RESUMEN
Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect-via ventral pallidium (VP)-pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects.
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Dopamina , Neuronas Dopaminérgicas , Motivación , Núcleo Accumbens , Recompensa , Estrés Psicológico , Animales , Masculino , Ratones , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Ratones Endogámicos C57BL , Motivación/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Estrés Psicológico/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
Rett syndrome (RTT) is an autism spectrum disorder caused by loss-of-function mutations in the methyl-CPG-binding protein 2 (Mecp2) gene. Frequent apneas and irregular breathing are prevalent in RTT, and also occur in rodent models of the disorder, including Mecp2Bird and Mecp2R168X mice. Sarizotan, a serotonin 5-HT1a and dopamine D2-like receptor agonist, reduces the incidence of apneas and irregular breathing in mouse models of RTT (Abdala et al., 2014). Targeting the 5HT1a receptor alone also improves respiration in RTT mice (Levitt et al., 2013). However, the contribution of D2-like receptors in correcting these respiratory disturbances remains untested. PAOPA, a dopamine D2-like receptor positive allosteric modulator, and quinpirole, a dopamine D2-like receptor orthosteric agonist, were used in conjunction with whole-body plethysmography to evaluate whether activation of D2-like receptors is sufficient to improve breathing disturbances in female heterozygous Mecp2Bird/+ and Mecp2R168X/+ mice. PAOPA did not significantly change apnea incidence or irregularity score in RTT mice. PAOPA also had no effect on the ventilatory response to hypercapnia (7â¯% CO2). In contrast, quinpirole reduced apnea incidence and irregularity scores and improved the hypercapnic ventilatory response in Mecp2R168X/+ and Mecp2Bird/+ mice, while also reducing respiratory rate. These results suggest that D2-like receptors could contribute to the positive effects of sarizotan in the correction of respiratory abnormalities in Rett syndrome. However, positive allosteric modulation of D2-like receptors alone was not sufficient to evoke these effects.
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Modelos Animales de Enfermedad , Agonistas de Dopamina , Proteína 2 de Unión a Metil-CpG , Quinpirol , Receptores de Dopamina D2 , Síndrome de Rett , Animales , Síndrome de Rett/tratamiento farmacológico , Síndrome de Rett/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/agonistas , Agonistas de Dopamina/farmacología , Femenino , Ratones , Quinpirol/farmacología , Proteína 2 de Unión a Metil-CpG/genética , Respiración/efectos de los fármacos , Ratones Transgénicos , Regulación Alostérica/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
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
Brexpiprazole is a new antipsychotic drug from the group of dopamine D2/D3 receptor partial agonists. It represents a development of the second-generation antipsychotics and is an important addition to the pharmacological treatment options for schizophrenia. The purpose of this article is to present, illustrated by the case of brexpiprazole, how advances in the pharmacological properties of new antipsychotics translate into improved results in the treatment of schizophrenia, not only in terms of symptom reduction, but also in terms of functional improvement. The ratio of activation to blocking of the D2/D3 receptor is lower for brexpiprazole than for aripiprazole and cariprazine, which may translate into a lower risk of akathisia. Brexpiprazole has also stronger antihistaminic activity, which is likely to be associated with a stronger sedative effect, a lower risk of akathisia, excessive agitation and insomnia. Brexpiprazole meets the traditional requirements for an antipsychotic drug's efficacy, i.e., compared to placebo, it brings a greater reduction in schizophrenia symptoms in short-term studies and prevents schizophrenia relapses in long-term follow-up. The highest antipsychotic efficacy was found with the highest registered dose (4 mg/day). In addition to reducing positive symptoms, brexpiprazole treatment also leads to a reduction in negative and depressive symptoms, as well as anxiety. It has also a positive effect on patients' social and personal functioning and quality of life. This action of the drug is in line with the expectations of patients and their families regarding effective treatment. It should not only reduce symptoms, but also enable a return to health, i.e., a state that, in addition to optimal health and a sense of psychological well-being, also makes it possible to maintain proper social relations.
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Antipsicóticos , Quinolonas , Esquizofrenia , Tiofenos , Humanos , Tiofenos/uso terapéutico , Tiofenos/efectos adversos , Tiofenos/farmacología , Quinolonas/uso terapéutico , Quinolonas/efectos adversos , Esquizofrenia/tratamiento farmacológico , Antipsicóticos/uso terapéutico , Antipsicóticos/efectos adversos , Resultado del Tratamiento , Agonistas de Dopamina/uso terapéutico , Agonistas de Dopamina/efectos adversos , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/efectos de los fármacosRESUMEN
The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals. The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus. Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP. Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation. Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation. These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D2Rs in the regulation of limbic information flow.
Asunto(s)
Prosencéfalo Basal , Agonistas de Dopamina , Relación Dosis-Respuesta a Droga , Microinyecciones , Quinpirol , Ratas Sprague-Dawley , Receptores de Dopamina D2 , Animales , Quinpirol/farmacología , Masculino , Prosencéfalo Basal/efectos de los fármacos , Prosencéfalo Basal/fisiología , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/efectos de los fármacos , Ratas , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiología , Estimulación Eléctrica , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/fisiologíaRESUMEN
Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors, including D2 (D2R) and D3 (D3R) receptors, remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analog of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.
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Bromocriptina , Agonistas de Dopamina , Receptores de Dopamina D2 , Transducción de Señal , Animales , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/agonistas , Bromocriptina/farmacología , Bromocriptina/uso terapéutico , Ratones , Transducción de Señal/efectos de los fármacos , Masculino , Agonistas de Dopamina/farmacología , Agonistas de Dopamina/uso terapéutico , Ratones Endogámicos C57BL , Resistencia a la Insulina/fisiología , Glucemia/metabolismo , Glucemia/efectos de los fármacos , Humanos , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/agonistasRESUMEN
A major effort of the pharmaceutical industry has been to identify and market drug treatments that are effective in ameliorating the symptoms of psychotic illness but without the limitations of the current treatments acting at dopamine D2 receptors. These limitations include the induction of a range of adverse effects, the inadequate treatment response of a substantial proportion of people with schizophrenia, and the generally poor response to negative and cognitive features of the disease. Recently introduced drug treatments have gone some way to avoiding the first of these, with a reduced propensity for weight gain, cardiovascular risk and extrapyramidal motor effects. Despite claims of some small improvements in negative symptoms, these drugs have not demonstrated substantial increases in efficacy. Of the drugs currently in development as antipsychotic agents, several are misleadingly described as having novel 'non-dopaminergic' mechanisms that may offer improvements in addressing the limitations of adverse effects and efficacy. It will be argued, using the trace amine-associated receptor 1 agonist as an example, that several of these new drugs still act primarily through modulation of dopaminergic neurotransmission and, in not addressing the primary pathology of schizophrenia, are therefore unlikely to have the much-needed improvements in efficacy required to address the unmet need associated with resistance to current treatments.
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Antipsicóticos , Receptores de Dopamina D2 , Receptores Acoplados a Proteínas G , Esquizofrenia , Humanos , Antipsicóticos/farmacología , Antipsicóticos/efectos adversos , Antipsicóticos/uso terapéutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Animales , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. RESULTS: Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. CONCLUSIONS: These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period.
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Bromocriptina , Agonistas de Dopamina , Ciclo Estral , Periodo Posparto , Ratas Wistar , Receptores de Dopamina D2 , Sueño , Animales , Bromocriptina/farmacología , Femenino , Periodo Posparto/efectos de los fármacos , Ratas , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacología , Ciclo Estral/efectos de los fármacos , Sueño/efectos de los fármacos , Vigilia/efectos de los fármacos , ProlactinaRESUMEN
BACKGROUND AND PURPOSE: Glial cell-derived neurotrophic factor (GDNF) maintains gut homeostasis. Dopamine promotes GDNF release in astrocytes. We investigated the regulation by dopamine of colonic GDNF secretion. EXPERIMENTAL APPROACH: D1 receptor knockout (D1 R-/- ) mice, adeno-associated viral 9-short hairpin RNA carrying D2 receptor (AAV9-shD2 R)-treated mice, 6-hydroxydopamine treated (6-OHDA) rats and primary enteric glial cells (EGCs) culture were used. Incubation fluid from colonic submucosal plexus and longitudinal muscle myenteric plexus were collected for GDNF and ACh measurements. KEY RESULTS: D2 receptor-immunoreactivity (IR), but not D1 receptor-IR, was observed on EGCs. Both D1 receptor-IR and D2 receptor-IR were co-localized on cholinergic neurons. Low concentrations of dopamine induced colonic GDNF secretion in a concentration-dependent manner, which was mimicked by the D1 receptor agonist SKF38393, inhibited by TTX and atropine and eliminated in D1 R-/- mice. SKF38393-induced colonic ACh release was absent in D1 R-/- mice. High concentrations of dopamine suppressed colonic GDNF secretion, which was mimicked by the D2 receptor agonist quinpirole, and absent in AAV-shD2 R-treated mice. Quinpirole decreased GDNF secretion by reducing intracellular Ca2+ levels in primary cultured EGCs. Carbachol ( ACh analogue) promoted the release of GDNF. Quinpirole inhibited colonic ACh release, which was eliminated in the AAV9-shD2 R-treated mice. 6-OHDA treated rats with low ACh and high dopamine content showed decreased GDNF content and increased mucosal permeability in the colon. CONCLUSION AND IMPLICATIONS: Low concentrations of dopamine promote colonic GDNF secretion via D1 receptors on cholinergic neurons, whereas high concentrations of dopamine inhibit GDNF secretion via D2 receptors on EGCs and/or cholinergic neurons.
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Dopamina , Factor Neurotrófico Derivado de la Línea Celular Glial , Ratas , Ratones , Animales , Dopamina/metabolismo , Quinpirol , Oxidopamina , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Receptores de Dopamina D1 , Receptores de Dopamina D2/agonistas , ColinérgicosRESUMEN
BACKGROUND: JX11502MA is a potent partial agonist of dopamine D2 and D3 receptors, with a preferential binding profile for D3 receptors in vitro, potentially for treating schizophrenia. METHODS: A first-in-human, randomized, double-blind, placebo-controlled, single ascending dose clinical trial was designed. The subjects were randomly assigned to receive JX11502MA and placebo capsules with seven ascending dose groups: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 6 mg, and 8 mg. The PK profiles of JX11502MA and its metabolites were evaluated, along with a safety and tolerability assessment. RESULTS: Considering the safety of participants, the dose escalation was halted at 3 mg. Following single-dose administration, JX11502MA exhibited rapid absorption with a median Tmax ranging from 1 to 1.75 h. The terminal half-life of JX11502MA ranged from 73.62 to 276.85 h. The most common treatment-emergent adverse events (TEAEs) for subjects receiving JX11502MA were somnolence (56.3%), dizziness (18.8%), nausea (21.9%), vomiting (18.8%), and hiccups (18.8%). CONCLUSIONS: JX11502MA was generally well tolerated at a single dose of 0.25 to 3 mg. The PK profiles and safety characteristics in this study indicated that JX11502MA has the potential to be a favorable treatment option for patients with schizophrenia. TRIAL REGISTRATION: https://clinicaltrials.gov (identifier: NCT05233657).
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Receptores de Dopamina D2 , Receptores de Dopamina D3 , Humanos , Área Bajo la Curva , China , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Pueblos del Este de Asia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistasRESUMEN
INTRODUCTION: Comorbidity of substance use disorder (SUD) with schizophrenia, referred to as dual disorder (DD), significantly increases morbidity and mortality compared to schizophrenia alone. A dopaminergic dysregulation seems to be a common pathophysiological basis of the comorbidity. AREAS COVERED: This article reports the current evidence on the role of dopamine dysregulations in DD, the pharmacological profile of cariprazine, a partial agonist of D3 and D2 dopamine receptors, and first clinical observations that may support its usefulness in the therapy of DD. PubMed/MEDLINE was searched for the keywords 'cariprazine,' 'schizophrenia,' 'dual disorder,' 'dopamine,' and 'dopamine receptor.' Preclinical and clinical studies, and reviews published in English were retrieved. EXPERT OPINION: Although the management of DD remains challenging, and the evidence for pharmacologic treatments is still unsatisfactory, cariprazine may be a candidate medication in DD due to its unique mechanism of action. Preliminary clinical experiences suggest that cariprazine has both antipsychotic and anticraving properties and should be considered early in patients with DD.
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Esquizofrenia , Trastornos Relacionados con Sustancias , Humanos , Esquizofrenia/tratamiento farmacológico , Dopamina/uso terapéutico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/uso terapéutico , Receptores de Dopamina D2/agonistas , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/tratamiento farmacológicoRESUMEN
D3 receptors, a key component of the dopamine system, have emerged as a potential target of therapies to improve motor symptoms across neurodegenerative and neuropsychiatric conditions. In the present work, we evaluated the effect of D3 receptor activation on the involuntary head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) at behavioral and electrophysiological levels. Mice received an intraperitoneal injection of either a full D3 agonist, WC 44 [4-(2-fluoroethyl)-N-[4-[4-(2-methoxyphenyl)piperazin 1-yl]butyl]benzamide] or a partial D3 agonist, WW-III-55 [N-(4-(4-(4-methoxyphenyl)piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamide] five minutes before the intraperitoneal administration of DOI. Compared to the control group, both D3 agonists delayed the onset of the DOI-induced head-twitch response and reduced the total number and frequency of the head twitches. Moreover, the simultaneous recording of neuronal activity in the motor cortex (M1) and dorsal striatum (DS) indicated that D3 activation led to slight changes in a single unit activity, mainly in DS, and increased its correlated firing in DS or between presumed cortical pyramidal neurons (CPNs) and striatal medium spiny neurons (MSNs). Our results confirm the role of D3 receptor activation in controlling DOI-induced involuntary movements and suggest that this effect involves, at least in part, an increase in correlated corticostriatal activity. A further understanding of the underlying mechanisms may provide a suitable target for treating neuropathologies in which involuntary movements occur.
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Discinesias , Receptores de Dopamina D3 , Ratones , Animales , Receptores de Dopamina D2/agonistas , Benzamidas/farmacología , Receptores de Dopamina D1RESUMEN
Designed ligands of G protein-coupled receptors can exert a spectrum of modulating effects, varying from full agonists and partial agonists to antagonists and inverse agonists. For the dopamine D2 receptor (D2R), partial agonist activity is the pharmacological feature of the third-generation antipsychotics, including aripiprazole, brexpiprazole, and cariprazine. Started from a benzofuran-derived D2R full agonist O4LE6 (4), which was identified using a structure-based method by us in previous studies, a series of D2R partial agonists were designed and synthesized by introducing different tail groups. Among them, compound 10b showed excellent activity in D2R pharmacological assays. Further optimizations using a structural rigidification approach led to the discovery of brain-penetrant compounds 29c and 29d, which exhibited potent antipsychotic effects in the mouse hyperlocomotion model. Compound 29c also showed excellent drug-like pharmacokinetic properties in rats and qualifies as an antipsychotic agent that is worth further evaluations.
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Antipsicóticos , Ratones , Ratas , Animales , Antipsicóticos/farmacología , Agonistas de Dopamina/farmacología , Dopamina , Agonismo Inverso de Drogas , Receptores de Dopamina D2/agonistasRESUMEN
Parkinson's disease (PD) is a chronic neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the striatum, leading to dopamine (DA) deficiency in the striatum and typical motor symptoms. A small molecule as a dietary supplement for PD would be ideal for practical reasons. Hordenine (HOR) is a phenolic phytochemical marketed as a dietary supplement found in cereals and germinated barley, as well as in beer, a widely consumed beverage. This study was aimed to identify HOR as a dopamine D2 receptor (DRD2) agonist in living cells, and investigate the alleviative effect and mechanism of HOR on PD-like motor deficits in mice and nematodes. Our results firstly showed that HOR is an agonist of DRD2, but not DRD1, in living cells. Moreover, HOR could improve the locomotor dysfunction, gait, and postural imbalance in MPTP- or 6-OHDA-induced mice or Caenorhabditis elegans, and prevent α-synuclein accumulation via the DRD2 pathway in C. elegans. Our results suggested that HOR could activate DRD2 to attenuate the PD-like motor deficits, and provide scientific evidence for the safety and reliability of HOR as a dietary supplement.
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Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Ratones , Animales , Dopamina/metabolismo , Caenorhabditis elegans/metabolismo , Reproducibilidad de los Resultados , Enfermedad de Parkinson/tratamiento farmacológico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Neuronas Dopaminérgicas , Ratones Endogámicos C57BL , Modelos Animales de EnfermedadRESUMEN
Dopamine is a biologically active amine synthesized in the central and peripheral nervous system. This biogenic monoamine acts by activating five types of dopamine receptors (D1-5 Rs), which belong to the G protein-coupled receptor family. Antagonists and partial agonists of D2 Rs are used to treat schizophrenia, Parkinson's disease, depression, and anxiety. The typical pharmacophore with high D2 R affinity comprises four main areas, namely aromatic moiety, cyclic amine, central linker and aromatic/heteroaromatic lipophilic fragment. From the literature reviewed herein, we can conclude that 4-(2,3-dichlorophenyl), 4-(2-methoxyphenyl)-, 4-(benzo[b]thiophen-4-yl)-1-substituted piperazine, and 4-(6-fluorobenzo[d]isoxazol-3-yl)piperidine moieties are critical for high D2 R affinity. Four to six atoms chains are optimal for D2 R affinity with 4-butoxyl as the most pronounced one. The bicyclic aromatic/heteroaromatic systems are most frequently occurring as lipophilic appendages to retain high D2 R affinity. In this review, we provide a thorough overview of the therapeutic potential of D2 R modulators in the treatment of the aforementioned disorders. In addition, this review summarizes current knowledge about these diseases, with a focus on the dopaminergic pathway underlying these pathologies. Major attention is paid to the structure, function, and pharmacology of novel D2 R ligands, which have been developed in the last decade (2010-2021), and belong to the 1,4-disubstituted aromatic cyclic amine group. Due to the abundance of data, allosteric D2 R ligands and D2 R modulators from patents are not discussed in this review.
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Dopamina , Receptores de Dopamina D2 , Humanos , Dopamina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Ligandos , Receptores Acoplados a Proteínas GRESUMEN
Leveraging biased signaling of G protein-coupled receptors has been proposed as a promising strategy for the development of drugs with higher specificity. However, the consequences of selectively targeting G protein- or ß-arrestin-mediated signaling on cellular functions are not comprehensively understood. In this study, we utilized phosphoproteomics to gain a systematic overview of signaling induced by the four biased and balanced dopamine D2 receptor (D2R) ligands MS308, BM138, quinpirole, and sulpiride in an in vitro D2R transfection model. Quantification of 14,160 phosphosites revealed a low impact of the partial G protein agonist MS308 on cellular protein phosphorylation, as well as surprising similarities between the balanced agonist quinpirole and the inverse agonist sulpiride. Analysis of the temporal profiles of ligand-induced phosphorylation events showed a transient impact of the G protein-selective agonist MS308, whereas the ß-arrestin-preferring agonist BM138 elicited a delayed, but more pronounced response. Functional enrichment analysis of ligand-impacted phosphoproteins and treatment-linked kinases confirmed multiple known functions of D2R signaling while also revealing novel effects, for example of MS308 on sterol regulatory element-binding protein-related gene expression. All raw data were deposited in MassIVE (MSV000089457).
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Agonismo Inverso de Drogas , Sulpirida , beta-Arrestinas/metabolismo , Quinpirol , Ligandos , Proteínas de Unión al GTP/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismoRESUMEN
The mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to display antiproliferative effects on a wide spectrum of tumors. In vitro studies demonstrated that everolimus inhibited pituitary neuroendocrine tumor (PitNET) cell growth in a subset of patients. Sensitivity to everolimus is reduced by an escape mechanism that increases AKT phosphorylation (p-AKT), leading to pro-survival pathway activation. Dopamine receptor type 2 (DRD2) mediates a reduction of p-AKT in a subgroup of non-functioning PitNETs (NF-PitNETs) and in prolactin-secreting tumor cells (MMQ cells) through a ß-arrestin 2-dependent mechanism. The aim of this study was to investigate the efficacy of everolimus combined with DRD2 agonist cabergoline in reducing NF-PitNET primary cells and MMQ cell proliferation and to evaluate AKT phosphorylation and a possible role of ß-arrestin 2. We found that 9 out of 14 NF-PitNETs were resistant to everolimus, but the combined treatment with cabergoline inhibited cell proliferation in 7 out of 9 tumors (-31.4 ± 9.9%, p < 0.001 vs. basal) and reduced cyclin D3 expression. In the everolimus-unresponsive NF-PitNET group, everolimus determined a significant increase of p-AKT/total-AKT ratio (2.1-fold, p < 0.01, vs. basal) that was reverted by cabergoline cotreatment. To investigate the molecular mechanism involved, we used MMQ cells as a model of everolimus escape mechanism. Indeed everolimus did not affect MMQ cell proliferation and increased the p-AKT/total-AKT ratio (+1.53 ± 0.24-fold, p < 0.001 vs. basal), whereas cabergoline significantly reduced cell proliferation (-22.8 ± 6.8%, p < 0.001 vs. basal) and p-AKT. The combined treatment of everolimus and cabergoline induced a reduction of both cell proliferation (-34.8 ± 18%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone) and p-AKT/total-AKT ratio (-34.5 ± 14%, p < 0.001 vs. basal and p < 0.05 vs. cabergoline alone). To test ß-arrestin 2 involvement, silencing experiments were performed in MMQ cells. Our data showed that the lack of ß-arrestin 2 prevented the everolimus and cabergoline cotreatment inhibitory effects on both p-AKT and cell proliferation. In conclusion, this study revealed that cabergoline might overcome the everolimus escape mechanism in NF-PitNETs and tumoral lactotrophs by inhibiting upstream AKT activation. The co-administration of cabergoline might improve mTOR inhibitor antitumoral activity, paving the way for a potential combined therapy in ß-arrestin 2-expressing NF-PitNETs or other PitNETs resistant to conventional treatments.
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Cabergolina , Everolimus , Tumores Neuroendocrinos , Neoplasias Hipofisarias , Receptores de Dopamina D2 , Serina-Treonina Quinasas TOR , Cabergolina/farmacología , Interacciones Farmacológicas , Everolimus/farmacología , Humanos , Tumores Neuroendocrinos/tratamiento farmacológico , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/patología , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/metabolismo , Arrestina beta 2/metabolismoRESUMEN
In vivo administration of dopamine (DA) receptor (DR)-related drugs modulate gastric pepsinogen secretion. However, DRs on gastric pepsinogen-secreting chief cells and DA D2 receptor (D2R) on somatostatin-secreting D cells were subsequently acquired. In this study, we aimed to further investigate the local effect of DA on gastric pepsinogen secretion through DRs expressed on chief cells or potential D2Rs expressed on D cells. To elucidate the modulation of DRs in gastric pepsinogen secretion, immunofluorescence staining, ex vivo incubation of gastric mucosa isolated from normal and D2R-/- mice were conducted, accompanied by measurements of pepsinogen or somatostatin levels using biochemical assays or enzyme-linked immunosorbent assays. D1R, D2R, and D5R-immunoreactivity (IR) were observed on chief cells in mouse gastric mucosa. D2R-IR was widely distributed on D cells from the corpus to the antrum. Ex vivo incubation results showed that DA and the D1-like receptor agonist SKF38393 increased pepsinogen secretion, which was blocked by the D1-like receptor antagonist SCH23390. However, D2-like receptor agonist quinpirole also significantly increased pepsinogen secretion, and D2-like receptor antagonist sulpiride blocked the promotion of DA. Besides, D2-like receptors exerted an inhibitory effect on somatostatin secretion, in contrast to their effect on pepsinogen secretion. Furthermore, D2R-/- mice showed much lower basal pepsinogen secretion but significantly increased somatostatin release and an increased number of D cells in gastric mucosa. Only SKF38393, not quinpirole, increased pepsinogen secretion in D2R-/- mice. DA promotes gastric pepsinogen secretion directly through D1-like receptors on chief cells and indirectly through D2R-mediated suppression of somatostatin release.
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Células Principales Gástricas/efectos de los fármacos , Agonistas de Dopamina/farmacología , Pepsinógeno A/metabolismo , Quinpirol/farmacología , Receptores de Dopamina D2/agonistas , Células Secretoras de Somatostatina/efectos de los fármacos , Somatostatina/metabolismo , Animales , Células Principales Gástricas/metabolismo , Antagonistas de Dopamina/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Vías Secretoras , Células Secretoras de Somatostatina/metabolismoRESUMEN
INTRODUCTION: Brain imaging studies have highlighted that the density of dopamine D2 receptors markedly fluctuates across the stages of Parkinson's disease and in response to pharmacological treatment. Moreover, receptor density constitutes a molecular determinant for the signaling profile of D2 receptor ligands. We therefore hypothesized that variations in receptor expression could influence D2 receptor response to antiparkinsonian drugs, most notably with respect to the recruitment bias between Gi1 and ß-arrestin2. METHODS: The recruitment bias of dopamine, pramipexole, ropinirole, and rotigotine was examined using a nanoluciferase-based biosensor for probing the interactions of the D2L receptor with either Gi1 or ß-arrestin2. The characterization of the functional selectivity of these D2 receptor agonists was performed at two distinct D2L receptor densities by taking advantage of a cell model carrying an inducible system that enables the overexpression of the D2L receptor when exposed to doxycycline. RESULTS: A high receptor density oriented the balanced signaling profile of dopamine towards a preferential recruitment of Gi1. It also moderated the marked Gi1 and ß-arrestin2 biases of pramipexole and rotigotine, respectively. At variance, the Gi1 bias of ropinirole appeared as not being influenced by D2L receptor density. CONCLUSIONS: Taken together, these observations highlight receptor density as a key driver of the signaling transducer recruitment triggered by antiparkinsonian agents. Moreover, given the putative beneficial properties of ß-arrestin2 in promoting locomotion, this study provides molecular insights that position the arrestin-biased ligand rotigotine as a putatively more beneficial D2 receptor agonist for the treatment of early and late Parkinson's disease.
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Antiparkinsonianos/farmacología , Agonistas de Dopamina/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/efectos de los fármacos , Arrestina beta 2/efectos de los fármacos , Técnicas Biosensibles , Dopamina/farmacología , Humanos , Indoles/farmacología , Luciferasas , Pramipexol/farmacología , Receptores de Dopamina D2/agonistas , Tetrahidronaftalenos/farmacología , Tiofenos/farmacologíaRESUMEN
Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the "D1/D2-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.