Dopamine Response Research Articles

Sex Differences in Behavioral Responding and Dopamine Release during Pavlovian Learning.

Learning associations between cues and rewards require the mesolimbic dopamine system. The dopamine response to cues signals differences in reward value in well trained animals. However, these value-related dopamine responses are absent during early training sessions when cues signal differences in the reward rate. These findings suggest cue-evoked dopamine release conveys differences between outcomes only after extensive training, though it is unclear whether this is unique to when cues signal differences in reward rate, or whether this is also evident when cues signal differences in other value-related parameters such as reward size. To address this, we used a Pavlovian conditioning task in which one audio cue was associated with a small reward (one pellet) and another audio cue was associated with a large reward (three pellets). We performed fast-scan cyclic voltammetry to record changes in dopamine release in the nucleus accumbens of male and female rats throughout learning. While female rats exhibited higher levels of conditioned responding, a faster latency to respond, and elevated post-reward head entries relative to male rats, there were no sex differences in the dopamine response to cues. Multiple training sessions were required before cue-evoked dopamine release signaled differences in reward size. Reward-evoked dopamine release scaled with reward size, though females displayed lower reward-evoked dopamine responses relative to males. Conditioned responding related to the decrease in the peak reward-evoked dopamine response and not to cue-evoked dopamine release. Collectively, these data illustrate sex differences in behavioral responding as well as in reward-evoked dopamine release during Pavlovian learning.

Aquaporin-4 deletion attenuates opioid-induced addictive behaviours associated with dopamine levels in nucleus accumbens

There is a lack of safe and effective non-opioid medications for the treatment of opioid addiction. Aquaporin-4 (AQP4), a water channel protein expressed in astrocytes, regulates the progression of neurological diseases. Our previous work demonstrated that AQP4 deficiency in mice attenuated morphine-induced physiological dependence. However, the role of AQP4 in the neurobiology of behaviours related to opioid addiction in mice remains unclear. Here, we report that Aqp4-knockout mice exhibited attenuated heroin consumption and heroin-seeking behaviours. Furthermore, Aqp4-knockout mice displayed diminished hyperactivity induced by morphine and heroin and subsequently showed dramatically inhibited morphine-induced behavioural sensitization. This attenuated hyperlocomotion to opioids was accompanied by a decreased dopamine response to the opioid-induced increase in the levels of extracellular dopamine in the NAc. In addition, Aqp4-knockout mice displayed upregulation of dopamine transporters in the striatum, suggesting a probable neurobiological mechanism for uptake of the extracellular dopamine. The present findings suggest that deficiency of AQP4 decreases opiate-induced drug seeking and taking behaviours, and AQP4 may be involved in the treatment of addiction. Therefore, the development of a pharmacological antagonist to AQP4 may be valuable to investigate as opioid addiction therapy.

Assessment of motion and model bias on the detection of dopamine response to behavioral challenge

Compartmental modeling analysis of 11C-raclopride (RAC) PET data can be used to measure the dopaminergic response to intra-scan behavioral tasks. Bias in estimates of binding potential (BPND) and its dynamic changes (ΔBPND) can arise both when head motion is present and when the compartmental model used for parameter estimation deviates from the underlying biology. The purpose of this study was to characterize the effects of motion and model bias within the context of a behavioral task challenge, examining the impacts of different mitigation strategies. Seventy healthy adults were administered bolus plus constant infusion RAC during a simultaneous PET/magnetic resonance (MR) scan with a reward task experiment. BPND and ΔBPND were estimated using an extension of the Multilinear Reference Tissue Model (E-MRTM2) and a new method (DE-MRTM2) was proposed to selectively discount the contribution of the initial uptake period. Motion was effectively corrected with a standard frame-based approach, which performed equivalently to a more complex reconstruction-based approach. DE-MRTM2 produced estimates of ΔBPND in putamen and nucleus accumbens that were significantly different from those estimated from E-MRTM2, while also decoupling ΔBPND values from first-pass k2′ estimation and removing skew in the spatial bias distribution of parametric ΔBPND estimates within the striatum.

Tissue distribution and changes in dopamine during development and stress responses in Malus germplasm

Dopamine is a catecholamine and an anti-oxidant which functions in responses to stress and it interacts with plant hormones to mediate plant development. At present, there are few studies on the functions of dopamine in apple. This study developed a method for dopamine determination which was used to analyze dopamine in Malus germplasm, in order to clarify the tissue distribution, developmental changes, diurnal variations, and stress responses in apple trees. First, the proposed method was verified. The linear range of quantification was robust from 0.1 to 20 ng mL−1. The instrumental, inter-day precision, and sample repeatability relative standard deviations were 1.024, 5.607, and 7.237%, respectively. The spiked recovery was greater than 100%, indicating the feasibility of the method and its suitability for the rapid analysis of dopamine in Malus. Next, the dopamine content was measured in 322 Malus tissues. The results showed that the dopamine level in Malus was low and the average dopamine content in leaf was higher than in peel and flesh. The dopamine had a skewed distribution that deviated to the right in cultivars and wild accessions. Finally, the tissue specificity, developmental changes, diurnal changes, and responses to stress were analyzed. In cultivar ‘Pinova’ (Malus domestica), the dopamine concentration was the highest in leaf buds and lowest in flesh. The dopamine contents in leaf and flesh decreased with the growth and development of cultivar ‘Liangxiang’ (Malus domestica). The dopamine content of apple leaves was higher after either drought or salinity stress as compared to the control. In this study, a dopamine detection method for apple was established based on HPLC-MS and shown to be a robust approach. This study provides a framework for future research on elucidating the tissue distribution, developmental changes, diurnal variation, and stress responses of dopamine in apple trees.

Nicotine Patch Alters Patterns of Cigarette Smoking-Induced Dopamine Release: Patterns Relate to Biomarkers Associated With Treatment Response.

IntroductionTobacco smoking is a major public health burden. The first-line pharmacological treatment for tobacco smoking is nicotine replacement therapy (eg, the nicotine patch (NIC)). Nicotine acts on nicotinic-acetylcholine receptors on dopamine terminals to release dopamine in the ventral and dorsal striatum encoding reward and habit formation, respectively.Aims and MethodsTo better understand treatment efficacy, a naturalistic experimental design combined with a kinetic model designed to characterize smoking-induced dopamine release in vivo was used. Thirty-five tobacco smokers (16 female) wore a NIC (21 mg, daily) for 1-week and a placebo patch (PBO) for 1-week in a randomized, counter-balanced order. Following 1-week under NIC and then overnight abstinence, smokers participated in a 90-minute [11C]raclopride positron emission tomography scan and smoked a cigarette while in the scanner. Identical procedures were followed for the PBO scan. A time-varying kinetic model was used at the voxel level to model transient dopamine release peaking instantaneously at the start of the stimulus and decaying exponentially. Magnitude and spatial extent of dopamine release were estimated. Smokers were subcategorized by nicotine dependence level and nicotine metabolism rate.ResultsDopamine release magnitude was enhanced by NIC in ventral striatum and diminished by NIC in dorsal striatum. More-dependent smokers activated more voxels than the less-dependent smokers under both conditions. Under PBO, fast metabolizers activated more voxels in ventral striatum and fewer voxels in dorsal striatum compared to slow metabolizers.ConclusionsThese findings demonstrate that the model captured a pattern of transient dopamine responses to cigarette smoking which may be different across smoker subgroup categorizations.ImplicationsThis is the first study to show that NIC alters highly localized patterns of cigarette smoking-induced dopamine release and that levels of nicotine dependence and nicotine clearance rate contribute to these alterations. This current work included a homogeneous subject sample with regards to demographic and smoking variables, as well as a highly sensitive model capable of detecting significant acute dopamine transients. The findings of this study add support to the recent identification of biomarkers for predicting the effect of nicotine replacement therapies on dopamine function which could help refine clinical practice for smoking cessation.

P044 Enteric dopaminergic pathways in mouse and human intestinal inflammation

Abstract Background Changes in dopamine beta-hydroxylase (DBH) and anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and related animal models. Thus, we aimed to evaluate the dopaminergic pathways in IBD patients as well as in a mouse model of dextran sodium sulphate (DSS)-induced ileitis. Methods Colon biopsies (CB) obtained from healthy volunteers (N=3) and matched-IBD patients (N=3), were used to evaluate DBH immunoreactivity by confocal microscopy. Male C57/Bl6 (8±2 weeks old; N=16 mice) received 1.5% DSS in drinking water for 5 days, then switched to regular drinking water for 3 days. Inflammatory cytokines (IL-1β, TNFα, IL-6) were measured to assess ileitis severity. Changes in ileal muscle tension were isometrically recorded following 30 μM dopamine or 30 μM SKF38393 (a dopamine receptor 1 (D1R) agonist) or 30 μM bromocriptine (a D2R agonist). Immunofluorescence distribution of Iba1 (a macrophage specific marker), D1R, DBH and dopamine transporter (DAT) were determined in longitudinal muscle-myenteric plexus whole-mount preparations (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR. Results CB from IBD patients and LMMPs from DSS mice showed a significant increase of DBH immunoreactivity compared to healthy patients and sham mice (+25% [p<0.01], +20% [p<0.01], respectively). DSS treatment caused a significant increase of DAT and D1R immunoreactivity as well as D1R mRNA levels (+27% [p<0.05], +24% [p<0.05], +6-fold [p<0.05], respectively), accompanied by a significant reduction of dopamine-mediated relaxation (-27% [p<0.01]). SKF38393 determined a marked inhibitory response in ileal preparations from DSS mice compared to sham mice (+73% [p<0.01]), suggesting that dopamine responses are mainly mediated through D1R. A 2-fold increase of resident Iba1+ macrophages was observed in the myenteric plexus of DSS mice associated with a 2.9- and 1.5-fold enhancement of IL-6 and IL-1β mRNA levels, respectively. Conclusion Human colitis and mouse ileitis affect dopamine machinery in the enteric nervous system. Experimentally induced ileitis impairs dopaminergic neurotransmission altering D1R-mediated responses. These findings provide novel information on the involvement of dopaminergic pathways in IBD.

All-fiber-transmission photometry for simultaneous optogenetic stimulation and multi-color neuronal activity recording

Manipulating and real-time monitoring of neuronal activities with cell-type specificity and precise spatiotemporal resolution during animal behavior are fundamental technologies for exploring the functional connectivity, information transmission, and physiological functions of neural circuits<italic>in vivo</italic>. However, current techniques for optogenetic stimulation and neuronal activity recording mostly operate independently. Here, we report an all-fiber-transmission photometry system for simultaneous optogenetic manipulation and multi-color recording of neuronal activities and the neurotransmitter release in a freely moving animal. We have designed and manufactured a wavelength-independent multi-branch fiber bundle to enable simultaneous optogenetic manipulation and multi-color recording at different wavelengths. Further, we combine a laser of narrow linewidth with the lock-in amplification method to suppress the optogenetic stimulation-induced artifacts and channel crosstalk. We show that the collection efficiency of our system outperforms a traditional epi-fluorescence system. Further, we demonstrate successful recording of dynamic dopamine (DA) responses to unexpected rewards in the nucleus accumbens (NAc) in a freely moving mouse. We also show simultaneous dual-color recording of neuronal Ca²⁺ signals and DA dynamics in the NAc upon delivering an unexpected reward and the simultaneous optogenetic activating at dopaminergic terminals in the same location. Thus, our multi-function fiber photometry system provides a compatible, efficient, and flexible solution for neuroscientists to study neural circuits and neurological diseases.

Cholinergic relevant functional reactivity is associated with dopamine responsiveness of tremor in Parkinson’s disease

Tremor in Parkinson’s disease (PD) has distinct responsiveness to dopamine, which is supposed not be exclusively related to dopamine deficiency but has a close relationship with cholinergic system. This phenomenon indicates that cholinergic system may be an important regulatory for distinct dopamine responsiveness of parkinsonian tremor. Through investigating the alterations of cholinergic and dopaminergic network during levodopa administration, we aimed at exploring the mechanisms of differed dopamine responsiveness of parkinsonian tremor. Fifty-two PD patients with tremor were enrolled. MRI scanning, UPDRS III and its sub-symptom scores were collected in OFF and ON status (dopaminergic challenge test). Then, patients were divided into two groups (dopamine-resistant tremor and dopamine-responsive tremor) according to the tremor change rate median score. Dopaminergic and cholinergic network were obtained. LASSO regression was conducted to identify functional connectivity with distinct reactivity during levodopa administration between groups. Afterwards, detailed group comparisons, interaction and correlation analyses were performed. The reactivity of cholinergic connectivity showed the highest possibility to distinguish two groups, especially connectivity of right basal forebrain 123 to right parietal operculum cortex (R.BF123-R.PO). After levodopa administration, connectivity of R.BF123-R.PO was decreased for dopamine-responsive tremor while which remained unchanged for dopamine-resistant tremor. The reactivity of R.BF123-R.PO was negatively correlated with tremor change rate. Reduced cholinergic connectivity to parietal operculum may be an underlying mechanism for the responsive tremor in PD and the distinct cholinergic reactivity of parietal operculum to levodopa may be a core pathophysiology for the differed DA responsiveness of tremor in PD.

Ghrelin restores the dopamine responses in the PFC to external stimuli via dopamine D1 receptor signaling and attenuates cognitive deficit in &lt;i&gt;MECP2&lt;/i&gt; KO mice, a model mouse for Rett syndrome

Ghrelin restores the dopamine responses in the PFC to external stimuli via dopamine D1 receptor signaling and attenuates cognitive deficit in &lt;i&gt;MECP2&lt;/i&gt; KO mice, a model mouse for Rett syndrome

Understanding and restoring dopaminergic function in fibromyalgia patients using a mindfulness-based psychological intervention: a [18F]-DOPA PET study. Study protocol for the FIBRODOPA study\u2014a randomized controlled trial

BackgroundFibromyalgia (FM) is a very prevalent and debilitating chronic pain disorder that is difficult to treat. Mindfulness-based techniques are regarded as a very promising approach for the treatment of chronic pain and in particular FM. The Mindfulness-Oriented Recovery Enhancement (MORE) intervention, a mindfulness-based group intervention, has shown beneficial effects in opioid-treated chronic pain patients, including reduced pain severity, functional interference, and opioid dosing, by restoring neurophysiological and behavioral responses to reward. The first evidence for a hypodopaminergic state and impaired reward processing in FM has been reported. However, little is known about its impact on dopamine (DA) function and in particular with regard to DA responses to monetary reward in FM. The aim of the present study protocol is to evaluate if MORE is able to restore the DA function in FM patients, in particular with regard to the DA responses to reward, and to reduce pain and mood complaints in FM.MethodsThe present study is a multi-center interventional RCT with 3 time points: before the intervention, after completion of the intervention, and 3 months after completion of the intervention. Sixty-four FM patients will be randomly assigned to either the MORE intervention (N = 32) or a non-intervention control group (N = 32). Additionally, a comparison group of healthy women (N = 20) for PET measures will be enrolled and another group of healthy women (N = 15) will do the ambulatory assessments only. The MORE intervention consists of eight 2-h-long group sessions administered weekly over a period of 8 weeks. Before and after the intervention, FM participants will undergo [18F] DOPA positron emission tomography (PET) and functional MR imaging while performing a reward task. The primary outcome will be endogeneous DA changes measured with [18F] DOPA PET at baseline, after the intervention (after 8 weeks for the non-intervention control group), and at 3 months’ follow-up. Secondary outcomes will be (1) clinical pain measures and FM symptoms using standardized clinical scales; (2) functional brain changes; (3) measures of negative and positive affect, stress, and reward experience in daily life using the ambulatory assessment method (AA); and (4) biological measures of stress including cortisol and alpha-amylase.DiscussionIf the findings of this study confirm the effectiveness of MORE in restoring DA function, reducing pain, and improving mood symptoms, MORE can be judged to be a promising means to improve the quality of life in FM patients. The findings of this trial may inform health care providers about the potential use of the MORE intervention as a possible non-pharmacological intervention for FM.Trial registrationClinicalTrials.govNCT 04451564. Registered on 3 July 2020. The trial was prospectively registered.

P.0850 Different dopamine responses in female rats with aggressive and defensive stress coping

P.0850 Different dopamine responses in female rats with aggressive and defensive stress coping

Electrochemical Detection of Dopamine Using a Prussian Blue Carbon Nanotube Composite Decorated with Agglomerated ZnO Particles

A Prussian Blue (PB) zinc oxide (ZnO) nanoparticle carboxylic acid-functionalized multiwalled carbon nanotube (PB/ZnO/COOH-MWNT) composite was fabricated for the determination of dopamine (DA). ZnO nanoparticles were tethered to COOH-MWNTs using sonication. Upon attachment of the PB to the ZnO/COOH-MWNTs, which consisted of ZnO nanoparticles 13 nm in diameter, the ZnO coalesced to larger clusters with an average diameter of 573 ± 4 nm. The current response versus various concentrations of DA was measured using chronoamperometry. The optimum conditions for DA measurements were at pH 7.0 using the oxidation current. The sensor has a linear dynamic range from 10 to 900 μM with a limit of detection of 0.378 ± 0.015 μM, suitable for practical neuroblastoma screening at the lower concentration range and process controls for polydopamine synthesis at the upper concentration range, important for modifying polymeric membranes for water purification.

A Double-Deck Structure of Reduced Graphene Oxide Modified Porous Ti3C2Tx Electrode towards Ultrasensitive and Simultaneous Detection of Dopamine and Uric Acid.

Considering the vital physiological functions of dopamine (DA) and uric acid (UA) and their coexistence in the biological matrix, the development of biosensing techniques for their simultaneous and sensitive detection is highly desirable for diagnostic and analytical applications. Therefore, Ti3C2Tx/rGO heterostructure with a double-deck layer was fabricated through electrochemical reduction. The rGO was modified on a porous Ti3C2Tx electrode as the biosensor for the detection of DA and UA simultaneously. Debye length was regulated by the alteration of rGO mass on the surface of the Ti3C2Tx electrode. Debye length decreased with respect to the rGO electrode modified with further rGO mass, indicating that fewer DA molecules were capable of surpassing the equilibrium double layer and reaching the surface of rGO to achieve the voltammetric response of DA. Thus, the proposed Ti3C2Tx/rGO sensor presented an excellent performance in detecting DA and UA with a wide linear range of 0.1–100 μM and 1–1000 μM and a low detection limit of 9.5 nM and 0.3 μM, respectively. Additionally, the proposed Ti3C2Tx/rGO electrode displayed good repeatability, selectivity, and proved to be available for real sample analysis.

Reverse-translational identification of a cerebellar satiation network.

The brain is the seat of body weight homeostasis. However, our inability to control the increasing prevalence of obesity highlights a need to look beyond canonical feeding pathways to broaden our understanding of body weight control1-3. Here we used a reverse-translational approach to identify and anatomically, molecularly and functionally characterize a neural ensemble that promotes satiation. Unbiased, task-based functional magnetic resonance imaging revealed marked differences in cerebellar responses to food in people with a genetic disorder characterized by insatiable appetite. Transcriptomic analyses in mice revealed molecularly and topographically-distinct neurons in the anterior deep cerebellar nuclei (aDCN) that are activated by feeding or nutrient infusion in the gut. Selective activation of aDCN neurons substantially decreased food intake by reducing meal size without compensatory changes to metabolic rate. We found that aDCN activity terminates food intake by increasing striatal dopamine levels and attenuating the phasic dopamine response to subsequent food consumption. Our study defines a conserved satiation centre that may represent a novel therapeutic target for the management of excessive eating, and underscores the utility of a 'bedside-to-bench' approach for the identification of neural circuits that influence behaviour.

Maternal dopamine encodes affective signals of human infants.

Mothers are highly responsive to their offspring. In non-human mammals, mothers secrete dopamine in the nucleus accumbens (NAcc) in response to their pups. Yet, it is still unknown which aspect of the offspring behavior elicits dopaminergic responses in mothers. Here, we tested whether infants’ affective signals elicit dopaminergic responses in the NAcc of human mothers. First, we conducted a behavioral analysis on videos of infants’ free play and quantified the affective signals infants spontaneously communicated. Then, we presented the same videos to mothers during a magnetic resonance-positron emission tomography scan. We traced the binding of [11C]raclopride to free D2/3-type receptors to assess maternal dopaminergic responses during the infant videos. When mothers observed videos with many infant signals during the scan, they had less [11C]raclopride binding in the right NAcc. Less [11C]raclopride binding indicates that less D2/3 receptors were free, possibly due to increased endogenous dopamine responses to infants’ affective signals. We conclude that NAcc D2/3 receptors are involved in maternal responsiveness to affective signals of human infants. D2/3 receptors have been associated with maternal responsiveness in nonhuman animals. This evidence supports a similar mechanism in humans and specifies infant-behaviors that activate the maternal dopaminergic system, with implications for social neuroscience, development and psychopathology.

Changes in Brain Dopamine Extracellular Concentration after Ethanol Administration; Rat Microdialysis Studies.

The purpose of this review is to evaluate microdialysis studies where alterations in the dopaminergic system have been evaluated after different intoxication states, in animals showing preference or not for alcohol, as well as during alcohol withdrawal. Ethanol administration induces varying alterations in dopamine microdialysate concentrations, thereby modulating the functional output of the dopaminergic system. Administration of low doses of ethanol, intraperitoneally, intravenously, orally or directly into the nucleus accumbens, NAc, increases mesolimbic dopamine, transmission, as shown by increases in dopamine content. Chronic alcohol administration to rats, which show alcohol-dependent behaviour, induced little change in basal dopamine microdialysis content. In contrast, reduced basal dopamine content occurred after ethanol withdrawal, which might be the stimulus to induce alcohol cravings and consumption. Intermittent alcohol consumption did not identify any consistent changes in dopamine transmission. Animals which have been selectively or genetically bred for alcohol preference did not show consistent changes in basal dopamine content although, exhibited a significant ethanol-evoked dopamine response by comparison to non-preference animals. Microdialysis has provided valuable information about ethanol-evoked dopamine release in the different animal models of alcohol abuse. Acute ethanol administration increases dopamine transmission in the rat NAc whereas chronic ethanol consumption shows variable results which might reflect whether the rat is prior to or experiencing ethanol withdrawal. Ethanol withdrawal significantly decreases the extracellular dopamine content. Such changes in dopamine surges will contribute to both drug dependence, e.g. susceptibility to drug withdrawal, and addiction, by compromising the ability to react to normal dopamine fluctuations.

Behavioral Engagement With Playable Objects Resolves Stress-Induced Adaptive Changes by Reshaping the Reward System

BackgroundThe reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood. MethodsMice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects. ResultsHere, we show that repeated restraint induces dopamine surges into the nucleus accumbens–lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D1 receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress–induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area–to–NAc-lSh and NAc-lSh–to–ventral pallidum circuits. ConclusionsThese results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.

Executive function and dopamine response in Parkinson's disease freezing of gait

BackgroundThis investigation examined whether aspects of attention and executive functioning differed between Parkinson's Disease (PD) patients with freezing of gait (FOG) based on responsiveness to dopamine. We also explored association of cognition with FOG severity and gait metrics. MethodsFifty-four individuals with PD completed the study protocol: 17 without freezing (PDC), 23 with dopa-responsive FOG (RFOG), and 14 with dopa-unresponsive (URFOG). Standardized neuropsychological tests assessed attention (focused and sustained), psychomotor speed, and set-switching (time and errors). FOG severity was measured using the new FOG Questionnaire (nFOG-Q). Metrics from timed up and go (TUG) tasks were obtained while “on” and “off” dopamine, with and without dual cognitive tasks. ResultsAfter controlling for clinical and demographic factors, analysis of covariance revealed a significant between-group difference for set-switching errors; planned contrasts revealed increased set-switching errors in URFOG relative to RFOG and PD control groups. Groups were not different in other cognitive domains. FOG severity was modestly associated with set-switching errors in RFOG but not URFOG. TUG performances while “on” were associated with set-switching errors in PD controls, and with focused attention in RFOG. ConclusionPD patients with dopa-unresponsive FOG are more prone to set-switching errors than those who respond to treatment. Furthermore, executive function appears relevant to FOG severity only in patients who show dopamine response. Together, these findings suggest disruption of a common dopamine-mediated pathway for FOG and ability to monitor rules while alternating cognitive processes. Consideration of dopa-response could be useful in characterizing cohorts and treating FOG in PD.

Nigrostriatal dopamine signals sequence-specific action-outcome prediction errors

Dopamine has been suggested to encode cue-reward prediction errors during Pavlovian conditioning, signaling discrepancies between actual versus expected reward predicted by the cues.1-5 While this theory has been widely applied to reinforcement learning concerning instrumental actions, whether dopamine represents action-outcome prediction errors and how it controls sequential behavior remain largely unknown. The vast majority of previous studies examining dopamine responses primarily have used discrete reward-predictive stimuli,1-15 whether Pavlovian conditioned stimuli for which no action is required to earn reward or explicit discriminative stimuli that essentially instruct an animal how and when to respond for reward. Here, by training mice to perform optogenetic intracranial self-stimulation, we examined how self-initiated goal-directed behavior influences nigrostriatal dopamine transmission during single and sequential instrumental actions, in behavioral contexts with minimal overt changes in the animal's external environment. We found that dopamine release evoked by direct optogenetic stimulation was dramatically reduced when delivered as the consequence of the animal's own action, relative to non-contingent passive stimulation. This dopamine suppression generalized to food rewards was specific to the reinforced action, was temporally restricted to counteract the expected outcome, and exhibited sequence-selectivity consistent with hierarchical control of sequential behavior. These findings demonstrate that nigrostriatal dopamine signals sequence-specific prediction errors in action-outcome associations, with fundamental implications for reinforcement learning and instrumental behavior in health and disease.

Recently Abstinent Smokers Exhibit Mood-Associated Dopamine Dysfunction in the Ventral Striatum Compared to Nonsmokers: A [11C]-(+)-PHNO PET Study.

Chronic nicotine exposure desensitizes dopamine responses in animals, but it is not known if this occurs in human tobacco smokers. Deficits in dopamine function are likely to make smoking cessation difficult. We used positron emission tomography (PET) brain imaging with the dopamine D2/3 receptor agonist radioligand [11C]-(+)-PHNO to determine if abstinent smokers exhibit less amphetamine-induced dopamine release in the ventral striatum than nonsmokers, and whether this was associated with clinical correlates of smoking cessation. Baseline [11C]-(+)-PHNO scans were acquired from smokers (n = 22, 7 female, abstinent 11 ± 9 days) and nonsmokers (n = 20, 7 female). A subset of thirty-seven participants (18 smokers) received oral amphetamine (0.5 mg/kg) three hours before a second [11C]-(+)-PHNO scan. Binding potential (BPND) (i.e., D2/3 receptor availability) was estimated at baseline and postamphetamine in the ventral striatum. Amphetamine-induced percent change in BPND was calculated to reflect dopamine release. Subjects also completed the Center for Epidemiologic Studies Depression Scale (CES-D). There were no group differences in baseline BPND. Amphetamine-induced percent change in BPND in the ventral striatum was significantly lower in abstinent smokers compared to nonsmokers (p=0.019; d=0.82). Higher CES-D scores were significantly associated with lower ventral striatal percent change in BPND for abstinent smokers (rs=-0.627, p=0.025). In conclusion, abstinent smokers exhibited significantly less amphetamine-induced dopamine release in the ventral striatum than nonsmokers. In abstinent smokers, worse mood was significantly associated with less striatal dopamine release. Our findings highlight a potential neural mechanism that may underlie negative mood symptoms during early abstinence. This study combined quantitative PET imaging and an amphetamine challenge to examine striatal dopamine function during early smoking cessation attempts. The findings demonstrate that recently abstinent tobacco smokers exhibit significant, mood-associated striatal dopamine dysfunction compared to nonsmokers. This study advances our knowledge of the neurobiology underlying early quit attempts, and bridges novel neural findings with clinically relevant symptoms of smoking cessation. These results may explain the challenge of maintaining long-term abstinence from smoking, and can lend insight into the development of treatment strategies for smoking cessation.