Dopamine Receptor Density Research Articles

Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders.

Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea (SC), and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine receptor D2 (D2R) signaling. However, AAb influence on dopamine receptor D1 (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia (BGE), a region of high dopamine receptor density. Here, we report a new mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic (ROC) curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived mAbs, which induced both D1R G protein- and -arrestin transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders. .

A shared spatial topography links the functional connectome correlates of cocaine use disorder and dopamine D2/3 receptor densities

The biological mechanisms that contribute to cocaine and other substance use disorders involve an array of cortical and subcortical systems. Prior work on the development and maintenance of substance use has largely focused on cortico-striatal circuits, with relatively less attention on alterations within and across large-scale functional brain networks, and associated aspects of the dopamine system. Here, we characterize patterns of functional connectivity in cocaine use disorder and their spatial association with neurotransmitter receptor densities and transporter bindings assessed through PET. Profiles of functional connectivity in cocaine use disorder reliably linked with spatial densities of dopamine D2/3 receptors across independent datasets. These findings demonstrate that the topography of dopamine receptor densities may underlie patterns of functional connectivity in cocaine use disorder, as assessed through fMRI.

Moderate-intensity aerobic exercise enhanced dopamine signaling in diet-induced obese female mice without preventing body weight gain

Obesity continues to rise in prevalence and financial burden despite strong evidence linking it to an increased risk of developing several chronic diseases. Dopamine response and receptor density are shown to decrease under conditions of obesity. However, it is unclear if this could be a potential mechanism for treatment without drugs that have a potential for abuse. Therefore, the aim of this study was to investigate whether moderate-intensity exercise could reduce body weight gain and the associated decreases in dopamine signaling observed with high-fat diet-induced adiposity. We hypothesized that exercise would attenuate body weight gain and diet-induced inflammation in high-fat (HF)-fed mice, resulting in dopamine signaling (release and reuptake rate) comparable to sedentary, low-fat (LF)-fed counterparts. This hypothesis was tested using a mouse model of diet-induced obesity (DIO) and fast-scan cyclic voltammetry to measure evoked dopamine release and reuptake rates. Although the exercise protocol employed in this study was not sufficient to prevent significant body weight gain, there was an enhancement of dopamine signaling observed in female mice fed a HF diet that underwent treadmill running. Additionally, aerobic treadmill exercise enhanced the sensitivity to amphetamine (AMPH) in this same group of exercised, HF-fed females. The estrous cycle might influence the ability of exercise to enhance dopamine signaling in females, an effect not observed in male groups. Further research into females by estrous cycle phase, in addition to determining the optimal intensity and duration of aerobic exercise, are logical next steps.

Early-life risperidone alters locomotor responses to apomorphine and quinpirole in adulthood

An escalating trend of antipsychotic drug use in children with ADHD, disruptive behavior disorder, or mood disorders has raised concerns about the impact of these drugs on brain development. Since antipsychotics chiefly target dopamine receptors, it is important to assay the function of these receptors after early-life antipsychotic administration. Using rats as a model, we examined the effects of early-life risperidone, the most prescribed antipsychotic drug in children, on locomotor responses to the dopamine D1/D2 receptor agonist, apomorphine, and the D2/D3 receptor agonist, quinpirole. Female and male Long-Evans rats received daily subcutaneous injections of risperidone (1.0 and 3.0 mg/kg) or vehicle from postnatal day 14–42. Locomotor responses to one of three doses (0.03, 0.1, and 0.3 mg/kg) of apomorphine or quinpirole were tested once a week for four weeks beginning on postnatal day 76 and 147 for each respective drug. The locomotor activity elicited by the two lower doses of apomorphine was significantly greater in adult rats, especially females, administered risperidone early in life. Adult rats administered risperidone early in life also showed more locomotor activity after the low dose of quinpirole. Overall, female rats were more sensitive to the locomotor effects of each agonist. In a separate group of rats administered risperidone early in life, autoradiography of forebrain D2 receptors at postnatal day 62 revealed a modest increase in D2 receptor density in the medial caudate. These results provide evidence that early-life risperidone administration can produce long-lasting changes in dopamine receptor function and density.

Sex difference in the effect of environmental enrichment on food restriction-induced persistence of cocaine conditioned place preference and mechanistic underpinnings

Psychosocial and environmental factors, including loss of natural reward, contribute to the risk of drug abuse. Reward loss has been modeled in animals by removal from social or sexual contact, transfer from enriched to impoverished housing, or restriction of food. We previously showed that food restriction increases the unconditioned rewarding effects of abused drugs and the conditioned incentive effects of drug-paired environments. Mechanistic studies provided evidence of decreased basal dopamine (DA) transmission, adaptive upregulation of signaling downstream of D1 DA receptor stimulation, synaptic upscaling and incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in medium spiny neurons (MSNs) of nucleus accumbens (NAc). These findings align with the still evolving ‘reward deficiency’ hypothesis of drug abuse. The present study tested whether a compound natural reward that is known to increase DA utilization, environmental enrichment, would prevent the persistent expression of cocaine conditioned place preference (CPP) otherwise observed in food restricted rats, along with the mechanistic underpinnings. Because nearly all prior investigations of both food restriction and environmental enrichment effects on cocaine CPP were conducted in male rodents, both sexes were included in the present study. Results indicate that environmental enrichment curtailed the persistence of CPP expression, decreased signaling downstream of the D1R, and decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in NAc MSNs of food restricted male, but not female, rats. The failure of environmental enrichment to significantly decrease food restriction-induced synaptic insertion of CP-AMPARs, and how this may accord with previous pharmacological findings that blockade of CP-AMPARs reverses behavioral effects of food restriction is discussed. In addition, it is speculated that estrous cycle-dependent fluctuations in DA release, receptor density and MSN excitability may obscure the effect of increased DA signaling during environmental enrichment, thereby interfering with development of the cellular and behavioral effects that enrichment produced in males.

Working memory gating in obesity: Insights from a case-control fMRI study

Computational models and neurophysiological data propose that a ‘gating mechanism’ coordinates distractor-resistant maintenance and flexible updating of working memory contents: While maintenance of information is mainly implemented in the prefrontal cortex, updating of information is signaled by phasic increases in dopamine in the striatum. Previous literature demonstrates structural and functional alterations in these brain areas, as well as differential dopamine transmission among individuals with obesity, suggesting potential impairments in these processes. To test this hypothesis, we conducted an observational case-control fMRI study, dividing participants into groups with and without obesity based on their BMI. We probed maintenance and updating of working memory contents using a modified delayed match to sample task and investigated the effects of SNPs related to the dopaminergic system. While the task elicited the anticipated brain responses, our findings revealed no evidence for group differences in these two processes, neither at the neural level nor behaviorally. However, depending on Taq1A genotype, which affects dopamine receptor density in the striatum, participants with obesity performed worse on the task. In conclusion, this study does not support the existence of overall obesity-related differences in working memory gating. Instead, we propose that potentially subtle alterations may manifest specifically in individuals with a ‘vulnerable’ genotype.

Catatonia: A narrative review of its historical development, diagnosis, pathophysiology, and therapeutics.

Catatonia was initially a clinical presentation of certain types of schizophrenia, but basic and epidemiological evidence has demonstrated its association with multiple somatic and psychiatric conditions. We describe and discuss current clinical, etiological, pathophysiological, and therapeutic concepts regarding catatonia. We conducted a broad narrative review of articles published in MEDLINE/PubMed. The diagnosis is clinical and can be supported by additional tests, but there are psychometric instruments with different clinical focus. The most validated subtypes are inhibited and excited catatonia. It is mostly associated with somatic, neurological, affective, psychotic, and autistic spectrum disorders. Genetic factors related to oligodendrocytes have been studied in its pathophysiology. Some findings point to an imbalance in neurotransmission and density of GABA and dopamine receptors, consistent with their function in motor pathways and therapeutic response with benzodiazepines. Likewise, glutamatergic activity has been analyzed from the pathophysiological model of autoimmune encephalitis. The cortico-cortical and cortico-subcortical pathways would have a central role, including structures such as the orbitofrontal and temporal cortex, basal nuclei, and brainstem, involved in decision-making, emotion regulation, storage, planning, and motor processing. The main therapeutic lines are benzodiazepines and electroconvulsive therapy. Other interventions studied are zolpidem, antipsychotics, mood stabilizers, glutamatergic modulators, and transcranial magnetic stimulation. New neurobiological findings challenge nosological and therapeutic precepts, renewing the cycle in the conceptualization of catatonia. We highlight the affective component of the psychomotor syndrome and the role of interventions aimed at its modulation.

Coronavírus e sua completude

Diante dos impactos desencadeados por uma das maiores pandemias da história da humanidade, viu-se necessário a abordagem desse fato para que seja sabido o que muitas vezes não é mostrado em televisões e internet. Tais informações camufladas correspondem desde a verdadeira origem do vírus até as sequelas do mesmo. O avanço da ciência em países “desenvolvidos” e a ausência desta em países “subdesenvolvidos”, escancaram a desigualdade atual em todo o mundo, ao mesmo tempo que os efeitos da globalização são sentidos por todos, mesmo que de forma maléfica. O negacionismo da ciência como empecilho para combater o vírus além de responsável por assustadores números de mortes, também são analisados no presente artigo com o intuito de alertar o quão perigoso e maléfico é a negação da verdade. O processo de confinamento- já assustador pelo nome- fez surgir empregos que antes não existiam além de estabelecer uma nova forma de vida; o mesmo fez pessoas desenvolverem problemas de saúde físicos e mentais em decorrência da vivência em uma nova prisão. As discussões entre as pessoas a respeito do jeito certo de se prevenir desencadeando em términos de amizades também são presentes no artigo como forma de escancarar o quão frágil estão as relações. Além de mostrar os números assustadores de mortes por todo o mundo, tendo o Brasil na triste posição de segundo lugar. Sendo este, o novo cenário mundial, promovendo insegurança e incertezas a respeito do futuro.

Spatiotemporal dynamics of functional connectivity and association with molecular architecture in schizophrenia.

Schizophrenia is a self-disorder characterized by disrupted brain dynamics and architectures of multiple molecules. This study aims to explore spatiotemporal dynamics and its association with psychiatric symptoms. Resting-state functional magnetic resonance imaging data were collected from 98 patients with schizophrenia. Brain dynamics included the temporal and spatial variations in functional connectivity density and association with symptom scores were evaluated. Moreover, the spatial association between dynamics and receptors/transporters according to prior molecular imaging in healthy subjects was examined. Patients demonstrated decreased temporal variation and increased spatial variation in perceptual and attentional systems. However, increased temporal variation and decreased spatial variation were revealed in higher order networks and subcortical networks in patients. Specifically, spatial variation in perceptual and attentional systems was associated with symptom severity. Moreover, case-control differences were associated with dopamine, serotonin and mu-opioid receptor densities, serotonin reuptake transporter density, dopamine transporter density, and dopamine synthesis capacity. Therefore, this study implicates the abnormal dynamic interactions between the perceptual system and cortical core networks; in addition, the subcortical regions play a role in the dynamic interaction among the cortical regions in schizophrenia. These convergent findings support the importance of brain dynamics and emphasize the contribution of primary information processing to the pathological mechanism underlying schizophrenia.

Striatal increase of dopamine receptor 2 density in idiopathic and syndromic mouse models of autism spectrum disorder.

Autism spectrum disorder (ASD) comprises a wide range of neurodevelopmental phenotypes united by impaired social interaction and repetitive behavior. Environmental and genetic factors are associated with the pathogenesis of ASD, while other cases are classified as idiopathic. The dopaminergic system has a profound impact in the modulation of motor and reward-motivated behaviors, and defects in dopaminergic circuits are implicated in ASD. In our study, we compare three well-established mouse models of ASD, one idiopathic, the BTBR strain, and two syndromic, Fmr1 and Shank3 mutants. In these models, and in humans with ASD, alterations in dopaminergic metabolism and neurotransmission were highlighted. Still, accurate knowledge about the distribution of dopamine receptor densities in the basal ganglia is lacking. Using receptor autoradiography, we describe the neuroanatomical distribution of D1 and D2 receptors in dorsal and ventral striatum at late infancy and adulthood in the above-mentioned models. We show that D1 receptor binding density is different among the models irrespective of the region. A significant convergence in increased D2 receptor binding density in the ventral striatum at adulthood becomes apparent in BTBR and Shank3 lines, and a similar trend was observed in the Fmr1 line. Altogether, our results confirm the involvement of the dopaminergic system, showing defined alterations in dopamine receptor binding density in three well-established ASD lines, which may provide a plausible explanation to some of the prevalent traits of ASD. Moreover, our study provides a neuroanatomical framework to explain the utilization of D2-acting drugs such as Risperidone and Aripiprazole in ASD.

Associations between the COMT rs4680 Gene Polymorphism and Personality Dimensions and Anxiety in Patients with a Diagnosis of Other Stimulants Dependence.

Background: Research on the hypodopaminergic hypothesis of addictions showed that hypodopaminergic activity in males predicted the number of drugs used and is associated with drug-seeking behavior. Variant alleles may cause hypodopaminergic functioning as a result of the reduced density of dopamine receptors, decreased response to dopamine, increased dopamine clearance or metabolism in the reward system. The catechol-O-methyltransferase (COMT) is involved in the metabolism of dopamine. Personality traits may mediate the genetic predisposition to substance use disorders additively by various motivations associated with reward-seeking and regulating negative emotions, and also relate to self-control and environment selection. The aim of the study: The aim of this study was to investigate the association of the rs4680 polymorphism of COMT with personality dimensions and anxiety in patients addicted to stimulants other than cocaine (F15 according to WHO ICD-10 nomenclature) in the case of examined patients amphetamine. Methods: The study was conducted among patients addicted to stimulants other than cocaine (amphetamine). The study group included 247 patients addicted to stimulants (amphetamine) and the control group comprised 280 healthy male volunteers. The real-time PCR method was used to carry out genetic tests; personality dimensions were assessed using the standardized NEO-FFI and state and trait anxiety were assessed with STAI. All analyses were performed using STATISTICA 13. Results: The results of the 2 × 3 factorial ANOVA showed a statistically significant effect of the combined factor COMT rs4680 genotype on the group of patients diagnosed with other stimulants dependence/control (F2,252 = 3.11, p = 0.0465, η2 = 0.024). Additionally, we observed that the results of the 2 × 3 factorial ANOVA showed a statistically significant influence of the combined factor COMT rs4680 on the genotype in the group of patients diagnosis with other stimulants dependence/control (F2,252 = 6.16, p = 0.0024, η2 = 0.047). Conclusions: In our research, the polymorphism G/G COMT rs4680 genotype was associated with higher scores of STAI traits and STAI states in the patients dependent on amphetamine. In the control group we observed no such interactions.

Receptor density influences the recruitment bias of aripiprazole and brexpiprazole at the dopamine D2L receptor.

Aripiprazole, brexpiprazole, and cariprazine are dopamine D2 receptor ligands considered as effective and tolerable antipsychotics. Brain imaging studies showed that schizophrenia is characterized by elevated dopamine receptor density, which is exacerbated by antipsychotic treatments. Despite the complexity of translating in vitro studies to human neurobiology, overexpression experiments in transfected cells provide a proof-of-concept model of the influence of receptor density on antipsychotic treatments. Since receptor density was demonstrated to influence the signaling profile of dopaminergic ligands, we hypothesized that high dopamine D2 receptor expression levels could influence the recruitment of Gi1 and β-arrestin2 in response to partial agonists used as antipsychotics. A nanoluciferase complementation assay was used to monitor β-arrestin2 and Gi1 recruitment at the dopamine D2L receptor in response to aripiprazole, brexpiprazole, and cariprazine. This was performed in transfected cells carrying a doxycycline-inducible system allowing to manipulate the expression of the dopamine D2L receptors. Increasing D2L receptor density reoriented aripiprazole's preferential recruitment from Gi1 to β-arrestin2. With respect to brexpiprazole, which showed inverse agonism for β-arrestin2 recruitment at the lower receptor density tested, inverse agonism for Gi1 recruitment was observed when tested at a high receptor expression level. At variance, cariprazine evoked a potent partial agonism for β-arrestin2 recruitment only, in all the tested conditions. D2L receptor density appears to shape the recruitment bias of aripiprazole and brexpiprazole, but not cariprazine. This suggests that changes in receptor expression level could qualitatively influence the functional response of partial agonists used in psychiatry.

Reading abilities and dopamine D2/D3 receptor availability: An inverted U-shaped association in subjects with schizophrenia

Reading impairments are prominent trait-like features of cognitive deficits in schizophrenia, predictive of overall cognitive functioning and presumably linked to dopaminergic abnormalities. To evaluate this, we used 18F-fallypride PET in 19 healthy and 21 antipsychotic-naïve schizophrenia subjects and correlated dopamine receptor binding potentials in relevant AFNI-derived regions and voxelwise with group performance on WRAT4 single-word reading subtest. Healthy subjects’ scores were positively and linearly associated with D2/D3 receptor availability in the rectus, orbital and superior frontal gyri, fusiform and middle temporal gyri, as well as middle occipital gyrus and precuneus, all predominantly in the left hemisphere and previously implicated in reading, hence suggesting that higher dopamine receptor density is cognitively advantageous. This relationship was weakened in schizophrenia subjects and in contrast to healthy participants followed an inverted U-shaped curve both in the cortex and dorsal striatum, indicating restricted optimal range of dopamine D2/D3 receptor availability for cognitive performance in schizophrenia.

Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging.

Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system's cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.

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.

Sex-dependent alterations of dopamine receptor and glucose transporter density in rat hypothalamus under long-term clozapine and haloperidol medication.

ObjectiveSex‐dependent disturbances of peripheral glucose metabolism are known complications of antipsychotic drug treatment. The influence of long‐term clozapine and haloperidol medication on hypothalamus, maintaining aspects of internal body homeostasis, has not yet been completely clarified.MethodsAfter puberty, male and female Sprague Dawley rats were fed orally with ground pellets containing haloperidol (1 mg/kgBW/day) or clozapine (20 mg/kgBW/day) for 12 weeks. The hypothalamic protein expression of dopamine receptors D2R and D4R, melanocortin receptor MC4R, and glucose transporters Glut1 and Glut3 was examined. Glucose, glycogen, lactate, and pyruvate levels were determined, also malondialdehyde equivalents as markers of oxidative stress.ResultsD2R expression was increased in the male haloperidol and clozapine group but decreased in females medicated with clozapine. D4R expression was upregulated under clozapine medication. While females showed increased Glut1, Glut3 was elevated in both male and female clozapine‐medicated animals. We found no changes of hypothalamic malondialdehyde, glycogen, and MC4R. Hypothalamic lactate was elevated in the female clozapine group.ConclusionClozapine sex‐dependently affects the expression of D2R, Glut1, and Glut3. The upregulation of the glucose transporters indicates glucose deprivation in the endothelial cells and consequently in astrocytes and neurons. Increased hypothalamic lactate in females under clozapine points to enhanced glycolysis with a higher glucose demand to produce the required energy. Haloperidol did not change the expression of the glucose transporters and upregulated D2R only in males.

Effects of stimulant drug use on the dopaminergic system: A systematic review and meta-analysis of in vivo neuroimaging studies

BackgroundStimulant drugs can cause persistent changes in the brain. Imaging studies show that these changes are most apparent in dopamine transporter (DAT) or receptor availability within the striatum. MethodsThis work focuses on influences of stimulant use on dopaminergic function assessed using nuclear-medicine imaging (PET/SPECT). Included are 39 studies on 655 cocaine, amphetamine, methamphetamine or nicotine users, as well as 690 healthy controls. Metaanalyses were conducted separately for D2/D3 receptors and dopamine transporters of the entire striatum, its subregions caudate and putamen respectively. ResultsMeta-analyses results regarding nicotine did not show significant effects between smokers and nonsmokers. In cocaine users there was a significant decrease in dopamine receptor availability in all regions. The striatal DAT availability was significantly increased in cocaine users. Methamphetamine users showed a significantly decreased dopamine receptor and transporter density in all regions. Significant results also indicate a lower transporter availability in all regions. Amphetamine users showed reduced DAT availability in the striatum, as well as in the sub regions. ConclusionThis meta-analysis provides evidence that there are ongoing changes in the dopaminergic system associated with the use of stimulants. Especially the results of cocaine, methamphetamine and amphetamine use mainly showed a downregulation. In addition, this meta-analysis is the first to include nicotine. This subset of studies showed evidence for a decreased receptor and DAT availability but no significant results were found in the metaanalyses.

Effects of local activation and blockade of dopamine D4 receptors in the spiking activity of the reticular thalamic nucleus in normal and in ipsilateral dopamine-depleted rats

The reticular thalamic nucleus (RTn) controls the overall activity of thalamo-cortical neurons information processing. GABAergic RTn neurons have one of the highest densities of D4-type dopamine receptors in subcortical structures. The unitary electrical activity of RTn neurons was recorded in vivo in Wistar rats in order to study the effects of local activation and blockade of D4 receptors under both conditions, normal and ipsilateral lesion of the dopaminergic pathways. Our data suggest that: i) there is a tonic dopaminergic input to the RTn; ii) local activation of D4 receptors increases the basal firing rate of RTn neurons in normal and lesioned rats, and iii) local blockade of D4 receptors diminishes the firing rate in normal but not in lesioned rats. Altogether, our findings support that dopamine contributes to the spontaneous basal firing of the RTn neurons through D4-type dopamine receptors.

The heterotetrameric structure of the adenosine A1-dopamine D1 receptor complex: Pharmacological implication for restless legs syndrome.

Dopaminergic and purinergic signaling play a pivotal role in neurological diseases associated with motor symptoms, including Parkinson's disease (PD), multiple sclerosis, amyotrophic lateral sclerosis, Huntington disease, Restless Legs Syndrome (RLS), spinal cord injury (SCI), and ataxias. Extracellular dopamine and adenosine exert their functions interacting with specific dopamine (DR) or adenosine (AR) receptors, respectively, expressed on the surface of target cells. These receptors are members of the family A of G protein-coupled receptors (GPCRs), which is the largest protein superfamily in mammalian genomes. GPCRs are target of about 40% of all current marketed drugs, highlighting their importance in clinical medicine. The striatum receives the densest dopamine innervations and contains the highest density of dopamine receptors. The modulatory role of adenosine on dopaminergic transmission depends largely on the existence of antagonistic interactions mediated by specific subtypes of DRs and ARs, the so-called A2AR-D2R and A1R-D1R interactions. Due to the dopamine/adenosine antagonism in the CNS, it was proposed that ARs and DRs could form heteromers in the neuronal cell surface. Therefore, adenosine can affect dopaminergic signaling through receptor-receptor interactions and by modulations in their shared intracellular pathways in the striatum and spinal cord. In this work we describe the allosteric modulations between GPCR protomers, focusing in those of adenosine and dopamine within the A1R-D1R heteromeric complex, which is involved in RLS. We also propose that the knowledge about the intricate allosteric interactions within the A1R-D1R heterotetramer, may facilitate the treatment of motor alterations, not only when the dopamine pathway is hyperactivated (RLS, chorea, etc.) but also when motor function is decreased (SCI, aging, PD, etc.).

Dopamine receptor density and white mater integrity: 18F-fallypride positron emission tomography and diffusion tensor imaging study in healthy and schizophrenia subjects.

Dopaminergic dysfunction and changes in white matter integrity are among the most replicated findings in schizophrenia. A modulating role of dopamine in myelin formation has been proposed in animal models and healthy human brain, but has not yet been systematically explored in schizophrenia. We used diffusion tensor imaging and 18F-fallypride positron emission tomography in 19 healthy and 25 schizophrenia subjects to assess the relationship between gray matter dopamine D2/D3 receptor density and white matter fractional anisotropy in each diagnostic group. AFNI regions of interest were acquired for 42 cortical Brodmann areas and subcortical gray matter structures as well as stereotaxically placed in representative white matter areas implicated in schizophrenia neuroimaging literature. Welch's t-test with permutation-based p value adjustment was used to compare means of z-transformed correlations between fractional anisotropy and 18F-fallypride binding potentials in hypothesis-driven regions of interest in the diagnostic groups. Healthy subjects displayed an extensive pattern of predominantly negative correlations between 18F-fallypride binding across a range of cortical and subcortical gray matter regions and fractional anisotropy in rostral white matter regions (internal capsule, frontal lobe, anterior corpus callosum). These patterns were disrupted in subjects with schizophrenia, who displayed significantly weaker overall correlations as well as comparatively scant numbers of significant correlations with the internal capsule and frontal (but not temporal) white matter, especially for dopamine receptor density in thalamic nuclei. Dopamine D2/D3 receptor density and white matter integrity appear to be interrelated, and their decreases in schizophrenia may stem from hyperdopaminergia with dysregulation of dopaminergic impact on axonal myelination.