RESUMEN
Dopamine D3 receptors have key roles in behavioral reward, addiction, Parkinson's disease, and schizophrenia, and there is interest in studying their role in these disorders using PET. However, current PET radiotracers for studying D3 receptors in humans all bind to both D2 and D3 due to similarities between the two receptors. Selective D2 and D3 radioligands would aid investigation of the differences between D2 and D3 circuitry in the central nervous system. While there are currently in vitro measures of ligand D3/D2 selectivity, there is a need for an in vivo PET measure of D3/D2 selectivity. This review discusses current PET imaging of dopamine D2/D3 receptors and proposes methodology for quantitating in vivo selectivity of probes for PET imaging of dopamine D3 receptors.
Asunto(s)
Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Autorradiografía/métodos , Radioisótopos de Carbono , Radioisótopos de Flúor , Humanos , Ligandos , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisisRESUMEN
The dopamine (DA) system is considered to be centrally involved in the pathophysiology of several major psychiatric disorders. Using positron emission tomography (PET), aberrations in dopamine D2/D3-receptors (D2-R) levels and uptake of the DA precursor FDOPA have been shown for schizophrenia, substance abuse and depression. Radioligands for the dopamine D1-receptor (D1-R) have been available for more than three decades, however this receptor subtype has received much less attention in psychiatry research. Here, studies investigating D1-R in psychiatric patients in comparison to healthy control subjects are summarized. Although small sample sizes, medication effects and heterogeneous methods of quantification limit the conclusions that can be drawn, the data is suggestive of higher levels of cortical D1-R in drug naïve patients with psychosis, and lower D1-R in patients with affective disorders. Data sharing and reanalysis using harmonized methodology are important next steps towards clarifying the role of D1-R in these disorders.
Asunto(s)
Trastornos Mentales/diagnóstico por imagen , Trastornos Mentales/metabolismo , Tomografía de Emisión de Positrones/métodos , Receptores de Dopamina D1/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Estudios de Casos y Controles , Humanos , Receptores de Dopamina D1/análisis , Receptores de Dopamina D2/análisis , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/análisis , Receptores de Dopamina D3/metabolismoRESUMEN
Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson's disease. The caudate-putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D2/D3 receptor (D2/D3R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [18F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT-A injection. Male Wistar rats were assigned to three different groups: controls, sham-injected hemi-PD rats, and BoNT-A-injected hemi-PD rats. Disease-specific motor impairment was verified by apomorphine and amphetamine rotation testing. Animal-specific magnetic resonance imaging was performed for co-registration and anatomical reference. PET quantification was achieved using PMOD software with the simplified reference tissue model 2. Hemi-PD rats exhibited a constant increase of 23% in D2/D3R availability in the CPu, which was almost normalized by intrastriatal application of BoNT-A. Importantly, the BoNT-A effect on striatal D2/D3R significantly correlated with behavioral results in the apomorphine rotation test. Our results suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing interhemispheric changes of striatal D2/D3R.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Química Encefálica , Trastornos Parkinsonianos/tratamiento farmacológico , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Animales , Conducta Animal , Benzamidas , Toxinas Botulínicas Tipo A/administración & dosificación , Inyecciones , Masculino , Trastornos Parkinsonianos/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pirrolidinas , Ratas , Ratas WistarRESUMEN
Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of 18 F-5-OH-FPPAT, and the newer 18 F-5-OH-FHXPAT and 18 F-7-OH-FHXPAT. Syntheses of 18 F-5-OH-FHXPAT and 18 F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74-111 kBq/cc). Competition with dopamine (1-100 nM) and Gpp(NH)p (10-50 µM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of 18 F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with 18 F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using 18 F-7-OH-FHXPAT (2-37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10-2 min-1 for 18 F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50-80% striatal binding with faster dissociation rates (5.0 × 10-2 min-1 ), suggesting HA-state binding of 18 F-5-OH-FPPAT and 18 F-5-OH-FHXPAT. Striatal binding of 18 F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of 18 F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum = 2.09 and dorsal striatum/cerebellum = 1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor.
Asunto(s)
Encéfalo/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacología , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Animales , Encéfalo/metabolismo , Radioisótopos de Flúor/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Tetrahidronaftalenos/farmacologíaRESUMEN
BACKGROUND: Cigarette smoking induces dopamine release in the striatum, and smoking- or nicotine-induced ventral striatal dopamine release is correlated with nicotine dependence. Smokers also exhibit lower dopamine D2/3 receptor availability in the dorsal striatum than nonsmokers. Negative correlations of striatal dopamine D2/3 receptor availability with smoking exposure and nicotine dependence, therefore, might be expected but have not been tested. METHODS: Twenty smokers had positron emission tomography scans with [18F]fallypride to measure dopamine D2/3 receptor availability in ventral and dorsal regions of the striatum and provided self-report measures of recent and lifetime smoking and of nicotine dependence. RESULTS: As reported before, lifetime smoking was correlated with nicotine dependence. New findings were that ventral striatal dopamine D2/3 receptor availability was negatively correlated with recent and lifetime smoking and also with nicotine dependence. CONCLUSION: The results suggest an effect of smoking on ventral striatal D2/3 dopamine receptors that may contribute to nicotine dependence.
Asunto(s)
Ganglios Basales/química , Fumar Cigarrillos/metabolismo , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Fumadores , Tabaquismo/metabolismo , Adolescente , Adulto , Ganglios Basales/diagnóstico por imagen , Ganglios Basales/fisiopatología , Benzamidas/administración & dosificación , Fumar Cigarrillos/fisiopatología , Medios de Contraste/administración & dosificación , Estudios Transversales , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen Molecular , Tomografía de Emisión de Positrones , Pirrolidinas/administración & dosificación , Fumadores/psicología , Tabaquismo/diagnóstico por imagen , Tabaquismo/fisiopatología , Tabaquismo/psicología , Adulto JovenRESUMEN
BACKGROUND: Dopamine receptors induce natriuresis in kidney. Previous studies have shown interactions between different subtypes of dopamine receptors in renal proximal tubule (RPT) cells. We hypothesize that D3 receptors have an interaction with D4 receptors in RPT cells from normotensive rats (Wistar-Kyoto, WKY) and spontaneously hypertensive rats (SHRs). METHODS: Immunoblotting and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to examine the expression of D3 and D4 receptors. Na-K-ATPase activity was used to measure the function of receptors. The distribution and colocalization of D3 and D4 receptors were detected by confocal microscopy and co-immunoprecipitation. RESULTS: D3 receptor agonist PD128907 increased the mRNA and protein expression of D4 receptors in RPT cells from WKY rats, but decreased that from SHRs. In the presence of PLC blocker (U73122, 10-mol/l) or PKC inhibitor 19 -31 (10-mol/l), the up-regulation of D3 receptor on D4 receptor was lost in WKY cells. Moreover, stimulation with PD128907 for 30 minutes decreased D4 receptor degradation in WKY cells, not in SHR cells. D3 and D4 receptors colocalized and co-immunoprecipitated in RPT cells. PD128907 increased co-immunoprecipitation of D3 and D4 receptors in WKY RPT cells, but not in SHR RPT cells. Pre-treatment with D3 receptor agonist also increases D4 receptor mediated inhibitory effect on Na-K-ATPase activity in WKY cells, but not in SHR cells. CONCLUSION: Renal D3 receptor regulates the expression and function of D4 receptor in RPT cells via PLC /PKC signaling pathway, the loss of this interaction might be involved in the pathogenesis of hypertension.
Asunto(s)
Túbulos Renales Proximales/citología , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D4/metabolismo , Animales , Benzopiranos/farmacología , Células Cultivadas , Agonistas de Dopamina/farmacología , Estrenos/farmacología , Túbulos Renales Proximales/química , Túbulos Renales Proximales/metabolismo , Oxazinas/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Pirrolidinonas/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Dopamina D3/análisis , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/genética , Receptores de Dopamina D4/análisis , Receptores de Dopamina D4/genética , Transducción de Señal , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Regulación hacia ArribaRESUMEN
Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Palmitatos/metabolismo , Receptores de Dopamina D3/metabolismo , Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Adaptadoras Transductoras de Señales/genética , Membrana Celular/metabolismo , Células HEK293 , Humanos , Simulación de Dinámica Molecular , Mutación , Unión Proteica , Mapas de Interacción de Proteínas , Transporte de Proteínas , Receptores de Dopamina D3/análisis , Receptores de Dopamina D3/genética , Transducción de SeñalRESUMEN
OBJECTIVE: To date, there are no reports on the cellular localization of dopamine receptors in the human pancreas. In our study, we determined the localization and expression of 5 dopamine receptors (D(1), D(2), D(3), D(4), and D(5)) in normal human pancreas tissue. METHODS: Human nonpathological pancreas tissues were fixed with 4% paraformaldehyde, paraffin-embedded, and processed for immunohistochemical analysis to detect dopamine receptors in the human pancreas tissue by using double immunofluorescent labeling and confocal microscopy. RESULTS: We found that the D(1) receptor is present in ß cells; the D(2) receptor is expressed by α, δ, and pancreatic polypeptide cells; the D(4) receptor is expressed by ß and polypeptide cells; whereas the D(5) receptor is expressed only by δ cells. CONCLUSIONS: Our results identify the dopamine receptors (D(1)-D(5)) in normal pancreas tissue and provide a morphological basis for studying the pancreatic endocrine effects of dopamine and suggest a new target for the clinical treatment of diabetes.
Asunto(s)
Islotes Pancreáticos/química , Receptores Dopaminérgicos/análisis , Técnica del Anticuerpo Fluorescente , Células Secretoras de Glucagón/química , Humanos , Células Secretoras de Insulina/química , Islotes Pancreáticos/citología , Microscopía Confocal , Células Secretoras de Polipéptido Pancreático/química , Adhesión en Parafina , Receptores de Dopamina D1/análisis , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Receptores de Dopamina D4/análisis , Receptores de Dopamina D5/análisis , Células Secretoras de Somatostatina/químicaRESUMEN
Defluorination of [18F]fallypride and accumulation of 18F in skull and glands leads to the contamination of brain structures with spillover activity due to partial volume effects, leading to considerable errors in binding potential estimations. Here we propose a modification of the simplified reference tissue model (SRTM) to take into account the contribution of skull activity to the radioactivity kinetic pattern in cerebellum and target regions. It consists of the introduction of an additional parameter for each volume of interest (sT) and one for the cerebellum (sR), corresponding to the fraction of skull activity contaminating these structures. Using five rat positron emission tomography experiments, we applied the modified SRTM (SRTMc), which resulted in excellent fits. As a relative means of comparison of results, we applied factor analysis (FA) to decompose dynamic data into images corresponding to brain and skull activity. With the skull factor images, we estimated the "true" sT and sR values, ultimately permitting us to fix the sR value. Parameters obtained with the SRTMc were closely correlated with values obtained from FA-corrected data. In conclusion, we propose an efficient method for reliable quantification of dopamine D2/3 receptors with single-injection [18F]fallypride scans that is potentially applicable to human studies where 18F skull accumulation compromises binding parameter estimation.
Asunto(s)
Benzamidas/farmacocinética , Pirrolidinas/farmacocinética , Radiofármacos/farmacocinética , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Animales , Cerebelo/diagnóstico por imagen , Análisis Factorial , Masculino , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Cráneo/diagnóstico por imagenRESUMEN
The dopaminergic system is especially vulnerable to the effects of human immunodeficiency virus (HIV) infection, rendering dopaminergic deficits early surrogate markers of HIV-associated neuropathology. We quantified dopamine D2/3 receptors in young HIV-1 transgenic (Tg) (n â=â 6) and age-matched control rats (n â=â 7) and adult Tg (n â=â 5) and age-matched control rats (n â=â 5) using [18F]fallypride positron emission tomography (PET). Regional uptake was quantified as binding potential (BPND) using the two-tissue reference model with the cerebellum as the reference. Time-activity curves were generated for the ventral striatum, dorsal striatum, thalamus, and cerebellum. Whereas BPND values were significantly lower in the ventral striatum (p < .001) and dorsal striatum (p â=â .001) in the adult Tg rats compared to controls rats, they were significantly lower only in the dorsal striatum (p < .05) in the young rats. Tg rats had smaller striatal volumes on magnetic resonance imaging. We also found lower expression levels of tyrosine hydroxylase on immunohistochemistry in the Tg animals. Our findings suggest that progressive striatal D2/3 receptor deficits occur in Tg rats as they age and can be detected using small-animal PET imaging. The effectiveness of various approaches in preventing or halting this dopaminergic loss in the Tg rat can thus be measured preclinically using [18F]fallypride PET as a molecular imaging biomarker of HIV-associated neuropathology.
Asunto(s)
Benzamidas/farmacocinética , Encéfalo/diagnóstico por imagen , Infecciones por VIH/diagnóstico por imagen , Pirrolidinas/farmacocinética , Radiofármacos/farmacocinética , Animales , Biomarcadores/análisis , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , VIH-1/fisiología , Humanos , Tomografía de Emisión de Positrones/métodos , Ratas , Ratas Transgénicas , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisisRESUMEN
D3 dopamine receptor (D3R)-deficient mice have renin-dependent hypertension associated with sodium retention, but the hypertension is mild. To determine whether any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3(-/-)) and heterozygous (D3(+/-)) knockout mice and their wild-type (D3(+/+)) littermates. The renal immunohistochemistry and protein expression of D5R were increased (n=5/group) in D3(-/-) mice; renal D4R protein expression was decreased, whereas renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3(+/-) (n=5/group) relative to D3(+/+) mice, whereas D1R, D2R, and D4R protein expressions were similar in D3(+/-) and D3(+/+) mice. The increase in renal D5R protein expression was abolished when D3(-/-) mice were fed a high-salt diet. Treatment with the D1-like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3(-/-) but not D3(+/+) mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3(-/-) mice. The renal D5R protein upregulation was not caused by increased transcription because renal mRNA expression of D5R was similar in D3(-/-) and D3(+/+) mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3(-/-) mice.
Asunto(s)
Hipertensión/etiología , Riñón/fisiología , Receptores de Dopamina D3/fisiología , Receptores de Dopamina D5/fisiología , Animales , Benzazepinas/farmacología , Hipertensión/prevención & control , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Receptores de Dopamina D3/análisis , Receptores de Dopamina D5/análisis , Sodio/metabolismo , Cloruro de Sodio Dietético/administración & dosificación , Regulación hacia ArribaRESUMEN
PURPOSE: Dopamine D receptors (DRs) have two affinity states for endogenous dopamine, referred to as high-affinity state (D ), which has a high affinity for endogenous dopamine, and low-affinity state (D ). The density of D can be measured with (R)-2-CHO-N-n-propylnorapomorphine ([C]MNPA), while total density of D and D (DRs) can be measured with [C]raclopride using positron emission tomography (PET). Thus, the ratio of the binding potential (BP) of [C]MNPA to that of [C]raclopride ([C]MNPA/[C]raclopride) may reflect the proportion of the density of D to that of DRs. In the caudate and putamen, [C]MNPA/[C]raclopride reflects the proportion of the density of D to that of DRs. To evaluate the reliability of the PET paradigm with [C]MNPA and [C]raclopride, we investigated the test-retest reproducibility of non-displaceable BP (BP ) measured with [C]MNPA and of [C]MNPA/[C]raclopride in healthy humans. METHODS: Eleven healthy male volunteers underwent two sets of PET studies on separate days that each included [C]MNPA and [C]raclopride scans. BP values in the caudate and putamen were calculated. Test-retest reproducibility of BP of [C]MNPA and [C]MNPA/[C]raclopride was assessed by intra-subject variability (absolute variability) and test-retest reliability (intraclass correlation coefficient: ICC). RESULTS: The absolute variability of [C]MNPA BP was 5.30 ± 3.96 % and 12.3 ± 7.95 % and the ICC values of [C]MNPA BP were 0.72 and 0.82 in the caudate and putamen, respectively. The absolute variability of [C]MNPA/[C]raclopride was 6.11 ± 3.68 % and 11.60 ± 5.70 % and the ICC values of [C]MNPA/[C]raclopride were 0.79 and 0.80 in the caudate and putamen, respectively. CONCLUSION: In the present preliminary study, the test-retest reproducibility of BP of [C]MNPA and of [C]MNPA/[C]raclopride was reliable in the caudate and putamen.
Asunto(s)
Apomorfina/análogos & derivados , Encéfalo/diagnóstico por imagen , Tomografía de Emisión de Positrones , Racloprida , Radiofármacos , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Adulto , Interpretación Estadística de Datos , Humanos , Masculino , Reproducibilidad de los ResultadosRESUMEN
Cariprazine is a dopamine D(3)/D(2) receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D(3) and D(2) receptors (with â¼10-fold higher in vitro affinity to D(3) vs. D(2) receptors) and with moderate affinity to 5-HT(1A) receptors. The main objective of the present molecular imaging investigation was to evaluate the uptake and reversible binding of 11-C labeled cariprazine in the nonhuman primate brain, in relation to the known distributions of dopamine D(2) and D(3) receptors. We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [(11) C]cariprazine. Of the total injected radioactivity, â¼7% entered the brain and â¼3-4% remained in the brain after 90 min, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [(11) C]cariprazine binds to dopamine D(3)/D(2) receptors. Nondisplaceable binding potential (BPND) measurements, using a simplified reference tissue model and cerebellum as the reference region, yielded values of â¼1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BPND values were reduced by 80 and 85% following pretreatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the nonhuman primate brain readily and binds to dopamine D(3)/D(2) receptors. Furthermore, in PET imaging [(11) C]cariprazine can effectively visualize dopamine D(3)/D(2) receptors in the nonhuman primate brain.
Asunto(s)
Agonistas de Dopamina/farmacocinética , Piperazinas/farmacocinética , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Animales , Barrera Hematoencefálica , Química Encefálica , Radioisótopos de Carbono/farmacocinética , Femenino , Macaca fascicularis , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Distribución TisularRESUMEN
Dopamine D(3) receptors have a pre- and postsynaptic localization in brain stem nuclei, limbic parts of the striatum, and cortex. Their widespread influence on dopamine release, on dopaminergic function, and on several other neurotransmitters makes them attractive targets for therapeutic intervention. The signaling pathways of D(3) receptors are distinct from those of other members of the D(2)-like receptor family. There is increasing evidence that D(3) receptors can form heteromers with dopamine D(1), D(2), and probably other G-protein-coupled receptors. The functional consequences remain to be characterized in more detail but might open new interesting pharmacological insight and opportunities. In terms of behavioral function, D(3) receptors are involved in cognitive, social, and motor functions, as well as in filtering and sensitization processes. Although the role of D(3) receptor blockade for alleviating positive symptoms is still unsettled, selective D(3) receptor antagonism has therapeutic features for schizophrenia and beyond as demonstrated by several animal models: improved cognitive function, emotional processing, executive function, flexibility, and social behavior. D(3) receptor antagonism seems to contribute to atypicality of clinically used antipsychotics by reducing extrapyramidal motor symptoms; has no direct influence on prolactin release; and does not cause anhedonia, weight gain, or metabolic dysfunctions. Unfortunately, clinical data with new, selective D(3) antagonists are still incomplete; their cognitive effects have only been communicated in part. In vitro, virtually all clinically used antipsychotics are not D(2)-selective but also have affinity for D(3) receptors. The exact D(3) receptor occupancies achieved in patients, particularly in cortical areas, are largely unknown, mainly because only nonselective or agonist PET tracers are currently available. It is unlikely that a degree of D(3) receptor antagonism optimal for antipsychotic and cognitive function can be achieved with existing antipsychotics. Therefore, selective D(3) antagonism represents a promising mechanism still to be fully exploited for the treatment of schizophrenia, cognitive deficits in schizophrenia, and comorbid conditions such as substance abuse.
Asunto(s)
Antipsicóticos/farmacología , Cognición/efectos de los fármacos , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D3/fisiología , Animales , Humanos , Multimerización de Proteína , Receptores de Dopamina D3/análisis , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/química , Transducción de SeñalRESUMEN
The goal of this work is to quantify the binding parameters of [(18)F]Fallypride in the striatal and extrastriatal regions of the rat brain using factor analysis (FA) to correct small animal PET kinetic imaging for spillover defluorination radioactivity. Eleven rats were employed for YAP-(S)PET acquisitions and metabolite studies. All kinetic parameters including B'(max) and K(d)V(R) were estimated with a three-tissue compartment seven-parameter model (3T-7k) on the basis of all the FA-corrected data from the multi-injection protocol. Binding potential (BP(ND)) was calculated with Logan's graphical analysis taking cerebellum as the reference region and using the first injection raw (BP(ND-RAW)) and FA-corrected (BP(ND-FA)) data. Three distinct factors corresponding to free+non-specific binding, specific binding and skull and gland accumulation were recovered from FA with their corresponding spatial distributions. The resulting reconstructed images without skull and gland accumulation were improved to provide a better contrast between specific and non-specific regions. Very bad fits were obtained when using time-activity curves (TACs) calculated from the raw [(18)F]Fallypride data, whereas all TACs were well fitted by the 3T-7k model after FA correction. FA-corrected data enables the cerebellar region to be used as reference for the Logan approach. The magnitude of the BP(ND-FA) values was increased from 21% to 108% across regions and the rank order of BP(ND-FA) values (CxAsunto(s)
Benzamidas/farmacocinética
, Encéfalo/diagnóstico por imagen
, Radiofármacos/farmacocinética
, Receptores de Dopamina D2/análisis
, Receptores de Dopamina D3/análisis
, Animales
, Encéfalo/metabolismo
, Química Encefálica
, Análisis Factorial
, Radioisótopos de Flúor/farmacocinética
, Masculino
, Tomografía de Emisión de Positrones
, Ratas
, Ratas Sprague-Dawley
, Distribución Tisular
RESUMEN
PURPOSE: [(123)I]Epidepride is a radio-tracer with very high affinity for dopamine D(2)/D(3) receptors in brain. The importance of alteration in dopamine D(2)/D(3) receptor binding condition has been wildly verified in schizophrenia. In the present study we set up a rat schizophrenia model by chronic injection of a non-competitive NMDA receptor antagonist, MK-801, to examine if [(123)I]epidepride could be used to evaluate the alterations of dopamine D(2)/D(3) receptor binding condition in specific brain regions. METHOD: Rats were given repeated injection of MK-801 (dissolved in saline, 0.3mg/kg) or saline for 1month. Afterwards, total distance traveled (cm) and social interaction changes were recorded. Radiochemical purity of [(123)I]epidepride was analyzed by Radio-Thin-Layer Chromatography (chloroform: methanol, 9:1, v/v) and [(123)I]epidepride neuroimages were obtained by ex vivo autoradiography and small animal SPECT/CT. Data obtained were then analyzed to determine the changes of specific binding ratio. RESULT: Chronic MK-801 treatment for a month caused significantly increased local motor activity and induced an inhibition of social interaction. As shown in [(123)I]epidepride ex vivo autoradiographs, MK-801 induced a decrease of specific binding ratio in the striatum (24.01%), hypothalamus (35.43%), midbrain (41.73%) and substantia nigra (37.93%). In addition, [(123)I]epidepride small animal SPECT/CT neuroimaging was performed in the striatum and midbrain. There were statistically significant decreases in specific binding ratio in both the striatum (P<.01) and midbrain (P<.05) between the saline and MK-801 group. CONCLUSION: These results suggest that [(123)I]epidepride is a useful radio-tracer to reveal the alterations of dopamine D(2)/D(3) receptor binding in a rat schizophrenia model and is also helpful to evaluate therapeutic effects of schizophrenia in the future.
Asunto(s)
Benzamidas , Maleato de Dizocilpina/farmacología , Neuroimagen/métodos , Pirrolidinas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Esquizofrenia/diagnóstico , Esquizofrenia/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Enfermedad Crónica , Modelos Animales de Enfermedad , Radioisótopos de Yodo , Masculino , Imagen Multimodal , Neostriado/diagnóstico por imagen , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Esquizofrenia/inducido químicamente , Esquizofrenia/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The condition of steady-state receptor binding in positron emission tomography (PET) studies is best obtained through the use of a bolus plus steady-infusion paradigm. This is a particularly important consideration in the context of in vivo competition studies, where a pharmacological challenge can be administered during the interval of steady-state ligand binding, as in the case of [¹¹C]-raclopride studies with amphetamine challenge. However, the short half-life of ¹¹C imposes limits on the practical duration of constant infusions. Therefore, we chose to test [¹8F]-DMFP as a tracer for dopamine D2/3 receptors in rat striatum in the paradigm. Using a conventional bolus injection, the [¹8F]-DMFP BP(ND) was 3.8 in striatum of anesthetized rats. When followed by a constant infusion, we obtained quasi-stable BP(ND) estimates of 4.5 within an interval of 45 min. During infusions lasting up to 4 h, BP(ND) declined progressively. This seemed due to the progressive spill-in of radioactivity from the cranium to the cerebellum reference region, despite optimized iterative reconstruction of the images. Therefore, we propose a new concept of compensation for this spill-in effect using pharmacokinetic considerations, without requiring high-resolution anatomical images. Challenge with amphetamine (1 and 4 mg/kg) evoked an â¼25% reduction in BP(ND) . There was no clear evidence of dose-dependence in the striatal-binding changes, despite the considerably greater physiological effect, as documented by ECG. Thus, the general applicability of the bolus plus infusion method with [¹8F]-DMFP for small animal studies is impeded by the substantial labeling of the cranium. The cranial uptake was linear, indicating first-order kinetics for the enzymatic defluorination of the tracer. Based on this phenomenon, we developed an analytic method compensating for the effects of progressive cranial labeling on the estimation of specific binding in striatum.
Asunto(s)
Neostriado/química , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Anfetamina/farmacología , Animales , Encéfalo/diagnóstico por imagen , Cerebelo/diagnóstico por imagen , Inhibidores de Captación de Dopamina/farmacología , Femenino , Radioisótopos de Flúor/administración & dosificación , Infusiones Parenterales , Tomografía de Emisión de Positrones , Ratas , Ratas Sprague-Dawley , Salicilamidas/administración & dosificación , Cráneo/diagnóstico por imagenRESUMEN
Antidepressant drug treatment and psychotherapy are both effective in treating major depression, but there are no published studies comparing the effects of these two treatments on the dopaminergic neurotransmitter system in major depression. We conducted a randomized comparative study on the effects of fluoxetine medication and short-term psychodynamic psychotherapy on striatal and thalamic dopamine D(2/3) receptors in patients with major depression. Duration of the treatment was 4 months, and dopamine D(2/3) receptor binding was quantified before and after treatment as the binding potential (BP (ND)) using [(11)C]raclopride and 3D positron emission tomography. Both treatments were clinically effective in treating major depression, as shown by substantial decreases in symptom ratings. Yet, there were no effects on D(2/3) receptor availability in the ventral striatum or other subdivisions of the striatum. Fluoxetine but not psychotherapy increased [(11)C]raclopride BP (ND) in lateral thalamus (+7.74%, p = 0.002) but this increase was not correlated with clinical improvement. In conclusion, this preliminary study does not support the involvement of ventral dopaminergic neurotransmission in the antidepressant effects of fluoxetine or psychodynamic psychotherapy. The effects of fluoxetine on thalamic dopamine systems need to be further explored.
Asunto(s)
Antidepresivos de Segunda Generación/uso terapéutico , Radioisótopos de Carbono , Cuerpo Estriado/metabolismo , Trastorno Depresivo Mayor/tratamiento farmacológico , Fluoxetina/uso terapéutico , Tomografía de Emisión de Positrones/métodos , Psicoterapia , Racloprida , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisis , Tálamo/metabolismo , Adulto , Trastorno Depresivo Mayor/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Dopamina/fisiología , Neuronas Dopaminérgicas/fisiología , Mesencéfalo/fisiopatología , Motivación/fisiología , Núcleo Accumbens/fisiopatología , Recompensa , Adulto , Radioisótopos de Carbono , Cocaína , Dopamina/análisis , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/análisis , Neuronas Dopaminérgicas/química , Femenino , Humanos , Masculino , Mesencéfalo/química , Mesencéfalo/diagnóstico por imagen , Núcleo Accumbens/química , Núcleo Accumbens/diagnóstico por imagen , Inventario de Personalidad , Tomografía de Emisión de Positrones , Racloprida , Radiofármacos , Receptores de Dopamina D2/análisis , Receptores de Dopamina D3/análisisRESUMEN
In the search for compounds with potential for development as positron emission tomography radioligands for brain D(3) receptor imaging, a series of N-[4-(4-arylpiperazin-1-yl)butyl]arylcarboxamides with appropriate lipophilicity (2Asunto(s)
Amidas/síntesis química
, Piperazinas/síntesis química
, Tomografía de Emisión de Positrones/métodos
, Receptores de Dopamina D3/análisis
, Diseño de Fármacos
, Humanos
, Ligandos
, Unión Proteica
, Radiofármacos
, Receptores de Dopamina D3/metabolismo