Cortical Dopamine Research Articles

Cortical D1 and D2 dopamine receptor availability modulate methylphenidate-induced changes in brain activity and functional connectivity

Dopamine signaling plays a critical role in shaping brain functional network organization and behavior. Prominent theories suggest the relative expression of D1- to D2-like dopamine receptors shapes excitatory versus inhibitory signaling, with broad consequences for cognition. Yet it remains unknown how the balance between cortical D1R versus D2R signaling coordinates the activity and connectivity of functional networks in the human brain. To address this, we collected three PET scans and two fMRI scans in 36 healthy adults (13 female/23 male; average age 43 ± 12 years), including a baseline D1R PET scan and two sets of D2R PET scans and fMRI scans following administration of either 60 mg oral methylphenidate or placebo (two separate days, blinded, order counterbalanced). The drug challenge allowed us to assess how pharmacologically boosting dopamine levels alters network organization and behavior in association with D1R-D2R ratios across the brain. We found that the relative D1R-D2R ratio was significantly greater in high-level association cortices than in sensorimotor cortices. After stimulation with methylphenidate compared to placebo, brain activity (as indexed by the fractional amplitude of low frequency fluctuations) increased in association cortices and decreased in sensorimotor cortices. Further, within-network resting state functional connectivity strength decreased more in sensorimotor than association cortices following methylphenidate. Finally, in association but not sensorimotor cortices, the relative D1R-D2R ratio (but not the relative availability of D1R or D2R alone) was positively correlated with spatial working memory performance, and negatively correlated with age. Together, these data provide a framework for how dopamine-boosting drugs like methylphenidate alter brain function, whereby regions with relatively higher inhibitory D2R (i.e., sensorimotor cortices) tend to have greater decreases in brain activity and connectivity compared to regions with relatively higher excitatory D1R (i.e., association cortices). They also support the importance of a balanced interaction between D1R and D2R in association cortices for cognitive function and its degradation with aging.

Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2–3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF—A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.

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.

Effects of pharmacological and genetic regulation of COMT activity in alcohol use disorder: a randomized, placebo-controlled trial of tolcapone.

Alcohol Use Disorder (AUD) is characterized by loss of control over drinking. Behavioral control is mediated, in part, by cortical dopamine signaling. Inhibition of catechol-O-methyltransferase (COMT), the enzyme primarily responsible for cortical dopamine inactivation, may increase cortical dopamine, especially among individuals with genetically mediated lower dopaminergic tone, such as COMT rs4680 (val158met) val-allele homozygotes. This study was a randomized, placebo-controlled, pharmacogenetic trial of the COMT inhibitor tolcapone. Ninety non-treatment-seeking AUD individuals were prospectively genotyped for rs4680 and randomized to tolcapone (200 mg t.i.d.) or placebo for 8 days. At baseline and on day 7, peripheral COMT activity was assayed, and participants completed an fMRI alcohol cue-reactivity task; on day 8, they completed a bar-lab paradigm. Primary outcomes were: (1) natural drinking during the medication period; (2) alcohol self-administration in the bar lab; and (3) alcohol cue-elicited cortical (right inferior frontal gyrus [rIFG]) and ventral striatal activation. At baseline, the rs4680 val-allele had an additive effect on COMT activity. Tolcapone, relative to placebo, reduced COMT activity in all genotype groups. COMT genotype moderated tolcapone’s effect on drinking during the medication period and in the bar lab, such that tolcapone, relative to placebo, reduced drinking only among val-allele homozygotes. Tolcapone did not affect cue-elicited ventral striatal activation but reduced rIFG activation; less rIFG activation on day 7 was associated with less drinking during the medication period. Taken together, these data suggest that COMT inhibition may reduce drinking specifically among individuals genetically predisposed to excessive COMT activity and potentially low cortical dopamine tone.ClinicalTrials.gov identifier: NCT02949934 https://clinicaltrials.gov/ct2/show/NCT02949934

Role of Cortical Dopamine circuits in regulating Striatal Dopamine dynamics during Reversal Learning

Dopamine is a catecholamine neuromodulator implicated in locomotion, motivation, learning and cognitive behaviors. Although striatal dopamine signaling and circuitry are well established, the role of cortical dopamine projection circuitry in regulating striatal dopamine dynamics and behavior is not clear. Glutamatergic pyramidal neurons in the prefrontal cortex (PFC) are topographically organized and dopamine D1 and D2 receptors are expressed on glutamatergic pyramidal neurons in the PFC. Using a retrograde adeno‐associated virus (AAVRG)‐based approach we show that D1R+ subpopulations in medial orbitofrontal or prelimbic regions project to nucleus accumbens core (NAcc) or dorsal striatum (dSTR), respectively. However, D2R+ subpopulations in medial orbitofrontal, or medial prelimbic PFC, project to NAcc or the midbrain (SNpc/VTA) but not dSTR, respectively. Additionally, D1R+ and D2R+ medial orbitofrontal subpopulations have indirect connections to the medial SNpc through the NAcc core. We next wanted to test which of these topographically organized circuits regulate striatal dopamine dynamics during reversal learning. We used fiber photometry to measure striatal dopamine dynamics in the dorsomedial striatum (DMS) during reversal learning. We were able to measure reward prediction error (RPE) like responses in the DMS during reversal learning. We will next use an intersectional genetic approach to specifically activate or inhibit dopamine receptor cortical projection circuits and test their effect on striatal dopamine dynamics and reversal learning. Our studies will identify previously unappreciated roles for cortical dopamine projection circuits and their regulation of striatal dopamine dynamics.

6-Methoxyflavone and Donepezil Behavioral Plus Neurochemical Correlates in Reversing Chronic Ethanol and Withdrawal Induced Cognitive Impairment.

PurposeChronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess antioxidant and anti-inflammatory properties believed to be contributory factors in reversing cognitive decline. 6-Methoxyflavone (6-MOF), a flavonoid occurring naturally in medicinal plants, has been reported to instigate neuroprotection by reversing cisplatin-induced hyperalgesia and allodynia. Consequently, this study was designed to investigate 6-MOF activity in models of chronic ethanol-induced cognitive impairment along with neurochemical correlates.MethodsMice were given ethanol orally (2.0 g/kg daily) for 24 days plus either saline, 6-MOF (25–75mg/kg) or donepezil (4mg/kg) and then ethanol was withdrawn for the next 6 days. Animals were subsequently assessed for their cognitive performance in several models on days 1, 12, and 24, during abstinence (Day-26) and on the 7th day of the washout period. Following behavioral assessment, post-mortem dopamine, noradrenaline and vitamin C concentrations were quantified in the frontal cortex, hippocampus and striatum, using HPLC with UV detection.ResultsChronic ethanol treatment suppressed locomotor activity and impaired cognitive tasks, which included novel object recognition, performance in the Morris water maze as well as the Y-maze, socialization and nest-building behavior throughout the protocol and during withdrawal. These behavioral deficits were at least partially restored by the co-administration of 6-MOF or donepezil with ethanol as were ethanol-induced deficits in frontal cortical and hippocampal dopamine plus noradrenaline, together with striatal dopamine. 6-MOF co-administration with ethanol also modestly restored striatal vitamin C levels.ConclusionIt is postulated that, apart from donepezil, 6-MOF may be useful not only in the treatment of ethanol withdrawal severity but also in the management of chronic ethanol withdrawal induced cognitive impairment.

Imaging extra-striatal dopamine D2 receptors in a maternal immune activation rat model

Maternal immune activation (MIA) is a risk factor for schizophrenia in the offspring. MIA in pregnant rodents can be induced by injection of synthetic polyriboinosinic-polyribocytidilic acid (Poly I:C), which causes decreased striatal dopamine D2 receptor (D2R) expression and behavioral dysfunction mediated by the dopaminergic system in the offspring. However, previous studies did not determine whether Poly I:C induced cortical dopamine D2R abnormality in an MIA rat model. In this study, we performed micro-positron emission tomography (micro-PET) in vivo imaging and ex vivo neurochemical analyses of cortical D2Rs in MIA. In the micro-PET analyses, the anterior cingulate cortex (ACC) region in the offspring showed significantly reduced binding potential for [11C]FLB457, a high affinity radio-ligand toward D2Rs. Neurochemical analysis showed reduction of D2Rs and augmentation of dopamine turnover in the ACC of the rat offspring. Thus, MIA induces dopaminergic dysfunction in the ACC of offspring, similar to the neuronal pathology reported in patients with schizophrenia.

Cortical dopamine reduces the impact of motivational biases governing automated behaviour.

Motivations shape our behaviour: the promise of reward invigorates, while in the face of punishment, we hold back. Abnormalities of motivational processing are implicated in clinical disorders characterised by excessive habits and loss of top-down control, notably substance and behavioural addictions. Striatal and frontal dopamine have been hypothesised to play complementary roles in the respective generation and control of these motivational biases. However, while dopaminergic interventions have indeed been found to modulate motivational biases, these previous pharmacological studies used regionally non-selective pharmacological agents. Here, we tested the hypothesis that frontal dopamine controls the balance between Pavlovian, bias-driven automated responding and instrumentally learned action values. Specifically, we examined whether selective enhancement of cortical dopamine either (i) enables adaptive suppression of Pavlovian control when biases are maladaptive; or (ii) non-specifically modulates the degree of bias-driven automated responding. Healthy individuals (n=35) received the catechol-o-methyltransferase (COMT) inhibitor tolcapone in a randomized, double-blind, placebo-controlled cross-over design, and completed a motivational Go NoGo task known to elicit motivational biases. In support of hypothesis (ii), tolcapone globally decreased motivational bias. Specifically, tolcapone improved performance on trials where the bias was unhelpful, but impaired performance in bias-congruent conditions. These results indicate a non-selective role for cortical dopamine in the regulation of motivational processes underpinning top-down control over automated behaviour. The findings have direct relevance to understanding neurobiological mechanisms underpinning addiction and obsessive-compulsive disorders, as well as highlighting a potential trans-diagnostic novel mechanism to address such symptoms.

A role for cortical dopamine in the paradoxical calming effects of psychostimulants

Psychostimulants have a paradoxical calming effect in the treatment of attention deficit hyperactivity disorder (ADHD), but their mechanism of action is unclear. Studies using dopamine (DA) transporter (DAT) knockout (KO) mice have suggested that the paradoxical calming effect of psychostimulants might occur through actions on serotonin (5-HT) neurotransmission. However, newer non-stimulant drugs, such as atomoxetine and guanfacine, suggest that targeting the norepinephrine (NE) system in the prefrontal cortex (PFC) might explain this paradoxical calming effect. Thus, we sought to clarify the mechanism of this paradoxical action of psychostimulants. Our ex vivo efflux experiments reveal that the NE transporter (NET) blocker desipramine elevates both norepinephrine (NE) and dopamine (DA), but not 5-HT levels, in PFC tissue slices from wild-type (WT) and DAT-KO, but not NET-KO mice. However, the 5-HT transporter (SERT) inhibitor fluoxetine elevates only 5-HT in all three genotypes. Systemic administration of desipramine or fluoxetine inhibits hyperactivity in DAT-KO mice, whereas local PFC infusion of desipramine alone produced this same effect. In contrast, pharmacological NE depletion and DA elevation using nepicastat also inhibits hyperactivity in DAT-KO mice. Together, these data suggest elevation of PFC DA and not NE or 5-HT, as a convergent mechanism for the paradoxical effects of psychostimulants observed in ADHD therapy.

No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis

Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (β = 0.013–0.074, partial r = −0.037–0.273, p = 0.131–0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BFH0:H1 = 3.3–8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.

A dopamine gradient controls access to distributed working memory in the large-scale monkey cortex

SUMMARYDopamine is required for working memory, but how it modulates the large-scale cortex is unknown. Here, we report that dopamine receptor density per neuron, measured by autoradiography, displays a macroscopic gradient along the macaque cortical hierarchy. This gradient is incorporated in a connectome-based large-scale cortex model endowed with multiple neuron types. The model captures an inverted U-shaped dependence of working memory on dopamine and spatial patterns of persistent activity observed in over 90 experimental studies. Moreover, we show that dopamine is crucial for filtering out irrelevant stimuli by enhancing inhibition from dendrite-targeting interneurons. Our model revealed that an activity-silent memory trace can be realized by facilitation of inter-areal connections and that adjusting cortical dopamine induces a switch from this internal memory state to distributed persistent activity. Our work represents a cross-level understanding from molecules and cell types to recurrent circuit dynamics underlying a core cognitive function distributed across the primate cortex.

Identification of dual inhibitor of phosphodiesterase 1B/10A using structure-based drug design approach

Schizophrenia is a neuropsychiatric disorder characterised by positive symptoms, negative symptoms, and cognitive impairment. Dopamine system dysfunction is strongly implicated in the aetiology of schizophrenia, where the hyperactivity in striatal dopamine and hypoactivity in cortical dopamine is considered the key feature of this serious mental disorder. Recent research has been directed toward finding new therapeutic agents to potentiate the D1-receptor signalling and inhibit the D2-receptor signalling. Two enzymes in the phosphodiesterase (PDE) family, PDE1B and PDE10A, have become desirable drug targets for psychiatric disorders in general and schizophrenia in particular due to their high expression in brain regions involved in schizophrenia. The PDE1B enzyme represents the major inactivation mechanism of D1-receptors; therefore, the inhibition of PDE1B activity will potentiate the D1-receptor signalling and mitigate the negative symptoms and cognitive impairments. Whereas the inhibition of PDE10A activity has generated much excitement as a potentially novel mechanism to treat the positive symptoms of schizophrenia, which are attributed to the increased dopamine D2-receptor signalling. In which the inhibition of PDE10A activity will block the D2-receptor signalling and improve the positive symptoms. Therefore, in the quest of searching for a new treatment for schizophrenia, we report here the identification of a novel inhibitor with dual action on PDE1B and PDE10A. A sequential pharmacophore-based virtual screening, molecular docking and molecular dynamic simulations; were combined to identify the new inhibitor. After a detailed analysis of the results, two ligands were selected for the biological evaluation, in which one of the two ligands showed significant inhibitory activity against both PDE1B and PDE10A. The newly identified inhibitor can be explored for further optimisation and evaluated in vivo for its antipsychotic-like effects.

Vagus Nerve Stimulation Induced Motor Map Plasticity Does Not Require Cortical Dopamine.

Background: Vagus nerve stimulation (VNS) paired with motor rehabilitation is an emerging therapeutic strategy to enhance functional recovery after neural injuries such as stroke. Training-paired VNS drives significant neuroplasticity within the motor cortex (M1), which is thought to underlie the therapeutic effects of VNS. Though the mechanisms are not fully understood, VNS-induced cortical plasticity is known to depend on intact signaling from multiple neuromodulatory nuclei that innervate M1. Cortical dopamine (DA) plays a key role in mediating M1 synaptic plasticity and is critical for motor skill acquisition, but whether cortical DA contributes to VNS efficacy has not been tested.Objective: To determine the impact of cortical DA depletion on VNS-induced cortical plasticity.Methods: Rats were trained on a skilled reaching lever press task prior to implantation of VNS electrodes and 6-hydroxydopamine (6-OHDA) mediated DA depletion in M1. Rats then underwent training-paired VNS treatment, followed by cortical motor mapping and lesion validation.Results: In both intact and DA-depleted rats, VNS significantly increased the motor map representation of task-relevant proximal forelimb musculature and reduced task-irrelevant distal forelimb representations. VNS also significantly increased tyrosine hydroxylase (TH+) fiber density in intact M1, but this effect was not observed in lesioned hemispheres.Conclusion: Our results reveal that though VNS likely upregulates catecholaminergic signaling in intact motor cortices, DA itself is not required for VNS-induced plasticity to occur. As DA is known to critically support M1 plasticity during skill acquisition, our findings suggest that VNS may engage a unique set of neuromodulatory signaling pathways to promote neocortical plasticity.

Dopamine D1R Receptor Stimulation as a Mechanistic Pro-cognitive Target for Schizophrenia.

Decades of research have highlighted the importance of optimal stimulation of cortical dopaminergic receptors, particularly the D1R receptor (D1R), for prefrontal-mediated cognition. This mechanism is particularly relevant to the cognitive deficits in schizophrenia, given the abnormalities in cortical dopamine (DA) neurotransmission and in the expression of D1R. Despite the critical need for D1R-based therapeutics, many factors have complicated their development and prevented this important therapeutic target from being adequately interrogated. Challenges include determination of the optimal level of D1R stimulation needed to improve cognitive performance, especially when D1R expression levels, affinity states, DA levels, and the resulting D1R occupancy by DA, are not clearly known in schizophrenia, and may display great interindividual and intraindividual variability related to cognitive states and other physiological variables. These directly affect the selection of the level of stimulation necessary to correct the underlying neurobiology. The optimal mechanism for stimulation is also unknown and could include partial or full agonism, biased agonism, or positive allosteric modulation. Furthermore, the development of D1R targeting drugs has been complicated by complexities in extrapolating from in vitro affinity determinations to in vivo use. Prior D1R-targeted drugs have been unsuccessful due to poor bioavailability, pharmacokinetics, and insufficient target engagement at tolerable doses. Newer drugs have recently become available, and these must be tested in the context of carefully designed paradigms that address methodological challenges. In this paper, we discuss how a better understanding of these challenges has shaped our proposed experimental design for testing a new D1R/D5R partial agonist, PF-06412562, renamed CVL-562.

Enhancing dopamine tone modulates global and local cortical perfusion as a function of COMT val158met genotype

The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone.

Augmenting Frontal Dopamine Tone Enhances Maintenance over Gating Processes in Working Memory.

The contents of working memory must be maintained in the face of distraction, but updated when appropriate. To manage these competing demands of stability and flexibility, maintained representations in working memory are complemented by distinct gating mechanisms that selectively transmit information into and out of memory stores. The operations of such dopamine-dependent gating systems in the midbrain and striatum and their complementary dopamine-dependent memory maintenance operations in the cortex may therefore be dissociable. If true, selective increases in cortical dopamine tone should preferentially enhance maintenance over gating mechanisms. To test this hypothesis, tolcapone, a catechol-O-methyltransferase inhibitor that preferentially increases cortical dopamine tone, was administered in a randomized, double-blind, placebo-controlled, within-subject fashion to 49 participants who completed a hierarchical working memory task that varied maintenance and gating demands. Tolcapone improved performance in a condition with higher maintenance requirements and reduced gating demands, reflected in a reduction in the slope of RTs across the distribution. Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual participants correlated with increased connectivity between a region important for stimulus response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the intraparietal sulcus and fusiform gyrus. Together, these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance.

Reinforcement learning links spontaneous cortical dopamine impulses to reward

In their pioneering study on dopamine release, Romo and Schultz speculated "...that the amount of dopamine released by unmodulated spontaneous impulse activity exerts a tonic, permissive influence on neuronal processes more actively engaged in preparation of self-initiated movements...."1 Motivated by the suggestion of "spontaneous impulses," as well as by the "ramp up" of dopaminergic neuronal activity that occurs when rodents navigate to a reward,2-5 we asked two questions. First, are there spontaneous impulses of dopamine that are released in cortex? Using cell-based optical sensors of extrasynaptic dopamine, [DA]ex,6 we found that spontaneous dopamine impulses in cortex of naive mice occur at a rate of ∼0.01 per second. Next, can mice be trained to change the amplitude and/or timing of dopamine events triggered by internal brain dynamics, much as they can change the amplitude and timing of dopamine impulses based on an external cue?7-9 Using a reinforcement learning paradigm based solely on rewards that were gated by feedback from real-time measurements of [DA]ex, we found that mice can volitionally modulate their spontaneous [DA]ex. In particular, by only the second session of daily, hour-long training, mice increased the rate of impulses of [DA]ex, increased the amplitude of the impulses, and increased their tonic level of [DA]ex for a reward. Critically, mice learned to reliably elicit [DA]ex impulses prior to receiving a reward. These effects reversed when the reward was removed. We posit that spontaneous dopamine impulses may serve as a salient cognitive event in behavioral planning.

The Associations between COMT and MAO-B Genetic Variants with Negative Symptoms in Patients with Schizophrenia.

Negative symptoms of schizophrenia, including anhedonia, represent a heavy burden on patients and their relatives. These symptoms are associated with cortical hypodopamynergia and impaired striatal dopamine release in response to reward stimuli. Catechol-O-methyltransferase (COMT) and monoamine oxidase type B (MAO-B) degrade dopamine and affect its neurotransmission. The study determined the association between COMT rs4680 and rs4818, MAO-B rs1799836 and rs6651806 polymorphisms, the severity of negative symptoms, and physical and social anhedonia in schizophrenia. Sex-dependent associations were detected in a research sample of 302 patients with schizophrenia. In female patients with schizophrenia, the presence of the G allele or GG genotype of COMT rs4680 and rs4818, as well as GG haplotype rs4818-rs4680, which were all related to higher COMT activity, was associated with an increase in several dimensions of negative symptoms and anhedonia. In male patients with schizophrenia, carriers of the MAO-B rs1799836 A allele, presumably associated with higher MAO-B activity, had a higher severity of alogia, while carriers of the A allele of the MAO-B rs6651806 had a higher severity of negative symptoms. These findings suggest that higher dopamine degradation, associated with COMT and MAO-B genetic variants, is associated with a sex-specific increase in the severity of negative symptoms in schizophrenia patients.

Distinct roles for dopamine clearance mechanisms in regulating behavioral flexibility

Dopamine plays a crucial role in adaptive behavior, and dysfunctional dopamine is implicated in multiple psychiatric conditions characterized by inflexible or inconsistent choices. However, the precise relationship between dopamine and flexible decision making remains unclear. One reason is that, while many studies have focused on the activity of dopamine neurons, efficient dopamine signaling also relies on clearance mechanisms, notably the dopamine transporter (DAT), which predominates in striatum, and catechol-O-methyltransferase (COMT), which predominates in cortex. The exact locus, extent, and timescale of the effects of DAT and COMT are uncertain. Moreover, there is limited data on how acute disruption of either mechanism affects flexible decision making strategies mediated by cortico-striatal networks. To address these issues, we combined pharmacological modulation of DAT and COMT with electrochemistry and behavior in mice. DAT blockade, but not COMT inhibition, regulated sub-second dopamine release in the nucleus accumbens core, but surprisingly neither clearance mechanism affected evoked release in prelimbic cortex. This was not due to a lack of sensitivity, as both amphetamine and atomoxetine changed the kinetics of sub-second release. In a multi-step decision making task where mice had to respond to reversals in either reward probabilities or the choice sequence to reach the goal, DAT blockade selectively impaired, and COMT inhibition improved, performance after reward reversals, but neither manipulation affected the adaptation of choices after action-state transition reversals. Together, our data suggest that DAT and COMT shape specific aspects of behavioral flexibility by regulating different aspects of the kinetics of striatal and cortical dopamine, respectively.

Dopaminergic organization of striatum is linked to cortical activity and brain expression of genes associated with psychiatric illness.

Dopamine signaling is constrained to discrete tracts yet has brain-wide effects on neural activity. The nature of this relationship between local dopamine signaling and brain-wide neuronal activity is not clearly defined and has relevance for neuropsychiatric illnesses where abnormalities of cortical activity and dopamine signaling coexist. Using simultaneous PET-MRI in healthy volunteers, we find strong evidence that patterns of striatal dopamine signaling and cortical blood flow (an index of local neural activity) contain shared information. This shared information links amphetamine-induced changes in gradients of striatal dopamine receptor availability to changes in brain-wide blood flow and is informed by spatial patterns of gene expression enriched for genes implicated in schizophrenia, bipolar disorder, and autism spectrum disorder. These results advance our knowledge of the relationship between cortical function and striatal dopamine, with relevance for understanding pathophysiology and treatment of diseases in which simultaneous aberrations of these systems exist.