most SNr projection neurons entered a recurrent bursting firing mode similar to that observed during Parkinsonism in both patients and animal models. These results raise the question as to whether the lack of dopamine in basal ganglia output nuclei is enough to generate some pathological signs of Parkinsonism.

Methylphenidate Attenuates Limbic Brain Inhibition after Cocaine-Cues Exposure in Cocaine Abusers

Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.

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.

Dopamine Modulates Persistent Synaptic Activity and Enhances the Signal-to-Noise Ratio in the Prefrontal Cortex

BackgroundThe importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, but its mechanisms of action remain controversial. DA is thought to increase signal gain in active networks according to an inverted U dose-response curve, and these effects may depend on both tonic and phasic release of DA from midbrain ventral tegmental area (VTA) neurons.Methodology/Principal FindingsWe used patch-clamp recordings in organotypic co-cultures of the PFC, hippocampus and VTA to study DA modulation of spontaneous network activity in the form of Up-states and signals in the form of synchronous EPSP trains. These cultures possessed a tonic DA level and stimulation of the VTA evoked DA transients within the PFC. The addition of high (≥1 µM) concentrations of exogenous DA to the cultures reduced Up-states and diminished excitatory synaptic inputs (EPSPs) evoked during the Down-state. Increasing endogenous DA via bath application of cocaine also reduced Up-states. Lower concentrations of exogenous DA (0.1 µM) had no effect on the up-state itself, but they selectively increased the efficiency of a train of EPSPs to evoke spikes during the Up-state. When the background DA was eliminated by depleting DA with reserpine and alpha-methyl-p-tyrosine, or by preparing corticolimbic co-cultures without the VTA slice, Up-states could be enhanced by low concentrations (0.1–1 µM) of DA that had no effect in the VTA containing cultures. Finally, in spite of the concentration-dependent effects on Up-states, exogenous DA at all but the lowest concentrations increased intracellular current-pulse evoked firing in all cultures underlining the complexity of DA's effects in an active network.Conclusions/SignificanceTaken together, these data show concentration-dependent effects of DA on global PFC network activity and they demonstrate a mechanism through which optimal levels of DA can modulate signal gain to support cognitive functioning.

Tending the source of parkinsonism through deep brain microstimulation

Introduction Descriptive models of basal ganglia operation have seen a recent increase in interest from the classical idea of direct and indirect pathways towards a more feedback-oriented view of statistic optimality [1]. These new views may prove to be valuable in explaining and finding new treatments for common basal ganglia disorders such as Parkinson's disease beyond current techniques of pure symptom fighting through widespread deep brain stimulation or chemical regulators for increasing tonic levels of dopamine.

Aripiprazole and haloperidol suppress excessive dopamine release in the amygdala in response to conditioned fear stress, but show contrasting effects on basal dopamine release in methamphetamine-sensitized rats

Although emotional dysfunction in patients with schizophrenia is thought to be associated with poorer outcomes in terms of overall quality of well-being, only a few basic studies have examined the biochemical effect of antipsychotics on emotional function. In this investigation, we examined differences in the effects of aripiprazole and haloperidol on the conditioned fear response in methamphetamine-sensitized and fear-conditioned rats in an in vivo microdialysis study. Aripiprazole is the first antipsychotic drug with an action involving partial dopamine D 2 receptor agonism, thus differing from haloperidol, a typical antipsychotic that shows selective dopamine D 2 receptor full antagonism. After exposure to a conditioned stimulus, methamphetamine-sensitized rats exhibited significantly higher dopamine release in the amygdala than unsensitized rats. We considered this hypersensitivity of dopamine release to be a biochemical marker of hypersensitivity and vulnerability to stress in psychosis. In the present study, we found that aripiprazole and haloperidol equally suppressed the marked increase in extracellular dopamine levels in fear-conditioned rats, whereas haloperidol increased and aripiprazole decreased tonic dopamine levels. In conclusion, the effect of an antipsychotic drug is likely to be involved in attenuation of the phasic increase in dopamine associated with the fear response, at least in the amygdala. In addition, the contrasting effects of haloperidol and aripiprazole on tonic dopamine levels in the amygdala are likely due to the difference in their actions (selective dopamine D 2 receptor full antagonist vs. partial agonist, respectively).

Phasic dopamine release in appetitive behaviors and drug addiction.

Although dopamine is implicated in the development of addiction, it is unclear how specific dopamine release patterns are involved with drug seeking. Addictive drugs increase tonic dopamine levels on the order of minutes, as well as phasic dopamine release events that occur on a subsecond time scale. Phasic dopamine release is associated with the initiation of goal-directed behaviors, and has been shown to promote drug seeking. Prior experience with addictive drugs modulates the synaptic and intrinsic properties of dopamine neurons, affects the pattern of dopamine neuron firing and release, and alters dopamine-dependent behaviors related to drug addiction. In this review, we synthesize the known drug-dependent changes to the dopamine system along with the established functions of phasic dopamine release in order to provide a framework for conceptualizing the role of phasic dopamine release in drug addiction. Because drug addiction is commonly thought to involve changes in brain circuits important for natural reinforcement, we first present the role of phasic dopamine release in appetitive and goal-directed behaviors in the context of contemporary theories regarding the function of dopamine. Next, we discuss the known drug-induced changes to dopamine neurons and phasic release in both in vitro and in vivo preparations. Finally, we offer a simple model that chronic drug experience increases the contrast, or 'signal to noise', of phasic dopamine release to basal dopamine levels in response to drug-related stimuli, which could result in aberrant associations between cues and reinforcers that contribute to the development of addiction.

Cognitive impairment of prefrontal-dependent decision-making in rats after the onset of chronic pain

Forced choice between alternative options of unpredictable outcome is a complex task that requires continual update of the value associated with each option. Prefrontal areas such as the orbitofrontal cortex (OFC) have been shown to play a major role in performance on ambiguous decision-making tasks with substantial risk component, broadly named as “gambling tasks.” We have recently demonstrated that rats display complex decision-making behavior in a rodent gambling task based on serial choices between rewards of different value and probability. This rodent task retains many of the key characteristics of the human Iowa Gambling Task (IGT), and performance in this novel task is also disrupted by OFC or amygdalar lesioning. In the present study we addressed if rat models of chronic pain would have impaired performance in this gambling task, since it is already known that the IGT response patterns of human pain patients are comparable to individuals with OFC lesions. We found that animals with a monoarthritic inflammatory model of chronic pain systematically preferred the lever associated with larger but infrequent rewards. In addition, we measured the neurochemical content of the OFC, amygdala and nucleus accumbens using HPLC, and found that in prolonged chronic pain animals there was a decrease in the tonic levels of dopamine, DOPAC (3,4-hydroxyphenyl-acetic acid) and 5-HIAA (5-hydroxyindole-3-acetic acid) in the OFC. This is the first report of the effect of chronic pain in rat decision-making processes and supports the notion that pain may have profound effects on the functioning of the reward-aversion circuitry relevant to strategic planning.

Small effect of dopamine release and no effect of dopamine depletion on [18F]fallypride binding in healthy humans

Molecular imaging has been used to estimate both drug-induced and tonic dopamine release in the striatum and most recently extrastriatal areas of healthy humans. However, to date, studies of drug-induced and tonic dopamine release have not been performed in the same subjects. This study performed positron emission tomography (PET) with [18F]fallypride in healthy subjects to assess (1) the reproducibility of [18F]fallypride and (2) both D-amphetamine-induced and alpha-methyl-p-tyrosine (AMPT)-induced changes in dopamin release on [(18)F]fallypride binding in striatal and extrastriatal areas. Subjects underwent [18F]fallypride PET studies at baseline and following oral D-amphetamine administration (0.5 mg/kg) and oral AMPT administration (3 g/70 kg/day over 44 h). Binding potential (BP) (BP(ND)) of [18F]fallypride was calculated in striatal and extrastriatal areas using a reference region method. Percent change in regional BP(ND) was computed and correlated with change in cognition and mood. Test-retest variability of [18F]fallypride was low in both striatal and extrastriatal regions. D-Amphetamine significantly decreased BP(ND) by 8-14% in striatal subdivisions, caudate, putamen, substantia nigra, medial orbitofrontal cortex, and medial temporal cortex. Correlation between change in BP(ND) and verbal fluency was seen in the thalamus and substantia nigra. In contrast, depletion of endogenous dopamine with AMPT did not effect [18F]fallypride BP(ND) in both striatum and extrastriatal regions. These findings indicate that [18F]fallypride is useful for measuring amphetamine-induced dopamine release, but may be unreliable for estimating tonic dopamine levels, in striatum and extrastriatal regions of healthy humans.