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RationaleDisorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms.ObjectivesThis study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses.MethodsWe applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood.ResultsStimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects.ConclusionsWe provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.

Signalling at dopamine D2/D3 receptors is thought to underlie motivated behaviour, pleasure experiences and emotional expression based on animal studies, but it is unclear if this is the case in humans or how this relates to neural processing of reward stimuli. Using a randomised, double-blind, placebo-controlled, crossover neuroimaging study, we show in healthy humans that sustained dopamine D2/D3 receptor antagonism for 7 days results in negative symptoms (impairments in motivated behaviour, hedonic experience, verbal and emotional expression) and that this is related to blunted striatal response to reward stimuli. In contrast, 7 days of partial D2/D3 agonism does not disrupt reward signalling, motivated behaviour or hedonic experience. Both D2/D3 antagonism and partial agonism induce motor impairments, which are not related to striatal reward response. These findings identify a central role for D2/D3 signalling and reward processing in the mechanism underlying motivated behaviour and emotional responses in humans, with implications for understanding neuropsychiatric disorders such as schizophrenia and Parkinson’s disease. Osugo et al show in healthy humans that sustained dopamine D2/D3 receptor antagonism impairs motivated behaviour, hedonic experience, and emotional expression, and that this is related to blunted striatal reward response following D2/D3 antagonism.

Dopamine, a key neuromodulator in the central nervous system, regulates cortical excitability and plasticity by interacting with glutamate and GABA receptors, which are affected by dopamine receptor subtypes (D1‐ and D2‐like). Non‐invasive brain stimulation techniques can induce plasticity and monitor cortical facilitation and inhibition in humans. In a randomized, placebo‐controlled, double‐blinded study, we investigated how dopamine and D1‐ and D2‐like receptors impact transcranial direct current stimulation (tDCS)‐induced plasticity concerning glutamatergic and GABAergic mechanisms. Eighteen healthy volunteers received 1 mA anodal (13 min) and cathodal tDCS (9 min) over the left motor cortex combined with the dopaminergic agents l‐dopa (general dopamine activation), bromocriptine (D2‐like receptor agonist), combined D2 antagonism via sulpiride and general dopaminergic activation via l‐dopa to activate D1‐like receptors, and placebo medication. Glutamate‐related cortical facilitation and GABA‐related cortical inhibition were monitored using transcranial magnetic stimulation techniques, including I–O curve, intracortical facilitation (ICF), short‐interval intracortical inhibition (SICI), and I‐wave facilitation protocols. Our results indicate that anodal tDCS alone enhanced the I–O curve and ICF while decreasing SICI. Conversely, cathodal tDCS decreased the I‐O curve and ICF while increasing SICI. General dopamine and D2 receptor activation combined with anodal tDCS decreased the I‐O curve and ICF, but enhanced SICI compared to tDCS alone. When paired with cathodal tDCS, general dopamine and D2‐like receptor activity enhancement prolonged the cathodal tDCS effect on excitability. After anodal tDCS, D1‐like receptor activation increased the I‐O curve and ICF while reducing SICI. These effects were abolished with cathodal tDCS. Dopaminergic substances combined with anodal and cathodal tDCS did not have a significant effect on I‐wave facilitation. These results suggest that D1‐like receptor activation enhanced LTP‐like plasticity and abolished LTD‐like plasticity via glutamatergic NMDA receptor enhancement, while global dopaminergic and D2‐like receptor enhancement weakened LTP‐like but strengthened LTD‐like plasticity primarily via glutamatergic NMDA receptor activity diminution. Background: Dopamine modulates cortical excitability and plasticity by influencing glutamate and GABA receptor activity. This study investigates the impact of general dopaminergic activation and D1‐ and D2‐like receptor modulation on transcranial direct current stimulation (tDCS)‐induced plasticity in humans.Methods:• Pharmacological intervention: l‐dopa (general DA activation), Bromocriptine (D2 agonist), Sulpiride + l‐dopa (D1‐like activation), and placebo.• tDCS: Anodal (1 mA, 13 min) and Cathodal (1 mA, 9 min) over the left motor cortex.• Neurophysiological measures: Glutamatergic activity (I‐O curve, ICF) and GABAergic activity (SICI, I‐wave facilitation).Results:• D2‐like receptor and global dopamine activation + anodal tDCS: decreased the I‐O curve and ICF, but enhanced SICI• D2‐like receptor and global dopamine activation + cathodal tDCS: prolonged the cathodal tDCS effect on SICI‐ICF and IO‐curve• D1‐like receptor activation + anodal tDCS: increased the I‐O curve and ICF while reducing SICI• D1‐like receptor activation + cathodal tDCS: abolished cathodal tDCS effects• No significant effect of dopaminergic substances combined with anodal and on I‐wave facilitationConclusion:D1‐like receptor activation enhanced LTP‐like plasticity and abolished LTD‐like plasticity via glutamatergic NMDA receptor enhancement, while global dopaminergic and D2‐like receptor enhancement weakened LTP‐like but strengthened LTD‐like plasticity primarily via glutamatergic NMDA receptor activity diminution.

Iron deposition in the substantia nigra has been implicated in Parkinson’s disease. Chelation with deferiprone reduced brain iron content but led to worse scores on scales of the movement disorder at 36 weeks.

Abstract Background Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. Methods We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. Results Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. Conclusion Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function.

Influential neurocomputational models emphasize dopamine (DA) as an electrophysiological and neurochemical correlate of reinforcement learning. However, evidence of a specific causal role of DA receptors in learning has been less forthcoming, especially in humans. Here we combine, in a between-subjects design, administration of a high dose of the selective DA D2/3-receptor antagonist sulpiride with genetic analysis of the DA D2 receptor in a behavioral study of reinforcement learning in a sample of 78 healthy male volunteers. In contrast to predictions of prevailing models emphasizing DA's pivotal role in learning via prediction errors, we found that sulpiride did not disrupt learning, but rather induced profound impairments in choice performance. The disruption was selective for stimuli indicating reward, whereas loss avoidance performance was unaffected. Effects were driven by volunteers with higher serum levels of the drug, and in those with genetically determined lower density of striatal DA D2 receptors. This is the clearest demonstration to date for a causal modulatory role of the DA D2 receptor in choice performance that might be distinct from learning. Our findings challenge current reward prediction error models of reinforcement learning, and suggest that classical animal models emphasizing a role of postsynaptic DA D2 receptors in motivational aspects of reinforcement learning may apply to humans as well.

Dopamine is thought to play a crucial role in value-based decision making. However, the specific contributions of different dopamine receptor subtypes to the computation of subjective value remain unknown. Here we demonstrate how the balance between D1 and D2 dopamine receptor subtypes shapes subjective value computation during risky decision making. We administered the D2 receptor antagonist amisulpride or placebo before participants made choices between risky options. Compared with placebo, D2 receptor blockade resulted in more frequent choice of higher risk and higher expected value options. Using a novel model fitting procedure, we concurrently estimated the three parameters that define individual risk attitude according to an influential theoretical account of risky decision making (prospect theory). This analysis revealed that the observed reduction in risk aversion under amisulpride was driven by increased sensitivity to reward magnitude and decreased distortion of outcome probability, resulting in more linear value coding. Our data suggest that different components that govern individual risk attitude are under dopaminergic control, such that D2 receptor blockade facilitates risk taking and expected value processing.

[11C]PHNO is a D2/D3 agonist positron emission tomography radiotracer, with higher in vivo affinity for D3 than for D2 receptors. As [11C]-( + )-PHNO is an agonist, its in vivo binding is expected to be more affected by acute fluctuations in synaptic dopamine than that of antagonist radiotracers such as [11C]raclopride. In this study, the authors compared the effects of an oral dose of the dopamine releaser amphetamine (0.3 mg/kg) on in vivo binding of [11C]-( + )-PHNO and [11C]raclopride in healthy subjects, using a within-subjects, counterbalanced, open-label design. In the dorsal striatum, where the density of D3 receptors is negligible and both tracers predominantly bind to D2 receptors, the reduction of [11C]-( + )-PHNO binding potential (BPND) was 1.5 times larger than that of [11C]raclopride. The gain in sensitivity associated with the agonist [11C]-( + )-PHNO implies that ~65% of D2 receptors are in the high-affinity state in vivo. In extrastriatal regions, where [11C]-( + )-PHNO predominantly binds to D3 receptors, the amphetamine effect on [11C]-( + )-PHNO BPND was even larger, consistent with the higher affinity of dopamine for D3. This study indicates that [11C]- ( + )-PHNO is superior to [11C]raclopride for studying acute fluctuations in synaptic dopamine in the human striatum. [11C]-( + )-PHNO also enables measurement of synaptic dopamine in D3 regions.