RESUMEN
Growing evidence supports dopamine's role in aversive states, yet systematic reviews focusing on dopamine receptors in defensive behaviors are lacking. This study presents a systematic review of the literature examining the influence of drugs acting on dopamine D2-like receptors on unconditioned and conditioned fear in rodents. The review reveals a predominant use of adult male rats in the studies, with limited inclusion of female rodents. Commonly employed tests include the elevated plus maze and auditory-cued fear conditioning. The findings indicate that systemic administration of D2-like drugs has a notable impact on both innate and learned aversive states. Generally, antagonists tend to increase unconditioned fear, while agonists decrease it. Moreover, both agonists and antagonists typically reduce conditioned fear. These effects are attributed to the involvement of distinct neural circuits in these states. The observed increase in unconditioned fear induced by D2-like antagonists aligns with dopamine's role in suppressing midbrain-mediated responses. Conversely, the reduction in conditioned fear is likely a result of blocking dopamine activity in the mesolimbic pathway. The study highlights the need for future research to delve into sex differences, explore alternative testing paradigms, and identify specific neural substrates. Such investigations have the potential to advance our understanding of the neurobiology of aversive states and enhance the therapeutic application of dopaminergic agents.
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Miedo , Receptores de Dopamina D2 , Animales , Miedo/efectos de los fármacos , Miedo/fisiología , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/farmacología , Ratas , Agonistas de Dopamina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Roedores , Masculino , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiologíaRESUMEN
BACKGROUND: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. AIMS: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. METHODS: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. RESULTS: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. CONCLUSION: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.
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Condicionamiento Clásico , Agonistas de Dopamina , Miedo , Generalización Psicológica , Quinpirol , Racloprida , Ratas Wistar , Receptores de Dopamina D2 , Animales , Miedo/efectos de los fármacos , Masculino , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Quinpirol/farmacología , Agonistas de Dopamina/farmacología , Ratas , Generalización Psicológica/efectos de los fármacos , Racloprida/farmacología , Condicionamiento Clásico/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/farmacologíaRESUMEN
INTRODUCTION: Acute stress, as a protective mechanism to respond to an aversive stimulus, can often be accompanied by suppressing pain perception via promoting consistent burst firing of dopamine neurons. Besides, sensitive and advanced research techniques led to the recognition of the mesohippocampal dopaminergic terminals, particularly in the hippocampal dentate gyrus (DG). Moreover, previous studies have shown that dopamine receptors within the hippocampal DG play a critical role in induced antinociceptive responses by forced swim stress (FSS) in the presence of inflammatory pain. Since different pain states can trigger various mechanisms and transmitter systems, the present experiments aimed to investigate whether dopaminergic receptors within the DG have the same role in the presence of acute thermal pain. METHODS: Ninety-seven adult male albino Wistar rats underwent stereotaxic surgery, and a stainless steel guide cannula was unilaterally implanted 1 mm above the DG. Different doses of SCH23390 or sulpiride as D1- and D2-like dopamine receptor antagonists were microinjected into the DG 5-10 min before exposure to FSS, and 5 min after FSS exposure, the tail-flick test evaluated the effect of stress on the nociceptive response at the time-set intervals. RESULTS: The results demonstrated that exposure to FSS could significantly increase the acute pain perception threshold, while intra-DG administration of SCH23390 and sulpiride reduced the antinociceptive effect of FSS in the tail-flick test. DISCUSSION: Additionally, it seems the D2-like dopamine receptor within the DG plays a more prominent role in FSS-induced analgesia in the acute pain model.
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Benzazepinas , Giro Dentado , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Estrés Psicológico , Sulpirida , Animales , Masculino , Ratas , Analgesia/métodos , Benzazepinas/farmacología , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Dolor/metabolismo , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor/métodos , Dimensión del Dolor/efectos de los fármacos , Ratas Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/fisiopatología , Sulpirida/farmacologíaRESUMEN
INTRODUCTION: Dopamine (D)2,3-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). AREAS COVERED: Eight D2,3-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects. EXPERT OPINION: Since the introduction of D2,3-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)3-RAs and neurokinin (NK)1-RAs have been developed. The classical D2,3-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D2,3-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT3-RA, dexamethasone and a NK1-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D2,3-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D2,3-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.
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Antieméticos , Antineoplásicos , Antagonistas de Dopamina , Náusea , Vómitos , Humanos , Náusea/inducido químicamente , Náusea/prevención & control , Vómitos/inducido químicamente , Vómitos/prevención & control , Antieméticos/farmacología , Antieméticos/farmacocinética , Antieméticos/administración & dosificación , Antieméticos/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/administración & dosificación , Antagonistas de Dopamina/efectos adversos , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/administración & dosificación , Animales , Antagonistas de los Receptores de Dopamina D2/efectos adversos , Antagonistas de los Receptores de Dopamina D2/farmacología , Receptores de Dopamina D3/antagonistas & inhibidoresRESUMEN
Traditional Chinese medicines (TCMs) are popular in clinic because of their safety and efficacy. They contain abundant natural active compounds, which are important sources of new drug discovery. However, how to efficiently identify active compounds from complex ingredients remains a challenge. In this study, a method combining UHPLC-MS/MS characterization and in silico screening was developed to discover compounds with dopamine D2 receptor (D2R) activity in Stephania epigaea (S. epigaea). By combining the compounds identified in S. epigaea by UHPLC-MS/MS with reported compounds, a virtual library of 80 compounds was constructed for in silico screening. Potentially active compounds were chosen based on screening scores and subsequently tested for in vitro activity on a transfected cell line CHO-K1-D2 model using label-free cellular phenotypic assay. Three D2R agonists and five D2R antagonists were identified. (-)-Asimilobine, N-nornuciferine and (-)-roemerine were reported for the first time as D2R agonists, with EC50 values of 0.35 ± 0.04⯵M, 1.37 ± 0.10⯵M and 0.82 ± 0.22⯵M, respectively. Their target specificity was validated by desensitization and antagonism assay. (-)-Isocorypalmine, (-)-tetrahydropalmatine, (-)-discretine, (+)-corydaline and (-)-roemeroline showed strong antagonistic activity on D2R with IC50 values of 92 ± 9.9â¯nM, 1.73 ± 0.13⯵M, 0.34 ± 0.02⯵M, 2.09 ± 0.22⯵M and 0.85 ± 0.08⯵M, respectively. Their kinetic binding profiles were characterized using co-stimulation assay and they were both D2R competitive antagonists. We docked these ligands with human D2R crystal structure and analyzed the structure-activity relationship of aporphine-type D2R agonists and protoberberine-type D2R antagonists. These results would help to elucidate the mechanism of action of S. epigaea for its analgesic and sedative efficacy and benefit for D2R drug design. This study demonstrated the potential of integrating UHPLC-MS/MS with in silico and in vitro screening for accelerating the discovery of active compounds from TCMs.
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Cricetulus , Receptores de Dopamina D2 , Stephania , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Células CHO , Animales , Cromatografía Líquida de Alta Presión/métodos , Stephania/química , Receptores de Dopamina D2/metabolismo , Simulación por Computador , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de los Receptores de Dopamina D2/química , Descubrimiento de Drogas/métodos , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/química , Humanos , Medicina Tradicional China/métodos , Cromatografía Líquida con Espectrometría de MasasRESUMEN
RATIONALE: Evidence on the effect of dopamine D1-like and D2-like receptor antagonists on licking microstructure and the forced swimming response led us to suggest that (i) dopamine on D1-like receptors plays a role in activating reward-directed responses and (ii) the level of response activation is reboosted based on a process of evaluation of response efficacy requiring dopamine on D2-like receptors. A main piece of evidence in support of this hypothesis is the observation that the dopamine D2-like receptor antagonist raclopride induces a within-session decrement of burst number occurring after the contact with the reward. The few published studies with a detailed analysis of the time-course of this measure were conducted in our laboratory. OBJECTIVES: The aim of this review is to recapitulate and discuss the evidence in support of the analysis of the within-session burst number as a behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and its relevance in the analysis of drug effects on ingestion. CONCLUSIONS: The evidence gathered so far suggests that the analysis of the within-session time-course of burst number provides an important behavioural substrate for the study of the mechanisms governing ingestion, behavioural activation and the related evaluation processes, and might provide decisive evidence in the analysis of the effects of drugs on ingestion. However, further evidence from independent sources is necessary to validate the use and the proposed interpretation of this measure.
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Dopamina , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Dopamina/metabolismo , Animales , Humanos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Factores de Tiempo , Antagonistas de Dopamina/farmacología , Recompensa , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta de Ingestión de Líquido/fisiología , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de los Receptores de Dopamina D2/administración & dosificaciónRESUMEN
The inhibitory effects of veralipride, a benzamide-class antipsychotic acting as dopamine D2 receptors antagonist incorporates a primary sulfonamide moiety and was investigated for its interactions with carbonic anhydrase (CA) isoforms. In vitro profiling using the stopped-flow technique revealed that veralipride exhibited potent inhibitory activity across all tested hCA isoforms, with exception of hCA III. Comparative analysis with standard inhibitors, acetazolamide (AAZ), and sulpiride, provided insights for understanding the relative efficacy of veralipride as CA inhibitor. The study reports the X-ray crystal structure analysis of the veralipride adduct with three human (h) isoforms, hCA I, II, and CA XII mimic, allowing the understanding of the molecular interactions rationalizing its inhibitory effects against each isoform. These findings contribute to our understanding of veralipride pharmacological properties and for the design of structural analogs endowed with polypharmacological properties.
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Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Humanos , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Cristalografía por Rayos X , Anhidrasas Carbónicas/metabolismo , Anhidrasas Carbónicas/química , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de los Receptores de Dopamina D2/química , Antagonistas de los Receptores de Dopamina D2/síntesis química , Benzamidas/química , Benzamidas/farmacología , Benzamidas/síntesis química , Receptores de Dopamina D2/metabolismo , Estructura Molecular , Modelos Moleculares , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Relación Estructura-ActividadRESUMEN
BACKGROUND: Diffuse midline glioma, H3 K27-altered (H3 K27M-altered DMG) are invariably lethal, disproportionately affecting the young and without effective treatment besides radiotherapy. The 2016 World Health Organization (WHO) Central Nervous System (CNS) Tumors Classification defined H3 K27M mutations as pathognomonic but restricted diagnosis to diffuse gliomas involving midline structures by 2018. Dordaviprone (ONC201) is an oral investigational small molecule, DRD2 antagonist, and ClpP agonist associated with durable responses in recurrent H3 K27M-mutant DMG. Activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas has not been reported. METHODS: Patients with recurrent non-midline H3 K27M-mutant diffuse gliomas treated with ONC201 were enrolled in 5 trials. Eligibility included measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma, Karnofsky/Lansky performance score ≥60, and ≥90 days from radiation. The primary endpoint was overall response rate (ORR). RESULTS: Five patients with cerebral gliomas (3 frontal, 1 temporal, and 1 parietal) met inclusion. One complete and one partial response were reported by investigators. Blinded independent central review confirmed ORR by RANO criteria for 2, however, 1 deemed nonmeasurable and another stable. A responding patient also noted improved mobility and alertness. CONCLUSIONS: H3 K27M-mutant diffuse gliomas occasionally occur in non-midline cerebrum. ONC201 exhibits activity in H3 K27M-mutant gliomas irrespective of CNS location.
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Neoplasias Encefálicas , Glioma , Imidazoles , Mutación , Recurrencia Local de Neoplasia , Receptores de Dopamina D2 , Humanos , Glioma/genética , Glioma/tratamiento farmacológico , Glioma/patología , Masculino , Femenino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Receptores de Dopamina D2/genética , Adulto , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/genética , Antagonistas de los Receptores de Dopamina D2/uso terapéutico , Antagonistas de los Receptores de Dopamina D2/farmacología , Pirimidinas/uso terapéutico , Pronóstico , Adulto Joven , Estudios de Seguimiento , Estudios de Cohortes , Agonistas de Dopamina/uso terapéutico , Piridinas/uso terapéutico , Piridinas/farmacologíaRESUMEN
This study aimed to investigate the changes in retinal neurotransmitters and the role of the dopamine D2 receptor (D2R) pathway in regulating the myopic refractive state. Tricolor guinea pigs were randomly divided into two groups: the normal control group (NC) and the form-deprivation myopia group (FDM). Animals in the FDM group had their right eye covered with a balloon for 4 weeks. These two groups were further divided into two subgroups based on intravitreal injection with D2R antagonist sulpiride once a week for 3 weeks (NC, NC-Sul, FDM, and FDM-Sul groups). Ultrahigh-performance liquid chromatography-tandem mass spectrometry was used to quantitatively detect the changes in 17 retinal neurotransmitters. Compared to the NC group, the concentrations of dopamine (DA) and γ-aminobutyric acid (GABA) decreased, while those of glutamate (Glu), 3-methoxytyramine (3-MT), and glycine increased, accompanied by an increase in myopic refraction and axial length (AL) in the FDM group. In the FDM-Sul group, glycine and DA levels were upregulated, whereas 3-MT and Glu levels were downregulated, accompanied by a decrease in myopic refraction and AL. The ratio of Glu to GABA (RGG) represents the balance between excitatory and inhibitory neurotransmitters. Notably, RGG changes occurred with corresponding AL changes, which increased in the FDM group and decreased in the FDM-Sul group. Decreased retinal DA concentration, with an increase in Glu, may be involved in the myopia progression. D2R antagonists might effectively slow myopia progression by increasing retinal DA, regulating Glu concentration to match GABA, and maintaining the balance between excitatory and inhibitory neurotransmitters.
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Antagonistas de los Receptores de Dopamina D2 , Miopía , Cobayas , Animales , Antagonistas de los Receptores de Dopamina D2/farmacología , Miopía/tratamiento farmacológico , Ácido Glutámico , Glicina , Ácido gamma-AminobutíricoRESUMEN
The retinal pigment epithelial (RPE)/choroid complex regulates myopia development, but the precise pathogenesis of myopia remains unclear. We aimed to investigate the changes in RPE/choroid complex metabolism in a form deprivation myopia model after dopamine D2 receptor (D2R) modulation. Guinea pigs were randomly divided into normal (NC), form deprivation myopia (FDM), and FDM treated with dopamine D2R antagonist groups. Differential metabolites were screened using SIMCA-P software and MetaboAnalyst metabolomics analysis tool. Functions of differential metabolites were analyzed using KEGG enrichment pathways. Relative to the NC group, 38 differential metabolites were identified, comprising 29 increased metabolites (including nicotinic acid, cytosine, and glutamate) and 9 decreased metabolites, of which proline exhibited the largest decrease. Pathway analysis revealed regulation of arginine/proline and aspartate/glutamate metabolism. Intravitreal D2R antagonist injection increased proline concentrations and activated arginine/proline and purine metabolism pathways. In sum, D2R antagonists alleviated the myopia trend of refractive biological parameters in form deprivation myopic guinea pigs, suggesting the involvement of dopamine D2R signaling in myopia pathogenesis. The RPE/choroid may provide glutamate to the retina by activating proline metabolism via metabolic coupling with the retina. Dopamine D2R antagonism may modulate proline/arginine metabolic pathways in the RPE/choroid and regulate metabolism, information presentation, and myopia.
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Dopamina , Miopía , Cobayas , Animales , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de los Receptores de Dopamina D2/metabolismo , Retina/metabolismo , Miopía/tratamiento farmacológico , Miopía/etiología , Miopía/metabolismo , Coroides/metabolismo , Coroides/patología , Glutamatos/metabolismo , Modelos Animales de EnfermedadRESUMEN
RATIONALE: Dopaminergic dysfunction is implicated in disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) has been used to quantify changes in attention and impulsivity. OBJECTIVE: To examine the roles of dopamine receptors in attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval schedules (vITI) using DA receptor antagonists. METHODS: Two cohorts of 35 and 36 female C57BL/6JRj mice were examined separately in the rCPT, vSD, and vITI schedules, respectively. Both cohorts received antagonists of the following receptors: D1/5 (SCH23390, SCH: 0.01, 0.02, 0.04 mg/kg) and D2/3 (raclopride, RAC 0.03, 0.10, 0.30 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity. RESULTS: SCH showed similar effects in both schedules, and the effects were reference-dependent in the vITI schedule. SCH reduced responding, but improved response accuracy, impulsivity, discriminability, and locomotor activity. RAC showed mixed effects on responsivity, but improved accuracy and discriminability. The discriminability improvement was driven by an increase in hit rate in the vITI schedule and a reduction in false alarm rate in the vSD schedule. RAC also decreased locomotor activity. CONCLUSION: Both D1/5 and D2/3 receptor antagonism reduced responding, but the outcome on discriminability differed, stemming from individual effects on hit and false alarm rate, and the weight of omissions within the calculation. The effects of SCH and RAC suggest that endogenous DA increases responding and impulsivity, but reduces accuracy and shows mixed effects on discriminability.
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Antagonistas de Dopamina , Roedores , Ratones , Animales , Femenino , Antagonistas de Dopamina/farmacología , Ratones Endogámicos C57BL , Receptores de Dopamina D1 , Atención , Conducta Impulsiva , Antagonistas de los Receptores de Dopamina D2/farmacología , Benzazepinas/farmacología , Relación Dosis-Respuesta a DrogaRESUMEN
PURPOSE: Temozolomide resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of temozolomide with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance. EXPERIMENTAL DESIGN: Haloperidol/temozolomide synergism was assessed in GBM cell lines with different dopamine D2 receptor (DRD2) expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum (ER) stress and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) were used to validate the specific mechanisms by which haloperidol and temozolomide induce ferroptosis in GBM cells. RESULTS: In the present work, we demonstrate that the DRD2 level is increased by temozolomide in a time-dependent manner and is inversely correlated with temozolomide sensitivity in GBM. The DRD2 antagonist haloperidol, a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances temozolomide efficacy in vivo and in vitro. Mechanistically, haloperidol suppressed the effect of temozolomide on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered ER stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis. CONCLUSIONS: Our results provide experimental evidence for repurposing haloperidol as an effective adjunct therapy to inhibit adaptive temozolomide resistance to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.
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Neoplasias Encefálicas , Ferroptosis , Glioblastoma , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Haloperidol/farmacología , Haloperidol/uso terapéutico , Antagonistas de los Receptores de Dopamina D2/farmacología , Línea Celular Tumoral , Autofagia , Estrés del Retículo Endoplásmico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Resistencia a Antineoplásicos/genética , Receptores de Dopamina D2/genéticaRESUMEN
Strong expression of the G protein-coupled receptor (GPCR) neurotensin receptor 1 (NTR1) in ventral tegmental area (VTA) dopamine (DA) neurons and terminals makes it an attractive target to modulate DA neuron activity and normalize DA-related pathologies. Recent studies have identified a novel class of NTR1 ligand that shows promising effects in preclinical models of addiction. A lead molecule, SBI-0654553 (SBI-553), can act as a positive allosteric modulator of NTR1 ß-arrestin recruitment while simultaneously antagonizing NTR1 Gq protein signaling. Using cell-attached recordings from mouse VTA DA neurons we discovered that, unlike neurotensin (NT), SBI-553 did not independently increase spontaneous firing. Instead, SBI-553 blocked the NT-mediated increase in firing. SBI-553 also antagonized the effects of NT on dopamine D2 auto-receptor signaling, potentially through its inhibitory effects on G-protein signaling. We also measured DA release directly, using fast-scan cyclic voltammetry in the nucleus accumbens and observed antagonist effects of SBI-553 on an NT-induced increase in DA release. Further, in vivo administration of SBI-553 did not notably change basal or cocaine-evoked DA release measured in NAc using fiber photometry. Overall, these results indicate that SBI-553 blunts NT's effects on spontaneous DA neuron firing, D2 auto-receptor function, and DA release, without independently affecting these measures. In the presence of NT, SBI-553 has an inhibitory effect on mesolimbic DA activity, which could contribute to its efficacy in animal models of psychostimulant use.
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Antagonistas de los Receptores de Dopamina D2 , Dopamina , Neuronas Dopaminérgicas , Neurotensina , Núcleo Accumbens , Receptores de Neurotensina , Área Tegmental Ventral , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Núcleo Accumbens/metabolismo , Dopamina/metabolismo , Masculino , Femenino , Animales , Ratones , Ratones Endogámicos C57BL , Terminales Presinápticos/metabolismo , Terminales Presinápticos/fisiología , Potenciales de Acción/efectos de los fármacos , Receptores de Neurotensina/antagonistas & inhibidores , Receptores de Neurotensina/metabolismo , Neurotensina/metabolismo , Neurotensina/farmacología , Ligandos , Antagonistas de los Receptores de Dopamina D2/metabolismo , Antagonistas de los Receptores de Dopamina D2/farmacologíaRESUMEN
BACKGROUND AND AIMS: Whereas striatal dopamine D2 receptor (D2R) availability has shown to be altered in individuals with alcohol use disorder (AUD) and in healthy individuals with a family history of AUD, the role of D2R in the development of AUD is unknown. In this positron emission tomography (PET) study, we measured whether D2R availability is associated with subsequent alcohol use and alcohol-related factors, at a follow-up 8 to 16 years post-PET scan, in social drinkers. DESIGN: Longitudinal study investigating the association between PET data and later self-report measures in healthy individuals. SETTING: Academic research imaging centre in Stockholm, Sweden. PARTICIPANTS: There were 71 individuals (68 of whom had evaluable PET data, 5 females, 42.0 years mean age) from a series of previous PET studies. MEASUREMENTS: One PET examination with the D2R antagonist radioligand [11 C]raclopride at baseline and self-report measures assessing alcohol use, drug use, impulsivity, reward sensitivity and family history of alcohol or substance use disorder at follow-up. FINDINGS: We found no evidence for an association between D2R availability and later alcohol use (B = -0.019, B 95% CI = -0.043 to -0.006, P = 0.147) nor for the majority of the alcohol-related factors (B 95% CI = -0.034 to 0.004, P = 0.273-0.288). A negative association with a small effect size was found between D2R availability and later impulsivity (B = -0.017, B 95% CI = -0.034 to -0.001, P = 0.046). CONCLUSIONS: Low striatal dopamine D2 receptor availability may not be a strong predictor in the development of alcohol use disorder.
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Consumo de Bebidas Alcohólicas , Alcoholismo , Cuerpo Estriado , Receptores de Dopamina D2 , Femenino , Humanos , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/metabolismo , Alcoholismo/diagnóstico por imagen , Alcoholismo/genética , Alcoholismo/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Etanol , Estudios Longitudinales , Tomografía de Emisión de Positrones/métodos , Racloprida/farmacología , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/metabolismo , Masculino , Adulto , Antagonistas de los Receptores de Dopamina D2/farmacología , Estudios de SeguimientoRESUMEN
Ten new indole alkaloids (1-10) as well as eleven known analogs (11-21) were isolated from the stems and hooks of Uncaria rhynchophylla. Their structure elucidation was based on extensive NMR studies, MS and ECD data, with the essential aid of DFT prediction of ECD spectra. Compound 1 was determined as a 17,19-seco-cadambine-type alkaloid, and compound 3 was confirmed to be a 3,4-seco-tricyclic monoterpene indole alkaloid, which are the first seco-alkaloids possessing such cleavage positions from U. rhynchophylla. All the isolated compounds were evaluated for their bioactivities on dopamine D2 and Mu opioid receptors for discovering natural therapeutic drugs targeting central nervous system (CNS) diseases. Compounds 1, 2, 4, 5, 20 and 21 showed antagonistic bioactivities on the D2 receptor (IC50 0.678-15.200 µM), and compounds 1, 3, 6, 9, 10, 13, 18, 19 and 21 exhibited antagonistic effects on the Mu receptor (IC50 2.243-32.200 µM). Among them, compounds 1 and 21 displayed dual-target activities. Compound 1 showed conspicuous antagonistic activity on D2 and Mu receptors with the IC50 values of 0.678 ± 0.182 µM and 13.520 ± 2.480 µM, respectively. Compound 21 displayed moderate antagonistic activity on the two receptors with the IC50 values at 15.200 ± 1.764 µM and 32.200 ± 5.695 µM, respectively.
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Antagonistas de los Receptores de Dopamina D2 , Alcaloides Indólicos , Uncaria , Alcaloides/química , Alcaloides/farmacología , Dopamina/metabolismo , Alcaloides Indólicos/farmacología , Alcaloides Indólicos/química , Receptores Opioides mu/antagonistas & inhibidores , Uncaria/química , Antagonistas de los Receptores de Dopamina D2/química , Antagonistas de los Receptores de Dopamina D2/farmacología , Antagonistas de Narcóticos/química , Antagonistas de Narcóticos/farmacologíaRESUMEN
Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or 'model-based' relative to habitual or 'model-free' behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.
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Dopamina , Antagonistas de Narcóticos , Humanos , Amisulprida , Voluntarios Sanos , Antagonistas de los Receptores de Dopamina D2/farmacología , Receptores OpioidesRESUMEN
Repeated methamphetamine exposure impairs reversal learning in laboratory animals and downregulates dopamine D2 receptor expression. In the present study, we tested the possibility that repeated exposure to the dopamine D2 antagonist, eticlopride, would increase D2 receptor expression, improve behavioral flexibility and restore behavioral flexibility that was disrupted by exposure to methamphetamine in rats. Male Sprague-Dawley rats received repeated daily pretreatment with the dopamine D2 antagonist, eticlopride (0.0 or 0.3 mg/kg/day, 14 days). Three days after the last treatment, whole brain (minus olfactory bulbs and cerebellum) dopamine D2 receptor expression was measured using flow cytometry in one group and reversal learning performance was measured in another group. Reversal learning was also measured in other groups prior to and after methamphetamine exposure (0.0 or 2.0 mg/kg, 4 injections, 2 h apart, 1 day) followed by repeated eticlopride (0.0 or 0.3 mg/kg, 14 days) treatment. Eticlopride treatment increased D2 receptor expression and improved reversal learning performance. Methamphetamine impaired reversal learning performance and eticlopride treatment reversed the deficit. These results suggest that repeated administration of eticlopride can restore behavioral flexibility and that upregulation of D2 receptors might be an effective adjunct to treatment of methamphetamine misuse.
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Metanfetamina , Animales , Dopamina/metabolismo , Antagonistas de los Receptores de Dopamina D2/farmacología , Masculino , Metanfetamina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/metabolismo , Salicilamidas/farmacologíaRESUMEN
Sex differences in cocaine-induced behaviors are well established. In rodents, females show enhanced locomotion to cocaine over multiple trials compared with males, a behavioral response known as sensitization. Estradiol enhances cocaine-induced sensitization in female rats by agonizing dopaminergic activity within the brain. In female quail, cocaine does not increase locomotion regardless of increased estradiol. A higher D2:D1 dopamine receptor ratio in quail compared with rodents may explain this sex and species difference. The goal of the present work was to investigate the role of D2 receptors in cocaine-induced locomotion and sensitization in Japanese quail and to determine whether a greater D2 receptor availability contributed to the lack of cocaine-induced sensitization in female quail found in previous studies. Male and female quail were administered 0, 0.03, 0.05, or 0.07 mg/kg of eticlopride (Eti) followed by 10 mg/kg of cocaine or saline then immediately placed in open-field chambers. Distance traveled was recorded for 30 min daily for 7 days. In female quail, cocaine-induced sensitization was observed with 0.03 or 0.05 mg/kg Eti, but not in cocaine-only females. In male quail, cocaine-induced sensitization was observed similar to previous research. However, Eti did not enhance cocaine-induced locomotion or produce sensitization in male quail. The D2 receptor likely mediates cocaine's motor stimulating effects in quail. In females, this effect is more pronounced. Since high D2 availability is protective against stimulant abuse, Japanese quail may be a useful model for investigating the role of the D2 receptor in cocaine addiction, but further research is needed.
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Cocaína , Animales , Conducta Animal , Cocaína/farmacología , Coturnix/fisiología , Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Estradiol/farmacología , Femenino , Masculino , Ratas , Receptores de Dopamina D1 , Receptores de Dopamina D2RESUMEN
Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive impairments stemming from DA blockade or deficiency is inconsistent. Given the predominance of D1 over D2 receptors (R) in the prefrontal cortex of primates, D1-R blockade should more strongly influence frontal executive function (including working memory), while D2-R blockade should impair processes more strongly associated with the dorsal striatum (including cognitive flexibility, and learning). To test how systemic DA blockade disrupts cognition, we administered D1-R and D2-R like antagonists to healthy monkeys while they performed a series of cognitive tasks. Two selective DA receptor antagonist drugs (SCH-23390 hydrochloride: D1/D5-R antagonist; or Eticlopride hydrochloride: D2/D3-R antagonist) or placebo (0.9% saline) were systemically administered. Four tasks were used: (1) 'visually guided reaching', to test response time and accuracy, (2) 'reversal learning', to test association learning and attention, (3) 'self-ordered sequential search' to test spatial working memory, and (4) 'delayed match to sample' to test object working memory. Increased reach response times and decreased motivation to work for liquid reward was observed with both the D1/D5-R and D2/D3-R antagonists at the maximum dosages that still enabled task performance. The D2/D3-R antagonist impaired performance in the reversal learning task, while object and spatial working memory performance was not consistently affected in the tested tasks for either drug. These results are consistent with the theory that systemic D2/D3-R antagonists preferentially influence striatum processes (cognitive flexibility) while systemic D1/D5-R administration is less detrimental to frontal executive function.
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Motivación , Receptores de Dopamina D1 , Animales , Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2/farmacología , Aprendizaje/fisiología , Primates , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2RESUMEN
Nitrous oxide (N2O) has a long history of abuse, but its abuse mechanism has not been clear yet. This research aimed at the possibility of mesolimbic dopaminergic system (MLDS) involved in the rewarding effect of N2O. In this work, the rewarding behavior of N2O in mice was evaluated using a typical gas-administered conditioned place preference (CPP) procedure. SCH 23390, a Dopamine D1 receptor (D1R) antagonist, and Haloperidol, a Dopamine D2 receptor (D2R) antagonist were administered during CPP to evaluate the role of dopamine receptors in the N2O-induced CPP. The accompanying changes in phosphorylation of extracellular signal-regulated kinase (ERK) in MLDS related brain regions, including the ventral tegmental area (VTA), caudate putamen (CPu), prefrontal cortex (PFC), and nucleus accumbens (NAc) were measured to assess the neural plasticity changes in the CPP mice by Western blot analysis. Results revealed that 60% N2O induced CPP in the gas-administered mice and promoted the ERK phosphorylation (p-ERK) in the NAc and CPu during the test session of the CPP test. Pretreatment of SCH 23390 (0.5 mg/kg) inhibited the acquisition of N2O-induced CPP and the enhanced p-ERK in NAc. It suggested that Dopamine D1 receptor may play an important role in the acquisition of N2O-induced CPP and the accompanied ERK activation in the NAc, which provide insight into the molecular mechanism in the rewarding properties of nitrous oxide.