Striatal Dopamine Release Research Articles

Synaptic-like axo-axonal transmission from striatal cholinergic interneurons onto dopaminergic fibers

Transmission from striatal cholinergic interneurons (CINs) controls dopamine release through nicotinic acetylcholine receptors (nAChRs) on dopaminergic axons. Anatomical studies suggest that cholinergic terminals signal predominantly through non-synaptic volume transmission. However, the influence of cholinergic transmission on electrical signaling in axons remains unclear. We examined axo-axonal transmission from CINs onto dopaminergic axons using perforated-patch recordings, which revealed rapid spontaneous EPSPs with properties characteristic of fast synapses. Pharmacology showed that axonal EPSPs (axEPSPs) were mediated primarily by high-affinity α6-containing receptors. Remarkably, axEPSPs triggered spontaneous action potentials, suggesting that these axons perform integration to convert synaptic input into spiking, a function associated with somatodendritic compartments. We investigated the cross-species validity of cholinergic axo-axonal transmission by recording dopaminergic axons in macaque putamen and found similar axEPSPs. Thus, we reveal that synaptic-like neurotransmission underlies cholinergic signaling onto dopaminergic axons, supporting the idea that striatal dopamine release can occur independently of somatic firing to provide distinct signaling.

Leptin Promotes Striatal Dopamine Release via Cholinergic Interneurons and Regionally Distinct Signaling Pathways.

Dopamine (DA) is a critical regulator of striatal network activity and is essential for motor activation and reward-associated behaviors. Previous work has shown that DA is influenced by the reward value of food, as well as by hormonal factors that reguate food intake and energy expenditure. Changes in striatal DA signaling also have been linked to aberrant eating patterns. Here we test the effect of leptin, an adipocyte-derived hormone involved in feeding and energy homeostasis regulation, on striatal DA release and uptake. Immunohistochemical evaluation identified leptin receptor (LepR) expression throughout mouse striatum, including on striatal cholinergic interneurons (ChIs) and their extensive processes. Using fast-scan cyclic voltammetry (FSCV), we found that leptin causes a concentration-dependent increase in evoked extra-cellular DA concentration ([DA]o) in dorsal striatum (dStr) and nucleus accumbens (NAc) core and shell in male mouse striatal slices, and also an increase in the rate of DA uptake. Further, we found that leptin increases ChI excitability, and that the enhancing effect of leptin on evoked [DA]o is lost when nicotinic acetylcholine (ACh) receptors are antagonized or when examined in striatal slices from mice lacking ACh synthesis. Evaluation of signaling pathways underlying leptin's action revealed a requirement for intracellular Ca2+, and the involvement of different downstream pathways in dStr and NAc core versus NAc shell. These results provide the first evidence for dynamic regulation of DA release and uptake by leptin within brain motor and reward pathways, and highlight the involvement of ChIs in this process.SIGNIFICANCE STATEMENT Given the importance of striatal dopamine (DA) in reward, motivation, motor behavior and food intake, identifying the actions of metabolic hormones on DA release in striatal subregions should provide new insight into factors that influence DA-dependent motivated behaviors. We find that one of these hormones, leptin, boosts striatal DA release through a process involving striatal cholinergic interneurons (ChIs) and nicotinic acetylcholine (ACh) receptors. Moreover, we find that the intracellular cascades downstream from leptin receptor (LepR) activation that lead to enhanced DA release differ among striatal subregions. Thus, we not only show that leptin regulates DA release, but also identify characteristics of this process that could be harnessed to alter pathologic eating behaviors.

Measurement of Striatal Dopamine Release Induced by Neuropsychological Stimulation in Positron Emission Tomography With Dual Injections of [11C]Raclopride.

ObjectivesPositron emission tomography (PET) with [11C]raclopride has been applied to measure changes in the concentration of endogenous dopamine induced by pharmacological challenge or neuropsychological stimulation by evaluating the binding potential (BP) between the baseline and activated state. Recently, to reliably estimate BP in the activated state, a new approach with dual-bolus injections in a single PET scan was developed. In this study, we investigated the feasibility of applying this dual-bolus injection approach to measure changes in endogenous dopamine levels induced by cognitive tasks in humans.MethodsFirst, the reproducibility of BP estimation using the dual-bolus injection approach was evaluated using PET scans without stimulation in nine healthy volunteers. A 90-min scan was performed with bolus injections of [11C]raclopride administered at the beginning of the scan and 45 min after the first injection. BPs in the striatum for the first injection (BP1) and second injection (BP2) were estimated using an extended simplified reference tissue model, and the mean absolute difference (MAD) between the two BPs was calculated. The MAD was also compared with the conventional bolus-plus-continuous infusion approach. Next, PET studies with a cognitive reinforcement learning task were performed on 10 healthy volunteers using the dual-bolus injection approach. The BP1 at baseline and BP2 at the activated state were estimated, and the reduction in BP was evaluated.ResultsIn the PET scans without stimulation, the dual-bolus injection approach showed a smaller MAD (<2%) between BP1 and BP2 than the bolus-plus-continuous infusion approach, demonstrating good reproducibility of this approach. In the PET scans with the cognitive task performance, the reduction in BP was not observed in the striatum by either approach, showing that the changes in dopamine level induced by the cognitive tasks performed in this study were not sufficient to be detected by PET.ConclusionOur results indicate that the cognitive task-induced changes in dopamine-related systems may be complex and difficult to measure accurately using PET scans. However, the proposed dual-bolus injection approach provided reliable BP estimates with high reproducibility, suggesting that it has the potential to improve the accuracy of PET scans for measuring changes in dopamine concentrations.

Imaging Dopaminergic Neurotransmission in Neurodegenerative Disorders.

Imaging of dopaminergic transmission in neurodegenerative disorders such as Parkinson disease (PD) or dementia with Lewy bodies plays a major role in clinical practice and in clinical research. We here review the role of imaging of the nigrostriatal pathway, as well as of striatal receptors and dopamine release, in common neurodegenerative disorders in clinical practice and research. Imaging of the nigrostriatal pathway has a high diagnostic accuracy to detect nigrostriatal degeneration in disorders characterized by nigrostriatal degeneration, such as PD and dementia with Lewy bodies, and disorders of more clinical importance, namely in patients with clinically uncertain parkinsonism. Imaging of striatal dopamine D2/3 receptors is not recommended for the differential diagnosis of parkinsonian disorders in clinical practice anymore. Regarding research, recently the European Medicines Agency has qualified dopamine transporter imaging as an enrichment biomarker for clinical trials in early PD, which underlines the high diagnostic accuracy of this imaging tool and will be implemented in future trials. Also, imaging of the presynaptic dopaminergic system plays a major role in, for example, examining the extent of nigrostriatal degeneration in preclinical and premotor phases of neurodegenerative disorders and to examine subtypes of PD. Also, imaging of postsynaptic dopamine D2/3 receptors plays a role in studying, for example, the neuronal substrate of impulse control disorders in PD, as well as in measuring endogenous dopamine release to examine, for example, motor complications in the treatment of PD. Finally, novel MRI sequences as neuromelanin-sensitive MRI are promising new tools to study nigrostriatal degeneration invivo.

Voluntary Exercise Boosts Striatal Dopamine Release: Evidence for the Necessary and Sufficient Role of BDNF.

Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in ex vivo corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise on DA release using mice that were heterozygous for BDNF deletion (BDNF+/-). In contrast to WT mice, evoked DA release did not differ between BDNF+/- runners and controls. Complementary pharmacological studies using a tropomyosin receptor kinase B (TrkB) agonist in WT mouse slices showed that TrkB receptor activation also increased evoked DA release throughout striatum in an ACh-independent manner. Together, these data support a causal role for BDNF in exercise-enhanced striatal DA release and provide mechanistic insight into the beneficial effects of exercise in neuropsychiatric disorders, including Parkinson's, depression, and anxiety.SIGNIFICANCE STATEMENT Exercise has been shown to improve movement and cognition in humans and rodents. Here, we report that voluntary exercise for 30 d leads to an increase in evoked DA release throughout the striatum and an increase in BDNF in the dorsal (motor) striatum. The increase in DA release appears to require BDNF, indicated by the absence of DA release enhancement with running in BDNF+/- mice. Activation of BDNF receptors using a pharmacological agonist was also shown to boost DA release. Together, these data support a necessary and sufficient role for BDNF in exercise-enhanced DA release and provide mechanistic insight into the reported benefits of exercise in individuals with dopamine-linked neuropsychiatric disorders, including Parkinson's disease and depression.

Prefrontal and Striatal Dopamine Release Are Inversely Correlated in Schizophrenia

BackgroundThe dopamine (DA) hypothesis postulates hyperactivity of subcortical DA transmission and hypoactivity of cortical DA in schizophrenia (SCH). Positron emission tomography provides the ability to assess this hypothesis in humans. However, no studies have examined the relationship between cortical DA and striatal DA in this illness. MethodsD2/3 receptor radiotracer [11C]FLB457 BPND (binding potential relative to nondisplaceable uptake) was measured in 14 off-medication subjects with SCH and 14 healthy control (HC) subjects at baseline and after the administration of 0.5 mg/kg oral d-amphetamine. The amphetamine-induced change in BPND (ΔBPND) was calculated as the difference between BPND in the postamphetamine condition and BPND in the baseline condition and expressed as a percentage of BPND at baseline. DA release in the striatum using the radiotracer [11C]NPA was also measured in these subjects. Results[11C]FLB457 ΔBPND was greater in the HC group compared with the SCH group (F1,26 = 5.7; p = .02) with significant differences in [11C]FLB457 ΔBPND seen across cortical brain regions. Only in the SCH group was a significant negative correlation observed between [11C]FLB457 ΔBPND in the dorsolateral prefrontal cortex and [11C]NPA ΔBPND in the dorsal caudate (r = −0.71, p = .005). ConclusionsSubjects with SCH demonstrated deficits of DA release in cortical brain regions relative to HC subjects. Examining both cortical and striatal DA release in the same subjects demonstrated an inverse relationship between cortical DA release and striatal DA release in SCH not present in HC subjects, providing support for the current DA hypothesis of SCH.

The relationship between glutamate, dopamine, and cortical gray matter: A simultaneous PET-MR study

Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [11C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D2/3R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D2/3R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D2/3R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D2/3R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D2/3R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations.

Continuous but not intermittent theta burst stimulation decreases striatal dopamine release and cortical excitability

Dopamine modulation is thought to underpin some of the therapeutic effects associated with repetitive transcranial magnetic stimulation (rTMS). However, patient studies have failed to demonstrate consistent changes in the dopamine system in vivo after a therapeutic course of rTMS. Here, we evaluated acute and chronic changes in striatal dopamine release elicited by a clinically relevant course of theta burst (TBS) or sham stimulation using [11C]raclopride in healthy non-human primates (n = 11). Subjects were scanned immediately after the first session of TBS and the day after a 3 week course of daily TBS delivery. After experiment completion, animals were euthanized, and immunofluorescence staining was carried out using antibodies targeting D2 receptors (D2R).Continuous TBS (cTBS, an inhibitory form of rTMS) over the left primary motor cortex acutely decreased dopamine release bilaterally in the putamen. However, no significant changes in dopamine receptors nor D2R immunoreactivity were noted 24 h after the last stimulation, while a decrease in cortical excitability, as measured by an increase in resting motor threshold, could still be quantified. On the opposite, intermittent TBS (iTBS, an excitatory form of rTMS) did not affect dopamine release, acutely or chronically, D2R immunoreactivity or cortical excitability. These findings suggest that the long-term therapeutic effects of TBS might be facilitated through the modulation of different neurotransmission systems beyond the dopamine system. However, given the small sample size, these results should be interpreted with caution.

Sigma receptor ligands haloperidol and ifenprodil attenuate hypoxia induced dopamine release in rat striatum

ABSTRACT Objective We aimed to investigate the hypothesis that sigma receptor ligands, haloperidol and ifenprodil, attenuate hypoxia-induced striatal dopamine release in vitro and determine the possible mechanisms. Methods Extracellular concentrations of dopamine were measured using acute brain slices method under hypoxic, aglycemic and ischemic conditions. Sigma receptor ligands haloperidol and ifenprodil attenuate striatal dopamine release induced by hypoxia in contrast to aglycemia and ischemia. To determine the possible contribution of glutamatergic system on this effect, we compared the effect of NMDA receptor antagonist MK-801 and haloperidol in hypoxia induced by Na-K-ATPaz enzyme inhibitor ouabain. Also, we compared the effect of dopamine uptake blocker nomifensine and haloperidol to determine the role of dopamine transporter on this effect. Results Haloperidol and nomifensine almost completely abolish ouabain-induced dopamine release unlike MK-801. Different effects of sigma ligands and glutamate receptor antagonists on the hypoxia and ouabain induced dopamine release show that glutamate receptor blockade is partial involved in inhibitory effect of sigma ligand on dopamine release under hypoxic conditions. Similar effect of dopamine uptake blocker nomifensine and sigma receptor ligand haloperidol on ouabain induced dopamine release supports the possibility that inhibition of reverse dopamine transport by sigma ligands might be involved in their protective effect. Conclusions Data in this study suggest that sigma ligands may be a new therapeutic intervention for the management of hypoxic conditions.

Changes in striatal dopamine release, sleep, and behavior during spontaneous Δ-9-tetrahydrocannabinol abstinence in male and female mice

Withdrawal symptoms are observed upon cessation of cannabis use in humans. Although animal studies have examined withdrawal symptoms following exposure to delta-9-tetrahydrocannabinol (THC), difficulties in obtaining objective measures of spontaneous withdrawal using paradigms that mimic cessation of use in humans have slowed research. The neuromodulator dopamine (DA) is affected by chronic THC treatment and plays a role in many behaviors related to human THC withdrawal symptoms. These symptoms include sleep disturbances that often drive relapse, and emotional behaviors like irritability and anhedonia. We examined THC withdrawal-induced changes in striatal DA release and the extent to which sleep disruption and behavioral maladaptation manifest during abstinence in a mouse model of chronic THC exposure. Using a THC treatment regimen known to produce tolerance, we measured electrically elicited DA release in acute brain slices from different striatal subregions during early and late THC abstinence. Long-term polysomnographic recordings from mice were used to assess vigilance state and sleep architecture before, during, and after THC treatment. We additionally assessed how behaviors that model human withdrawal symptoms are altered by chronic THC treatment in early and late abstinence. We detected altered striatal DA release, sleep disturbances that mimic clinical observations, and behavioral maladaptation in mice following tolerance to THC. Altered striatal DA release, sleep, and affect-related behaviors associated with spontaneous THC abstinence were more consistently observed in male mice. These findings provide a foundation for preclinical study of directly translatable non-precipitated THC withdrawal symptoms and the neural mechanisms that affect them.

The Placebo Response in Double-Blind Randomised Trials Evaluating Regenerative Therapies for Parkinson's Disease: A Systematic Review and Meta-Analysis.

In the field of stem cell technologies, exciting advances are taking place leading to translational research to develop cell-based therapies which may replace dopamine releasing neurons lost in patients with Parkinson's disease (PD). A major influence on trial design has been the assumption that the use of sham operated comparator groups is required in the implementation of randomised double-blind trials to evaluate the placebo response and effects associated with the surgical implantation of cells. The aim of the present review is to identify the improvements in motor functioning and striatal dopamine release in patients with PD who have undergone sham surgery. Of the nine published trials, there was at the designated endpoints, a pooled average improvement of 4.3 units, with 95% confidence interval of 3.1 to 5.6 on the motor subscale of the Unified Parkinson's Disease Scale in the 'OFF' state. This effect size indicates a moderate degree of improvement in the motor functioning of the patients in the sham surgical arms of the trials. Four of the nine trials reported the results of 18F-Fluorodopa PET scans, indicating no improvements of dopaminergic nigrostriatal neurones following sham surgery. Therefore, while the initial randomised trials relying on the use of sham operated controls were justified on methodological grounds, we suggest that the analysis of the evidence generated by the completed and published trials indicates that placebo controlled trials are not necessary to advance and evaluate the safety and efficacy of emerging regenerative therapies for PD.

Blockade of M4 muscarinic receptors on striatal cholinergic interneurons normalizes striatal dopamine release in a mouse model of TOR1A dystonia

Trihexyphenidyl (THP), a non-selective muscarinic receptor (mAChR) antagonist, is commonly used for the treatment of dystonia associated with TOR1A, otherwise known as DYT1 dystonia. A better understanding of the mechanism of action of THP is a critical step in the development of better therapeutics with fewer side effects. We previously found that THP normalizes the deficit in striatal dopamine (DA) release in a mouse model of TOR1A dystonia (Tor1a+/ΔE knockin (KI) mice), revealing a plausible mechanism of action for this compound, considering that abnormal DA neurotransmission is consistently associated with many forms of dystonia. However, the mAChR subtype(s) that mediate the rescue of striatal dopamine release remain unclear. In this study we used a combination of pharmacological challenges and cell-type specific mAChR conditional knockout mice of either sex to determine which mAChR subtypes mediate the DA release-enhancing effects of THP. We determined that THP acts in part at M4 mAChR on striatal cholinergic interneurons to enhance DA release in both Tor1a+/+ and Tor1a+/ΔE KI mice. Further, we found that the subtype selective M4 antagonist VU6021625 recapitulates the effects of THP. These data implicate a principal role for M4 mAChR located on striatal cholinergic interneurons in the mechanism of action of THP and suggest that subtype selective M4 mAChR antagonists may be effective therapeutics with fewer side effects than THP for the treatment of TOR1A dystonia.

Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum

Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesised that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 min in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.

Protective effects of antioxidants on striatal dopamine release induced by organophosphorus pesticides

Although the toxic effects of organophosphorus (OP) pesticides have been classically attributed to inhibition of the acetylcholinesterase, other neurotoxic mechanisms, as oxidative stress can also occur. Here we evaluated if antioxidants prevent the excessive dopamine release induced by OP pesticides in conscious and freely moving rats, using cerebral microdialysis technique. Intrastriatal infusion of paraoxon (5 mM), glufosinate (10 mM) or glyphosate (5 mM) significantly increased the dopamine release (1006 ± 106%, 991 ± 142%, and 1164 ± 128%, relative to baseline, respectively). To evaluate if these increased dopamine release could be related to oxidative stress, we pretreated animals with antioxidants glutathione (GSH, 400 or 800 μM), dithiothreitol (DTT, 5 or 10 μM), trolox (1 or 3 mM), and α-lipoic acid (ALA, 400 or 800 μM) before administration of OP pesticides. Intrastriatal administration of the antioxidants GSH, DTT, trolox, and ALA was highly effective in preventing the glyphosate and glufosinate-induced dopamine overflow. However, only GSH (800 μM) significantly decreased the effect of paraoxon on dopamine levels. The high toxicity of this pesticide and the low concentrations used could explain this lack of effect in our experimental conditions. The fact that ROS scavengers prevent the excessive dopamine release induced by OP pesticides, further supports the view that dopamine overflow can cause neuronal damage mediated, at least in part, by oxidative stress.

Amphetamine-induced dopamine release and impulsivity in Parkinson's disease.

Impulsive-compulsive behaviours manifest in a substantial proportion of subjects with Parkinson's disease. Reduced ventral striatum dopamine receptor availability, and increased dopamine release is noted in patients with these symptoms. Prior studies of impulsivity suggest that midbrain D2 autoreceptors regulate striatal dopamine release in a feedback inhibitory manner, and in healthy populations, greater impulsivity is linked to poor proficiency of this inhibition. This has not been assessed in a Parkinson's disease population. Here, we applied 18F-fallypride PET studies to assess striatal and extrastriatal D2-like receptor uptake in a placebo-controlled oral dextroamphetamine sequence. We hypothesized that Parkinson's disease patients with impulsive-compulsive behaviours would have greater ventral striatal dopaminergic response to dextroamphetamine, and that an inability to attenuate ventral striatal dopamine release via midbrain D2 autoreceptors would underlie this response. Twenty patients with Parkinson's disease (mean age = 64.1 ± 5.8 years) both with (n = 10) and without (n = 10) impulsive-compulsive behaviours, participated in a single-blind dextroamphetamine challenge (oral; 0.43 mg/kg) in an OFF dopamine state. All completed PET imaging with 18F-fallypride, a high-affinity D2-like receptor ligand, in the placebo and dextroamphetamine state. Both voxelwise and region of interest analyses revealed dextroamphetamine-induced endogenous dopamine release localized to the ventral striatum, and the caudal-medial orbitofrontal cortex. The endogenous dopamine release observed in the ventral striatum correlated positively with patient-reported participation in reward-based behaviours, as quantified by the self-reported Questionnaire for Impulsivity in Parkinson's disease Rating Scale. In participants without impulsive-compulsive behaviours, baseline midbrain D2 receptor availability negatively correlated with ventral striatal dopamine release; however, this relationship was absent in those with impulsive-compulsive behaviours. These findings emphasize that reward-based behaviours in Parkinson's disease are regulated by ventral striatal dopamine release, and suggest that loss of inhibitory feedback from midbrain autoreceptors may underlie the manifestation of impulsive-compulsive behaviours.

Brain opioid segments and striatal patterns of dopamine release induced by naloxone and morphine.

Opioid receptors are expressed throughout the brain and play a major role in regulating striatal dopamine (DA) release. Clinical studies have shown that naloxone (NAL, a nonspecific opioid antagonist) in individuals with opioid use disorder and morphine (MRP, a nonspecific opioid agonist) in healthy controls, resulted in DA release in the dorsal and ventral striatum, respectively. It is not known whether the underlying patterns of striatal DA release are associated with the striatal distribution of opioid receptors. We leveraged previously published PET datasets (collected in independent cohorts) to study the brain‐wide distribution of opioid receptors and to compare striatal opioid receptor availability with striatal DA release patterns. We identified three major gray matter segments based on availability maps of DA and opioid receptors: striatum, and primary and secondary opioid segments with high and intermediate opioid receptor availability, respectively. Patterns of DA release induced by NAL and MRP were inversely associated and correlated with kappa (NAL: r(68) = −0.81, MRP: r(68) = 0.54), and mu (NAL: r(68) = −0.62, MRP: r(68) = 0.46) opioid receptor availability. Kappa opioid receptor availability accounted for a unique part of variance in NAL‐ and MRP‐DA release patterns (ΔR 2 >0.14, p <.0001). In sum, distributions of opioid receptors distinguished major cortical and subcortical regions. Patterns of NAL‐ and MRP‐induced DA release had inverse associations with striatal opioid receptor availability. Our approach provides a pattern‐based characterization of drug‐induced DA targets and is relevant for modeling the role of opioid receptors in modulating striatal DA release.

Long-Term Depression of Striatal DA Release Induced by mGluRs via Sustained Hyperactivity of Local Cholinergic Interneurons.

The cellular mechanisms regulating dopamine (DA) release in the striatum have attracted much interest in recent years. By in vitro amperometric recordings in mouse striatal slices, we show that a brief (5 min) exposure to the metabotropic glutamate receptor agonist DHPG (50 μM) induces a profound depression of synaptic DA release, lasting over 1 h from DHPG washout. This long-term depression is sensitive to glycine, which preferentially inhibits local cholinergic interneurons, as well as to drugs acting on nicotinic acetylcholine receptors and to the pharmacological depletion of released acetylcholine. The same DHPG treatment induces a parallel long-lasting enhancement in the tonic firing of presumed striatal cholinergic interneurons, measured with multi-electrode array recordings. When DHPG is bilaterally infused in vivo in the mouse striatum, treated mice display an anxiety-like behavior. Our results demonstrate that metabotropic glutamate receptors stimulation gives rise to a prolonged depression of the striatal dopaminergic transmission, through a sustained enhancement of released acetylcholine, due to the parallel long-lasting potentiation of striatal cholinergic interneurons firing. This plastic interplay between dopamine, acetylcholine, and glutamate in the dorsal striatum may be involved in anxiety-like behavior typical of several neuropsychiatric disorders.

A genetically defined insula-brainstem circuit selectively controls motivational vigor

The anterior insular cortex (aIC) plays a critical role in cognitive and motivational control of behavior, but the underlying neural mechanism remains elusive. Here, we show that aIC neurons expressing Fezf2 (aICFezf2), which are the pyramidal tract neurons, signal motivational vigor and invigorate need-seeking behavior through projections to the brainstem nucleus tractus solitarii (NTS). aICFezf2 neurons and their postsynaptic NTS neurons acquire anticipatory activity through learning, which encodes the perceived value and the vigor of actions to pursue homeostatic needs. Correspondingly, aIC → NTS circuit activity controls vigor, effort, and striatal dopamine release but only if the action is learned and the outcome is needed. Notably, aICFezf2 neurons do not represent taste or valence. Moreover, aIC → NTS activity neither drives reinforcement nor influences total consumption. These results pinpoint specific functions of aIC → NTS circuit for selectively controlling motivational vigor and suggest that motivation is subserved, in part, by aIC's top-down regulation of dopamine signaling.

Dissecting Motor and Cognitive Component Processes of a Finger-Tapping Task With Hybrid Dopamine Positron Emission Tomography and Functional Magnetic Resonance Imaging.

Striatal dopamine is involved in facilitation of motor action as well as various cognitive and emotional functions. Positron emission tomography (PET) is the primary imaging method used to investigate dopamine function in humans. Previous PET studies have shown striatal dopamine release during simple finger tapping in both the putamen and the caudate. It is likely that dopamine release in the putamen is related to motor processes while dopamine release in the caudate could signal sustained cognitive component processes of the task, but the poor temporal resolution of PET has hindered firm conclusions. In this study we simultaneously collected [11C]Raclopride PET and functional Magnetic Resonance Imaging (fMRI) data while participants performed finger tapping, with fMRI being able to isolate activations related to individual tapping events. The results revealed fMRI-PET overlap in the bilateral putamen, which is consistent with a motor component process. Selective PET responses in the caudate, ventral striatum, and right posterior putamen, were also observed but did not overlap with fMRI responses to tapping events, suggesting that these reflect non-motor component processes of finger tapping. Our findings suggest an interplay between motor and non-motor-related dopamine release during simple finger tapping and illustrate the potential of hybrid PET-fMRI in revealing distinct component processes of cognitive functions.

Impact of α-synuclein spreading on the nigrostriatal dopaminergic pathway depends on the onset of the pathology.

Misfolded α‐synuclein spreads along anatomically connected areas through the brain, prompting progressive neurodegeneration of the nigrostriatal pathway in Parkinson's disease. To investigate the impact of early stage seeding and spreading of misfolded α‐synuclein along with the nigrostriatal pathway, we studied the pathophysiologic effect induced by a single acute α‐synuclein preformed fibrils (PFFs) inoculation into the midbrain. Further, to model the progressive vulnerability that characterizes the dopamine (DA) neuron life span, we used two cohorts of mice with different ages: 2‐month‐old (young) and 5‐month‐old (adult) mice. Two months after α‐synuclein PFFs injection, we found that striatal DA release decreased exclusively in adult mice. Adult DA neurons showed an increased level of pathology spreading along with the nigrostriatal pathway accompanied with a lower volume of α‐synuclein deposition in the midbrain, impaired neurotransmission, rigid DA terminal composition, and less microglial reactivity compared with young neurons. Notably, preserved DA release and increased microglial coverage in the PFFs‐seeded hemisphere coexist with decreased large‐sized terminal density in young DA neurons. This suggests the presence of a targeted pruning mechanism that limits the detrimental effect of α‐synuclein early spreading. This study suggests that the impact of the pathophysiology caused by misfolded α‐synuclein spreading along the nigrostriatal pathway depends on the age of the DA network, reducing striatal DA release specifically in adult mice.