Dopamine Hyperactivity Research Articles

“D-Cell Hypothesis of Schizophrenia” Leading to Develop Non-D2 Receptor-Binding Antipsychotics

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though they were scarcely found in the monkey, and D-neuron reduction in these regions by using post-mortem brains of patients with schizophrenia. The reduction of D-neurons was significant (t-test, p<0.05) in Acc of schizophrenia. I proposed “D-cell hypothesis of schizophrenia”, a link of dopamine (DA) hypothesis and neural stem cell (NSC) dysfunction hypothesis, showing NSC dysfunction-based D-neuron reduction being cellular basis of mesolimbic DA hyperactivity of schizophrenia, and predicted prospectiveness of TAAR1 ligands for treatment of schizophrenia. This hypothesis has been verified by effectiveness of a TAAR1 agonist in reducing symptoms of schizophrenia.

Cry1Δ11 mutation induces ADHD-like symptoms through hyperactive dopamine D1 receptor signaling.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder that affects approximately 5.3% of children and approximately 2.5% of adults. There is an intimate relationship between ADHD and sleep disturbance. Specifically, individuals carry a mutation in the core circadian gene CRY1 (c. 1657 + 3A > C), which results in the deletion of exon 11 expression in the CRY1 protein (CRY1Δ11), causing them to exhibit typical ADHD symptoms. However, the underlying mechanism is still elusive. In this study, we demonstrate that Cry1Δ11 (c. 1717 + 3A > C) mice showed ADHD-like symptoms, including hyperactivity, impulsivity, and deficits in learning and memory. A hyperactive cAMP signaling pathway was found in the nucleus accumbens (NAc) of Cry1Δ11 mice. We further demonstrated that upregulated c-Fos was mainly localized in dopamine D1 receptor-expressing medium spiny neurons (DRD1-MSNs) in the NAc. Neuronal excitability of DRD1-MSNs in the NAc of Cry1Δ11 mice was significantly higher than that of WT controls. Mechanistically, the CRY1Δ11 protein, in contrast to the WT CRY1 protein, failed to interact with the Gαs protein and inhibit DRD1 signaling. Finally, the DRD1 antagonist SCH23390 normalized most ADHD-like symptoms in Cry1Δ11 mice. Thus, our results reveal hyperactive DRD1 signaling as an underlying mechanism and therapeutic target for ADHD induced by the highly prevalent CRY1Δ11 mutation.

Probing midbrain dopamine function in pediatric obsessive-compulsive disorder via neuromelanin-sensitive magnetic resonance imaging.

Obsessive-compulsive disorder (OCD) is an impairing psychiatric condition, which often onsets in childhood. Growing research highlights dopaminergic alterations in adult OCD, yet pediatric studies are limited by methodological constraints. This is the first study to utilize neuromelanin-sensitive MRI as a proxy for dopaminergic function among children with OCD. N = 135 youth (6-14-year-olds) completed high-resolution neuromelanin-sensitive MRI across two sites; n = 64 had an OCD diagnosis. N = 47 children with OCD completed a second scan after cognitive-behavioral therapy. Voxel-wise analyses identified that neuromelanin-MRI signal was higher among children with OCD compared to those without (483 voxels, permutation-corrected p = 0.018). Effects were significant within both the substania nigra pars compacta (p = 0.004, Cohen's d = 0.51) and ventral tegmental area (p = 0.006, d = 0.50). Follow-up analyses indicated that more severe lifetime symptoms (t = -2.72, p = 0.009) and longer illness duration (t = -2.22, p = 0.03) related to lower neuromelanin-MRI signal. Despite significant symptom reduction with therapy (p < 0.001, d = 1.44), neither baseline nor change in neuromelanin-MRI signal associated with symptom improvement. Current results provide the first demonstration of the utility of neuromelanin-MRI in pediatric psychiatry, specifically highlighting in vivo evidence for midbrain dopamine alterations in treatment-seeking youth with OCD. Neuromelanin-MRI likely indexes accumulating alterations over time, herein, implicating dopamine hyperactivity in OCD. Given evidence of increased neuromelanin signal in pediatric OCD but negative association with symptom severity, additional work is needed to parse potential longitudinal or compensatory mechanisms. Future studies should explore the utility of neuromelanin-MRI biomarkers to identify early risk prior to onset, parse OCD subtypes or symptom heterogeneity, and explore prediction of pharmacotherapy response.

Adolescent sleep defects and dopaminergic hyperactivity in mice with a schizophrenia-linked Shank3 mutation.

Shank3 is a shared risk gene for autism spectrum disorders and schizophrenia. Sleep defects have been characterized for autism models with Shank3 mutations; however, evidence has been lacking for the potential sleep defects caused by Shank3 mutation associated with schizophrenia and how early in development these defects may occur. Here we characterized the sleep architecture of adolescent mice carrying a schizophrenia-linked, R1117X mutation in Shank3. We further employed GRABDA dopamine sensor and fiber photometry to record dopamine release in the nucleus accumbens during sleep/wake states. Our results show that homozygous mutant R1117X mice have significantly reduced sleep in the dark phase during adolescence, altered electroencephalogram power, especially during the rapid-eye-movement sleep, and dopamine hyperactivity during sleep but not during wakefulness. Further analyses suggest that these adolescent defects in sleep architecture and dopaminergic neuromodulation tightly correlate with the social novelty preference later in adulthood and predict adult social performance during same-sex social interactions. Our results provide novel insights into the sleep phenotypes in mouse models of schizophrenia and the potential use of developmental sleep as a predictive metric for adult social symptoms. Together with recent studies in other Shank3 models, our work underscores the idea that Shank3-involved circuit disruptions may be one of the shared pathologies in certain types of schizophrenia and autism. Future research is needed to establish the causal relationship among adolescent sleep defects, dopaminergic dysregulation, and adult behavioral changes in Shank3 mutation animals and other models.

Dexamphetamine widens temporal and spatial binding windows in healthy participants.

The pathophysiology of psychosis is complex, but a better understanding of stimulus binding windows (BWs) could help to improve our knowledge base. Previous studies have shown that dopamine release is associated with psychosis and widened BWs. We can probe BW mechanisms using drugs of specific interest to psychosis. Therefore, we were interested in understanding how manipulation of the dopamine or catecholamine systems affect psychosis and BWs. We aimed to investigate the effect of dexamphetamine, as a dopamine-releasing stimulant, on the BWs in a unimodal illusion: the tactile funneling illusion (TFI). We conducted a randomized, double-blind, counterbalanced placebo-controlled crossover study to investigate funnelling and errors of localization. We administered dexamphetamine (0.45 mg/kg) to 46 participants. We manipulated 5 spatial (5-1 cm) and 3 temporal (0, 500 and 750 ms) conditions in the TFI. We found that dexamphetamine increased funnelling illusion (p = 0.009) and increased the error of localization in a delay-dependent manner (p = 0.03). We also found that dexamphetamine significantly increased the error of localization at 500 ms temporal separation and 4 cm spatial separation (p interaction = 0.009; p 500ms|4cm v. baseline = 0.01). Although amphetamine-induced models of psychosis are a useful approach to understanding the physiology of psychosis related to dopamine hyperactivity, dexamphetamine is equally effective at releasing noradrenaline and dopamine, and, therefore, we were unable to tease apart the effects of the 2 systems on BWs in our study. We found that dexamphetamine increases illusory perception on the unimodal TFI in healthy participants, which suggests that dopamine or other catecholamines have a role in increasing tactile spatial and temporal BWs.

Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats.

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT-/-) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity.

The Research Progress of Parkinson&amp;apos;s Nonverbal Cognitive Impairment

Parkinson's disease (PD) is one of the most disabling diseases in the middle-aged and elderly population. The cognitive decline of the middle-aged and elderly, such as verbal disorder and nonverbal disorder, has severely impacted their life. This paper systematically expounds the specific manifestations of Parkinson's patients with nonverbal cognitive impairment, like memory impairment, executive ability impairment and attention impairment, as well as revealing the neural mechanism behind them. The result shows that the decline of working memory may be related to the damage of the lateral frontal lobe and parietal cortex. PD patients' executive ability is mainly reflected in their difficulty in keeping balance, which is related to the reduction of the volume and surface area of their cerebral cortex. The attention of PD patients is easily diverted and damaged, associating with the hyperactivity of dopamine in midbrain, the decrease of medial prefrontal cortex and lateral prefrontal cortex. Based on these nonverbal cognitive impairment of PD patients, this paper also introduces the diagnosis methods of PD through the patients' hands and voice, the treatment of motor symptoms and non-motor symptoms, and the gait intervention methods, so as to improve people's understanding of PD patients.

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

The Boy in the Borstal: Gene Hunting, Dopaminergic Dogma, and the Science of Schizophrenia

Behavioral Response to Catecholamine Depletion in Individuals With Schizophrenia and Healthy Volunteers.

Dysfunction of the dopamine system is the leading neurobiological hypothesis of schizophrenia. In this study, we tested this hypothesis in the context of aberrance salience theory of delusions using catecholamine depletion. We hypothesized that acute dopamine depletion improves both positive symptoms and salience attribution in individuals with schizophrenia. Catecholamine depletion was achieved by oral administration of alpha-methyl-para-tyrosine (AMPT) in 15 individuals with schizophrenia and 15 healthy volunteers. The study design consisted of a randomized, double-blind, placebo-controlled crossover, single-site experimental trial. The main outcome measures were the Scale for the Assessment of Positive Symptoms and the Salience Attribution Test. Catecholamine depletion transiently reduced specific psychotic symptoms in symptomatic individuals with schizophrenia, namely delusions and positive formal thought disorder (interaction treatment-by-timepoint, P = .013 and P = .010, respectively). We also found trends for catecholamine depletion to increase relevant bias and adaptive salience in participants with schizophrenia while decreasing them in healthy controls (interaction group-by-treatment, P = .060 and P = .089, respectively). Exploratory analyses revealed that in participants with schizophrenia, higher relevant bias at 3 hours after the end of AMPT treatment corresponded to lower delusional symptoms (Spearman's rho = -0.761, P = .001). This study suggests that the relationship between dopamine hyperactivity and delusional symptoms in schizophrenia is mediated by impaired attribution of salience to reward-predicting stimuli.

Sex- and exposure age-dependent effects of adolescent stress on ventral tegmental area dopamine system and its afferent regulators.

Adolescent stress is a risk factor for schizophrenia. Emerging evidence suggests that age-dependent sensitive windows for childhood trauma are associated more strongly with adult psychosis, but the neurobiological basis and potential sex differences are unknown.Using in vivo electrophysiology and immunohistology in rats, we systematically compared the effects of two age-defined adolescent stress paradigms, prepubertal (postnatal day [PD] 21-30; PreP-S) and postpubertal (PD41-50; PostP-S) foot-shock and restraint combined stress, on ventral tegmental area (VTA) dopaminergic activity, pyramidal neuron activity in the ventral hippocampus (vHipp) and the basolateral amygdala (BLA), corticoamygdalar functional inhibitory control, and vHipp and BLA parvalbumin interneuron (PVI) impairments. These endpoints were selected based on their well-documented roles in the pathophysiology of psychosis.Overall, we found distinct sex- and exposure age-dependent stress vulnerability. Specifically, while males were selectively vulnerable to PreP-S-induced adult VTA dopamine neuron and vHipp hyperactivities, females were selectively vulnerable to PostP-S. These male selective PreP-S effects were correlated with stress-induced aberrant persistent BLA hyperactivity, dysfunctional prefrontal inhibitory control of BLA neurons, and vHipp/BLA PVI impairments. In contrast, female PostP-S only produced vHipp PVI impairments in adults, with the BLA structure and functions largely unaffected.Our results indicated distinct adolescent-sensitive periods during which stress can sex-dependently confer maximal risks to corticolimbic systems to drive dopamine hyperactivity, which provide critical insights into the neurobiological basis for sex-biased stress-related psychopathologies emphasizing but not limited to schizophrenia. Furthermore, our work also provides a framework for future translational research on age-sensitive targeted interventions.

Aripiprazole Improved Post-Streptococcal Dyskinesia by Modulating Dopaminergic Activity: A Case Report

This case report aimed to discuss the efficacy of aripiprazole for dyskinesia in patients with functional movement disorder after streptococcal infection, with its biological action of modulating dopamine hyperactivity in the basal ganglia as a dopamine partial agonist. This report has shown that the [18F] N‐(3‐Fluoropropyl)‐2β‐carbon ethoxy‐3β‐(4‐iodophenyl) nortropane positron emission tomography findings of the patient revealed that the dopamine hyperactivity in the basal ganglia at baseline was normalized after aripiprazole treatment due to its balancing effect as a dopamine partial agonist.

From a Pathophysiological Concept to a New Drug

Although antipsychotics were discovered over fifty years ago, it took another decade until dopamine antagonism was demonstrated as central to their clinical effectiveness. Since accumulated evidence implicates the dopamine system in the pathophysiology of schizophrenia, all licensed first-line treatments operate primarily via antagonism of the dopamine D2 receptor. However, dopamine D2 receptor blockade does not effectively treat negative, cognitive and affective symptoms and, in a significant proportion of patients, it does not improve positive symptoms either. Therefore, additional neurochemical targets were considered. The “revised dopamine hypothesis” proposes that positive symptoms emerge due to hyperactive dopamine transmission in mesolimbic areas, while hypoactive dopamine transmission via the mesocortical pathway in the prefrontal cortex is linked to negative, cognitive, and partly affective symptoms. In this context, the role of D3 receptors were recognised. However, there is also evidence for the involvement of other neurotransmitter systems, suggesting that dopamine signalling relies on a suite of receptors that are thought to either facilitate or inhibit neurotransmitter activity through several interconnected neural circuits. Furthermore, there seem to be clusters of symptoms that cross the boundaries of disorders. Symptoms having similar pathophysiology at neurotransmitter level can be treated with the same drug or class of drugs. Thus, one particular drug might be effective in more than one indication. This lecture aims to illustrate the process of a new drug development by explaining how the underlying pathophysiology on receptor level impacts clinical studies and vice versa.DisclosureEmployee of Gedeon Richter Plc.

Hyperactivity of a midbrain dopamine to 5-HT circuit causes anorexia.

Hyperactivity of a midbrain dopamine to 5-HT circuit causes anorexia.

Nicotinic receptors promote susceptibility to social stress in female mice linked with neuroadaptations within VTA dopamine neurons

There are about twice as many women as men who experience depression during their lifetime. Although life circumstances and especially exposure to stressful situations constitute a major risk factor to develop depression, the underlying mechanisms have yet to be unraveled. We employed the chronic social defeat procedure to elicit depressive-like symptoms in females and ketamine to validate the model. We performed ex-vivo patch clamp recordings to assess cellular adaptations and used pharmacological agents to dissect these deregulations. Chronic social defeat exposure triggers a hyperactivity of VTA putative dopamine (DA) neurons in females susceptible to stress but not resilient ones. This hyperactivity was fully reversed by a single administration of ketamine. In virally-identified brain circuits of both susceptible and resilient females, we found a hypercholinergic tone to the VTA arising from the laterodorsal tegmentum. Application of puffs of nicotine revealed a decreased sensitivity of DA neurons in resilient mice when compared to naive or susceptible ones. The in vivo acute administration of the positive allosteric modulator for α7 nicotinic acetylcholine receptors (nAChRs) not only increased susceptibility to stress by enhancing activity of VTA DA neurons, but also triggered a switch in phenotype from resilient to susceptible. Our data unravel dysregulations of VTA DA neurons activity exclusively in females exhibiting depressive-like symptoms and identify VTA nAChRs as key molecular substrates that exacerbate susceptibility to stress.

P 13 Application of antipsychotic drugs in the treatment of schizophrenia according to single nucleotide polymorphisms of risk genes

Introduction: Schizophrenia is a chronic mental disease which has a genetic etiology in 80% of the cases. In the last years, about 260 risk genes with a predisposition to schizophrenia have been described, and correlations between single nucleotide polymorphisms (SNPs) of risk genes and the therapeutic efficacy of an antipsychotic treatment/pharmacotherapy resistance have been reported. Methods: In schizophrenia, important risk genes, such as catechol-O-methyl transferase (COMT), monoamine oxidase (MAO A/B), glutamic acid decarboxylase 67 (GAD 67), dysbindin-1 and neuregulin-1 are mentioned. To describe the function of these risk genes, neural networks in the ventral tegmental area, hippocampus and prefrontal cortex are developed. Results: An association between the SNPs of some risk genes and the efficacy of an antipsychotic treatment is reported: SNPs such as rs165599 ( COMT gene), rs1801028 ( D2 receptor gene) and rsSer9 Gly ( D3 receptor gene) are associated with a better antipsychotic treatment efficacy. In this case, a treatment of positive and negative schizophrenic symptoms with risperidone is secured. The rs4680 SNP ( COMT and D2 receptor genes) is associated with antipsychotic-induced dopamine hypersensitivity and pharmacotherapy resistance. The function of the COMT and MAO A/B risk genes is described. In schizophrenia, through a reduced activity in the corresponding enzymes, a decrease in dopamine degradation occurs and hence, via D2 receptors, and dopamine hyperactivity has been observed. The GAD 67 risk gene is linked with GABAergic dysfunction and consequently GABAergic neurons weakly presynaptically inhibit D2 dopaminergic neurons. The D-amino acid oxidase activator (DAOA) risk gene is connected with glutamatergic dysfunction via NMDA receptors. Glutamatergic neurons might exert a weak presynaptic inhibition upon 5-HT2A serotonergic neurons located in the ventral tegmental area and hippocampus. Conclusion: It is important to examine the SNPs of the risk genes involved in schizophrenia to establish a correlation between these SNPs and the efficacy of a determined antipsychotic drug. Thus, schizophrenic patients with a good response to a determined antipsychotic treatment and patients with resistance to this treatment could be well differentiated. The latter patients with pharmacoresistance might be treated with the antipsychotic drug clozapine and an additional treatment with cariprazine, a partial agonist at D2 and D3 receptors.

D-neuron, ligand neuron of trace amine-associated receptor 1 (TAAR1): Key of novel non-D2 receptor-binding antipsychotics

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. The compound is trace amine-associated receptor 1 (TAAR1) full agonist and also 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), a neuroleptic acting site, of human brains, though failed to find in the homologous area of monkey brains. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. The number of D-neuron in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p&lt;0.05) in Acc. I proposed “D-cell hypothesis of schizophrenia”, that NSC dysfunction-based D-neuron reduction is cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, progressive pathophysiology and prospectiveness of TAAR1 medicinal chemistry, emphasizing importance of D-neuron.

“D-cell hypothesis of schizophrenia”: Background theory of Novel non-D2 receptor medicinal chemistry

The latest psychopharmacological study showed effectiveness of a novel non-D2-receptor-binding drug, SEP-363856, for the treatment of schizophrenia. Characteristic receptor profile of the compound is shown to be trace amine-associated receptor 1 (TAAR1) full agonist and 5-hydroxytryptamin 1A (5-HT 1A) receptor partial agonist. I found the TAAR1 ligand neuron, D-neuron, in the striatum and nucleus accumbens (Acc), an antipsychotic acting site, of human brain, though failed to find in the homologous area of monkey. To study human D-neuron functions, total of 154 post-mortem brains, and a modified immunohistochemical method using high qualified antibodies against monoamine-related substances, was applied. Number of D-neurons in the caudate nucleus, putamen, and Acc was reduced in post-mortem brains with schizophrenia. The reduction was significant (p&lt;0.05) in Acc. “D-cell hypothesis of schizophrenia”, which I proposed based on this post-mortem brain study, that NSC dysfunction-induced D-neuron reduction as cellular and molecular basis of mesolimbic dopamine (DA) hyperactivity, showing progressive pathophysiology of schizophrenia, has been proved to be a predictive hypothesis for TAAR1 medicinal chemistry.

Dorsal striatal dopamine induces fronto-cortical hypoactivity and attenuates anxiety and compulsive behaviors in rats.

Dorsal striatal dopamine transmission engages the cortico-striato-thalamo-cortical (CSTC) circuit, which is implicated in many neuropsychiatric diseases, including obsessive-compulsive disorder (OCD). Yet it is unknown if dorsal striatal dopamine hyperactivity is the cause or consequence of changes elsewhere in the CSTC circuit. Classical pharmacological and neurotoxic manipulations of the CSTC and other brain circuits suffer from various drawbacks related to off-target effects and adaptive changes. Chemogenetics, on the other hand, enables a highly selective targeting of specific neuronal populations within a given circuit. In this study, we developed a chemogenetic method for selective activation of dopamine neurons in the substantia nigra, which innervates the dorsal striatum in the rat. We used this model to investigate effects of targeted dopamine activation on CSTC circuit function, especially in fronto-cortical regions. We found that chemogenetic activation of these neurons increased movement (as expected with increased dopamine release), rearings and time spent in center, while also lower self-grooming. Furthermore, this activation increased prepulse inhibition of the startle response in females. Remarkably, we observed reduced [18F]FDG metabolism in the frontal cortex, following dopamine activation in the dorsal striatum, while total glutamate levels- in this region were increased. This result is in accord with clinical studies of increased [18F]FDG metabolism and lower glutamate levels in similar regions of the brain of people with OCD. Taken together, the present chemogenetic model adds a mechanistic basis with behavioral and translational relevance to prior clinical neuroimaging studies showing deficits in fronto-cortical glucose metabolism across a variety of clinical populations (e.g. addiction, risky decision-making, compulsivity or obesity).

Monoaminergic hypo- or hyperfunction in adolescent and adult attention-deficit hyperactivity disorder?

Disturbances of dopamine (DA), serotonin (5-HT) and/or norepinephrine (NE) functions are implied in attention-deficit hyperactivity disorder (ADHD). However, the precise cortical and subcortical mechanisms are still not fully understood. In the present survey, we conducted a PUBMED search, which provided 37 in vivo investigations with PET and SPECT on 419 ADHD patients and 490 controls. The retrospective analysis revealed increased striatal DA transporter (DAT) in adolescent as well as adult medication-naïve and not acutely medicated patients. In acutely medicated adults, DAT was not different from controls. Midbrain DAT was normal in adults, but decreased in adolescents. Striatal D2 receptor (R) binding was normal in both adolescents (not acutely medicated) and adults (acutely medicated and not acutely medicated). In medication-naïve adults, DA synthesis was decreased in putamen and amygdala, but normal in the whole striatum and midbrain. In not acutely medicated adults, DA synthesis was reduced in putamen, whole striatum, prefrontal cortex, frontal cortex, amygdala and midbrain, whereas, in adolescents, no regional differences were observed. In adult (not acutely medicated) subjects, cingulate D1R was reduced. 5-HT transporter (SERT) binding was decreased in striatum and thalamus, but normal in midbrain, neocortex and limbic regions, whereas, in medication-naïve adults, SERT was diminished in striatum and midbrain, but normal in thalamus and neocortex. The findings suggest transient stages of synaptic DA shortage as well as DA surplus in individual brain regions, which elicit presynaptic as well as postsynaptic compensatory mechanisms, striving to attain functional homeostasis. Thereby, it remains a matter of debate, whether ADHD may be characterized by a general hypo- or hyperactivity of DA and/or 5-HT function.

Neuromelanin-Sensitive MRI as a Marker of Dopamine Hyperactivity and CBT Response in Children With Obsessive-Compulsive Disorder

Positron Emission Tomography (PET) findings suggest that increased striatal dopamine neurotransmission may underlie Obsessive-Compulsive Disorder (OCD) in adults. This is untested in pediatric OCD since PET is overly invasive and untenable for pediatric research. Thus, we used neuromelanin-sensitive MRI (NM-MRI) to assess nigrostriatal dopamine transmission in children with OCD and predict response to cognitive behavioral therapy (CBT).