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1.
Curr Biol ; 32(15): R817-R824, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35944478

RESUMO

Dopamine was first described by George Barger, James Ewens, and Henry Dale in 1910 as an epinephrine-like monoamine compound. Initially believed to be a mere precursor of norepinephrine, it was mostly ignored for the next four decades (Figure 1A). However, in the 1950s Kathleen Montagu showed that dopamine occurred in the brain by itself, and a series of studies by Arvid Carlsson and collaborators demonstrated that dopamine is a bona fide neurotransmitter, a finding that would earn Carlsson the 2000 Nobel Prize in Physiology and Medicine. In a landmark experiment, he pharmacologically blocked all dopamine neurotransmission in rabbits, which rendered them completely paralyzed, and then fully recovered their behavior with an injection of the dopamine precursor L-DOPA, demonstrating that dopamine was essential for self-initiated movement (Figure 1B). A similar effect was quickly reproduced by Oleg Hornykiewicz and collaborators in human Parkinsonian patients. Within a few years, dopamine jumped from relative obscurity to being critical for life as we know it.


Assuntos
Dopamina , Prêmio Nobel , Animais , Encéfalo/fisiologia , Dopamina/fisiologia , Epinefrina , Humanos , Levodopa , Masculino , Coelhos , Transmissão Sináptica
2.
Proc Natl Acad Sci U S A ; 119(33): e2117903119, 2022 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-35939697

RESUMO

Dopamine D1 receptors (D1Rs) in the hippocampal dentate gyrus (DG) are essential for antidepressant effects. However, the midbrain dopaminergic neurons, the major source of dopamine in the brain, only sparsely project to DG, suggesting possible activation of DG D1Rs by endogenous substances other than dopamine. We have examined this possibility using electrophysiological and biochemical techniques and found robust activation of D1Rs in mouse DG neurons by noradrenaline. Noradrenaline at the micromolar range potentiated synaptic transmission at the DG output and increased the phosphorylation of protein kinase A substrates in DG via activation of D1Rs and ß adrenergic receptors. Neuronal excitation preferentially enhanced noradrenaline-induced synaptic potentiation mediated by D1Rs with minor effects on ß-receptor-dependent potentiation. Increased voluntary exercise by wheel running also enhanced noradrenaline-induced, D1R-mediated synaptic potentiation, suggesting a distinct functional role of the noradrenaline-D1R signaling. We then examined the role of this signaling in antidepressant effects using mice exposed to chronic restraint stress. In the stressed mice, an antidepressant acting on the noradrenergic system induced a mature-to-immature change in the DG neuron phenotype, a previously proposed cellular substrate for antidepressant action. This effect was evident only in mice subjected to wheel running and blocked by a D1R antagonist. These results suggest a critical role of noradrenaline-induced activation of D1Rs in antidepressant effects in DG. Experience-dependent regulation of noradrenaline-D1R signaling may determine responsiveness to antidepressant drugs in depressive disorders.


Assuntos
Dopamina , Norepinefrina , Animais , Antidepressivos/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipocampo/metabolismo , Camundongos , Atividade Motora , Norepinefrina/metabolismo , Norepinefrina/farmacologia , Receptores de Dopamina D1/metabolismo
3.
Reprod Biol Endocrinol ; 20(1): 112, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35927731

RESUMO

BACKGROUND: Three primary monoamines-serotonin, norepinephrine, and dopamine-play major roles in the placenta-fetal brain axis. Analogously to the brain, the placenta has transport mechanisms that actively take up these monoamines into trophoblast cells. These transporters are known to play important roles in the differentiated syncytiotrophoblast layer, but their status and activities in the undifferentiated, progenitor cytotrophoblast cells are not well understood. Thus, we have explored the cellular handling and regulation of monoamine transporters during the phenotypic transitioning of cytotrophoblasts along the villous pathway. METHODS: Experiments were conducted with two cellular models of syncytium development: primary trophoblast cells isolated from the human term placenta (PHT), and the choriocarcinoma-derived BeWo cell line. The gene and protein expression of membrane transporters for serotonin (SERT), norepinephrine (NET), dopamine (DAT), and organic cation transporter 3 (OCT3) was determined by quantitative PCR and Western blot analysis, respectively. Subsequently, the effect of trophoblast differentiation on transporter activity was analyzed by monoamine uptake into cells. RESULTS: We present multiple lines of evidence of changes in the transcriptional and functional regulation of monoamine transporters associated with trophoblast differentiation. These include enhancement of SERT and DAT gene and protein expression in BeWo cells. On the other hand, in PHT cells we report negative modulation of SERT, NET, and OCT3 protein expression. We show that OCT3 is the dominant monoamine transporter in PHT cells, and its main functional impact is on serotonin uptake, while passive transport strongly contributes to norepinephrine and dopamine uptake. Further, we show that a wide range of selective serotonin reuptake inhibitors affect serotonin cellular accumulation, at pharmacologically relevant drug concentrations, via their action on both OCT3 and SERT. Finally, we demonstrate that BeWo cells do not well reflect the molecular mechanisms and properties of healthy human trophoblast cells. CONCLUSIONS: Collectively, our findings provide insights into the regulation of monoamine transport during trophoblast differentiation and present important considerations regarding appropriate in vitro models for studying monoamine regulation in the placenta.


Assuntos
Serotonina , Trofoblastos , Dopamina/metabolismo , Feminino , Humanos , Norepinefrina/farmacologia , Placenta/metabolismo , Gravidez , Serotonina/metabolismo , Serotonina/farmacologia , Trofoblastos/metabolismo
4.
Biomater Adv ; 136: 212775, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35929293

RESUMO

Atherosclerosis (AS), the formation of plaque lesions in the walls of arteries, causes many mortalities and morbidities worldwide. Currently, achieving site-specific delivery and controlled release at plaques is difficult. Herein, we implemented the strategy of constructing a bionic multifunctional nanoplatform (BM-NP) for targeting and improving plaques. BM-NPs were prepared based on probucol-loaded mesoporous polydopamine (MPDA) carriers and were coated with platelet membranes to impart bionic properties. In vitro experiments confirmed that BM-NPs, which respond to near-infrared (NIR) for drug release, remove reactive oxygen species (ROS), thereby reducing the level of oxidized low-density lipoprotein (ox-LDL) and ultimately helping to inhibit macrophage foaming. In vivo experiments proved that BM-NPs actively accumulated in plaques in the mouse right carotid artery (RCA) ligation model. During treatment, BM-NPs with NIR laser irradiation more effectively reduced the area of plaque deposition and slowed the thickening of the arterial wall intima. More importantly, BM-NPs showed the advantage of inhibiting the increase in triglyceride (TG) content in the body, and good biocompatibility. Hence, our research results indicate that intelligent BM-NPs can be used as a potential nanotherapy to precisely and synergistically improve AS.


Assuntos
Aterosclerose , Nanopartículas , Placa Aterosclerótica , Animais , Aterosclerose/tratamento farmacológico , Dopamina/uso terapêutico , Liberação Controlada de Fármacos , Camundongos , Nanopartículas/uso terapêutico , Placa Aterosclerótica/tratamento farmacológico , Espécies Reativas de Oxigênio/uso terapêutico
5.
Philos Trans R Soc Lond B Biol Sci ; 377(1860): 20210295, 2022 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-35934969

RESUMO

Primate social bonds are described as being especially complex in their nature, and primates have unusually large brains for their body size compared to other mammals. Communication in primates has attracted considerable attention because of the important role it plays in social bonding. It has been proposed that differentiated social relationships are cognitively complex because primates need to continuously update their knowledge about different types of social bonds. Therefore, primates infer whether an opportunity for social interaction is rewarding (valuable to individual goals) based on their knowledge of the social relationships of the interactants. However, exposure to distraction and stress has detrimental effects on the dopaminergic system, suggesting that understanding social relationships as rewarding is affected in these conditions. This paper proposes that complex communication evolved to augment the capacity to form social relationships during stress through flexibly modifying intentionality in communication (audience checking, response waiting and elaboration). Intentional communication may upregulate dopamine dynamics to allow recognition that an interaction is rewarding during stress. By examining these associations between complexity of communication and stress, we provide new insights into the cognitive skills involved in forming social bonds in primates and the evolution of communication systems in both primates and humans. This article is part of the theme issue 'Cognition, communication and social bonds in primates'.


Assuntos
Cognição , Comportamento Social , Animais , Encéfalo/fisiologia , Comunicação , Dopamina , Humanos , Mamíferos , Primatas/psicologia
6.
Adv Exp Med Biol ; 1400: 65-73, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35930226

RESUMO

Treating schizophrenia is a challenge currently handled with the use of antipsychotic drugs. Despite being the most applied treatment strategy, current antipsychotics present severe limitations and side effects which impact patients' health and quality of life. For instance, although these drugs target mainly the dopamine system, they present target promiscuity and work by distinct mechanisms of action. As a consequence, complete comprehension of their pharmacological properties remains elusive. This chapter highlights research from the past 5 years that contributed to our current understanding of the mechanism of action and molecular features triggered by antipsychotic drugs in brain cells. In addition, we briefly discuss potential new therapeutic targets and strategies to treat schizophrenia.


Assuntos
Antipsicóticos , Esquizofrenia , Antipsicóticos/efeitos adversos , Encéfalo , Dopamina/química , Humanos , Qualidade de Vida , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico
7.
Adv Exp Med Biol ; 1400: 15-33, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35930223

RESUMO

Schizophrenia is a complex and heterogeneous neurodevelopmental psychiatric disorder characterized by a variety of symptoms classically grouped into three main domains: positive (hallucinations, delusions, and thought disorder) and negative symptoms (social withdrawal, lack of affect) and cognitive dysfunction (attention, working and episodic memory functions, and processing speed). This disorder places an immense emotional and economic pressure on the individual and society-at-large. Although the etiology of schizophrenia is not completely known, it is proposed to involve abnormalities in neurodevelopmental processes and dysregulation in the signaling mediated by several neurotransmitters, such as dopamine, glutamate, and GABA. Preclinical research using animal models are essential in our understanding of disease development and pathology as well as the discovery and advance of novel treatment choices. Here we describe rodent models for studying schizophrenia, including those based on the effects of drugs (pharmacological models), neurodevelopmental disruption, demyelination, and genetic alterations. The advantages and limitations of such models are highlighted. We also discussed the great potential of proteomic technologies in unraveling the molecular mechanism of schizophrenia through animal models.


Assuntos
Esquizofrenia , Animais , Atenção , Modelos Animais de Doenças , Dopamina/química , Humanos , Modelos Animais , Proteômica , Esquizofrenia/diagnóstico
8.
PLoS One ; 17(8): e0271697, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35917331

RESUMO

Simultaneous imaging of l-dihydroxyphenylalanine (l-DOPA), dopamine (DA) and norepinephrine (NE) in the catecholamine metabolic pathway is particularly useful because l-DOPA is a neurophysiologically important metabolic intermediate. In this study, we found that 2,4,6-trimethylpyrillium tetrafluoroborate (TMPy) can selectively and efficiently react with target catecholamine molecules. Specifically, simultaneous visualization of DA and NE as metabolites of l-DOPA with high steric hinderance was achieved by derivatized-imaging mass spectrometry (IMS). Interestingly, l-DOPA showed strong localization in the brainstem, in contrast to the pattern of DA and NE, which co-localized with tyrosine hydroxylase (TH). In addition, to identify whether the detected molecules were endogenous or exogenous l-DOPA, mice were injected with l-DOPA deuterated in three positions (D3-l-DOPA), which was identifiable by a mass shift of 3Da. TMPy-labeled l-DOPA, DA and NE were detected at m/z 302.1, 258.1 and 274.1, while their D3 versions were detected at 305.0, 261.1 and 277.1 in mouse brain, respectively. l-DOPA and D3-l-DOPA were localized in the BS. DA and NE, and D3-DA and D3-NE, all of which are metabolites of L-DOPA and D3-l-DOPA, were localized in the striatum (STR) and locus coeruleus (LC). These findings suggest a mechanism in the brainstem that allows l-DOPA to accumulate without being metabolized to monoamines downstream of the metabolic pathway.


Assuntos
Dopamina , Levodopa , Animais , Catecolaminas , Dopamina/metabolismo , Espectrometria de Massas , Camundongos , Norepinefrina/metabolismo
9.
Transl Psychiatry ; 12(1): 309, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922402

RESUMO

Dopamine dysfunction has been associated with depression. However, results of recent neuroimaging studies on dopamine transporter (DAT), which reflect the function of the dopaminergic system, are inconclusive. The aim of this study was to apply texture analysis, a novel method to extract information about the textural properties of images (e.g., coarseness), to single-photon emission computed tomography (SPECT) imaging in depression. We performed SPECT using 123I-ioflupane to measure DAT binding in 150 patients with major depressive disorder (N = 112) and bipolar disorder (N = 38). The texture features of DAT binding in subregions of the striatum were calculated. We evaluated the relationship between the texture feature values (coarseness, contrast, and busyness) and severity of depression, and then examined the effects of medication and diagnosis on such relationship. Furthermore, using the data from 40 healthy subjects, we examined the effects of age and sex on the texture feature values. The degree of busyness of the limbic region in the left striatum linked to the severity of depression (p = 0.0025). The post-hoc analysis revealed that this texture feature value was significantly higher in both the severe and non-severe depression groups than in the remission group (p = 0.001 and p = 0.028, respectively). This finding remained consistent after considering the effect of medication. The effects of age and sex in healthy individuals were not evident in this texture feature value. Our findings imply that the application of texture analysis to DAT-SPECT may provide a state-marker of depression.


Assuntos
Transtorno Depressivo Maior , Proteínas da Membrana Plasmática de Transporte de Dopamina , Depressão/diagnóstico por imagem , Transtorno Depressivo Maior/diagnóstico por imagem , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Humanos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
10.
Elife ; 112022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35786443

RESUMO

Chemical neurotransmission constitutes one of the fundamental modalities of communication between neurons. Monitoring release of these chemicals has traditionally been difficult to carry out at spatial and temporal scales relevant to neuron function. To understand chemical neurotransmission more fully, we need to improve the spatial and temporal resolutions of measurements for neurotransmitter release. To address this, we engineered a chemi-sensitive, two-dimensional composite nanofilm that facilitates visualization of the release and diffusion of the neurochemical dopamine with synaptic resolution, quantal sensitivity, and simultaneously from hundreds of release sites. Using this technology, we were able to monitor the spatiotemporal dynamics of dopamine release in dendritic processes, a poorly understood phenomenon. We found that dopamine release is broadcast from a subset of dendritic processes as hotspots that have a mean spatial spread of ≈ 3.2 µm (full width at half maximum [FWHM]) and are observed with a mean spatial frequency of one hotspot per ≈ 7.5 µm of dendritic length. Major dendrites of dopamine neurons and fine dendritic processes, as well as dendritic arbors and dendrites with no apparent varicose morphology participated in dopamine release. Remarkably, these release hotspots co-localized with Bassoon, suggesting that Bassoon may contribute to organizing active zones in dendrites, similar to its role in axon terminals.


To form the vast and complex network necessary for an organism to sense and react to the world, neurons must connect at highly specialized junctions. Individual cells communicate at these 'synapses' by releasing chemical signals (or neurotransmitters) such as dopamine, a molecule involved in learning and motivation. Despite the central role that synapses play in the brain, it remains challenging to measure exactly where neurotransmitters are released and how far they travel from their release site. Currently, most tools available to scientists only allow bulk measurements of neurotransmitter release. To tackle this limitation, Bulumulla et al. developed a new way to measure neurotransmitter release from neurons, harnessing a technique which uses fluorescent nanosensors that glow brighter when exposed to dopamine. These sensors form a very thin film upon which neurons can grow; when the cells release dopamine, the sensors 'light up' as they encounter the molecule. Dubbed DopaFilm, the technology reveals exactly where the neurotransmitter comes from and how it spreads between cells in real time. In particular, the approach showed that dopamine emerges from 'hot spots' at specific sites in cells; it also helped Bulumulla et al. study how dopamine is released from subcellular compartments that have previously not been well characterized. Improving the sensors so that the film could detect other neurotransmitters besides dopamine would broaden the use of this approach. In the future, combining this technology with other types of imaging should enable studies of individual synapses with intricate detail.


Assuntos
Dopamina , Transmissão Sináptica , Neurônios Dopaminérgicos , Terminações Pré-Sinápticas , Transmissão Sináptica/fisiologia
11.
Elife ; 112022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35856493

RESUMO

In the striatum, acetylcholine (ACh) neuron activity is modulated co-incident with dopamine (DA) release in response to unpredicted rewards and reward-predicting cues and both neuromodulators are thought to regulate each other. While this co-regulation has been studied using stimulation studies, the existence of this mutual regulation in vivo during natural behavior is still largely unexplored. One long-standing controversy has been whether striatal DA is responsible for the induction of the cholinergic pause or whether DA D2 receptors (D2Rs) modulate a pause that is induced by other mechanisms. Here, we used genetically encoded sensors in combination with pharmacological and genetic inactivation of D2Rs from cholinergic interneurons (CINs) to simultaneously measure ACh and DA levels after CIN D2R inactivation in mice. We found that CIN D2Rs are not necessary for the initiation of cue-induced decrease in ACh levels. Rather, they prolong the duration of the decrease and inhibit ACh rebound levels. Notably, the change in cue-evoked ACh levels is not associated with altered cue-evoked DA release. Moreover, D2R inactivation strongly decreased the temporal correlation between DA and ACh signals not only at cue presentation but also during the intertrial interval pointing to a general mechanism by which D2Rs coordinate both signals. At the behavioral level D2R antagonism increased the latency to lever press, which was not observed in CIN-selective D2R knock out mice. Press latency correlated with the cue-evoked decrease in ACh levels and artificial inhibition of CINs revealed that longer inhibition shortens the latency to press compared to shorter inhibition. This supports a role of the ACh signal and it's regulation by D2Rs in the motivation to initiate actions.


Assuntos
Acetilcolina , Receptores de Dopamina D2 , Animais , Colinérgicos , Corpo Estriado/metabolismo , Sinais (Psicologia) , Dopamina , Camundongos , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo
12.
Biomolecules ; 12(7)2022 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-35883433

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder, classically associated with extensive loss of dopaminergic neurons of the substantia nigra pars compacta. The hallmark of the disease is the accumulation of pathogenic conformations of the presynaptic protein, α-synuclein (αSyn), and the formation of intraneuronal protein aggregate inclusions. Neurodegeneration of dopamine neurons leads to a prominent dopaminergic deficiency in the basal ganglia, responsible for motor disturbances. However, it is now recognized that the disease involves more widespread neuronal dysfunction, leading to early and late non-motor symptoms. The development of in vitro systems based on the differentiation of human-induced pluripotent stem cells provides us the unique opportunity to monitor alterations at the cellular and molecular level throughout the differentiation procedure and identify perturbations that occur early, even at the neuronal precursor stage. Here we aim to identify whether p.A53T-αSyn induced disturbances at the molecular level are already present in neural precursors. Towards this, we present data from transcriptomics analysis of control and p.A53T-αSyn NPCs showing altered expression in transcripts involved in axon guidance, adhesion, synaptogenesis, ion transport, and metabolism. The comparative analysis with the transcriptomics profile of p.A53T-αSyn neurons shows both distinct and overlapping pathways leading to neurodegeneration while meta-analysis with transcriptomics data from both neurodegenerative and neurodevelopmental disorders reveals that p.A53T-pathology has a significant overlap with the latter category. This is the first study showing that molecular dysregulation initiates early at the p.A53T-αSyn NPC level, suggesting that synucleinopathies may have a neurodevelopmental component.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Sinucleinopatias , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Doença de Parkinson/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
13.
Biomolecules ; 12(7)2022 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-35883437

RESUMO

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson's and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Dopamina , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Motivação/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos
14.
Neurosci Lett ; 786: 136774, 2022 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-35809878

RESUMO

Opioid use disorder mainly results from functional defects in the brain reward loop, which includs the ventral tegmental area (VTA) and nucleus accumbens (NAc; consisting of shell and core, NAcS and NAcC). Reward effects contribute to opioid use disorder. RMTg M3 receptors play a role in opioid reward by regulating the γ-aminobutyric acid (GABA) neuron activity. Dopamine D1 receptors expressed on GABA neurons regulate opioid reward by mediating the dopamine neuron activity in the VTA. Therefore, we investigated the effect of activating M3 receptors by microinjecting pilocarpine into the RMTg along with activating D1 receptors by microinjecting SKF38393 into the VTA on morphine-induced reward effect, using the conditioned place preference (CPP) paradigm (locomotion was also recorded). We also investigated whether the activation of M3 receptors in the RMTg influenced dopamine release in the NAcS. The results showed that the inhibitory role of RMTg pilocarpine (60 µg/rat) infusions in morphine-induced CPP was reversed by VTA SKF38393 (4 µg/rat) infusions. Moreover, morphine (5 mg/kg, i.p.) increased dopamine release in the NAcS, which was blunted by microinjecting pilocarpine (60 µg/rat) into the RMTg. These results indicate that RMTg M3 receptors mediate morphine-induced reward effect, which is probably related to the dopamine activity within the VTA and NAcS. The relationship between RMTg M3 receptors and the mesolimbic dopamine system could be a potential direction for the treatment of opioid use disorder, but further verification through more comprehensive techniques is needed.


Assuntos
Morfina , Transtornos Relacionados ao Uso de Opioides , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Analgésicos Opioides/farmacologia , Animais , Encéfalo , Colinérgicos/farmacologia , Dopamina/farmacologia , Neurônios Dopaminérgicos , Morfina/farmacologia , Núcleo Accumbens , Pilocarpina/farmacologia , Ratos , Receptores Muscarínicos , Recompensa , Área Tegmentar Ventral
15.
Behav Processes ; 200: 104697, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35803487

RESUMO

Rats emit 50-kHz ultrasonic vocalizations (USVs) via the accumbal dopaminergic system in response to rhythmic stroking (RS). However, it is unknown whether RS can lead to approach behavior, which is a reliable marker of positive affective states. To assess the effects of RS on the behavioral response and its correlation with call subtypes, we measured the total number of 50-kHz USVs (overall and within call subtypes) and approach behavior in response to RS. Rats were randomly divided into two equal groups. One group received RS and the control group received light touch (LT). RS stimulation was administered for 30 s once a day for 7 consecutive days, and USVs were recorded immediately before, during, and after stimulation. RS induced 50-kHz USVs from day 1 and led to quick approach on day 2 and after. However, those responses were absent in the LT group. Specific frequency-modulated (FM) calls observed after RS were significantly correlated with approach latency. These results suggest that RS has rewarding effects, and the specific FM calls observed immediately after RS can be used as indices of innate positive reinforcement.


Assuntos
Motivação , Vocalização Animal , Animais , Dopamina , Ratos , Recompensa , Ultrassom , Vocalização Animal/fisiologia
16.
Pharmacol Biochem Behav ; 218: 173427, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35810923

RESUMO

In psychostimulant drug addiction, relapse is the most concerning outcome to be managed, considering there is no approved treatment for this neuropsychiatric condition. Here, we investigated the effects of the CBD treatment on the relapse behavior triggered by stress, after being submitted to the amphetamine (AMPH)-induced conditioned place preference (CPP) in rats. To elucidate the mechanisms of action underlying the CBD treatment, we evaluated the neuroadaptations on dopaminergic and endocannabinoid targets in the ventral striatum (VS) and ventral tegmental area (VTA) of the brain. Animals received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the CPP paradigm for 8 days. Following the first CPP test, animals were treated with CBD (10 mg/kg, i.p.) or its vehicle for 5 days and subsequently submitted to forced swim stress protocol to induce AMPH-CPP relapse. Behavioral findings showed that CBD treatment prevented AMPH-reinstatement, also exerting anxiolytic activity. At the molecular level, in the VTA, CBD restored the CB1R levels decreased by AMPH-exposure, increased NAPE-PLD, and decreased FAAH levels. In the VS, the increase of D1R and D2R, as well as the decrease of DAT levels induced by AMPH were restored by CBD treatment. The current outcomes evidence a substantial preventive action of the CBD on the AMPH-reinstatement evoked by stress, also involving neuroadaptations in both dopaminergic and endocannabinoid systems in brain areas closely involved in the addiction. Although further studies are needed, these findings support the therapeutic potential of CBD in AMPH-relapse prevention.


Assuntos
Anfetamina , Canabidiol , Anfetamina/farmacologia , Animais , Canabidiol/farmacologia , Dopamina , Endocanabinoides/farmacologia , Ratos , Recidiva
17.
Mol Pharm ; 19(8): 2992-3001, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35849844

RESUMO

Adenosine A2A and dopamine D2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A2A receptor-mediated modulation of D2 receptor binding in vivo using positron emission tomography (PET) with the D2 antagonist tracer [11C]raclopride. Healthy male Wistar rats (n = 8) were scanned (60 min dynamic scan) with [11C]raclopride at baseline and 7 days later following an acute administration of the A2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BPND) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [11C]raclopride BPND (p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BPND from the k3/k4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [11C]raclopride scans after pretreatment with a vehicle (n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group (p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k3/k4 ratio (p < 0.01), but k3 and k4 estimates may be less reliable. The BPND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 (p = 0.080) or 1.961 ± 0.11 (p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A2A agonist CGS21680, but not the antagonist KW6002, may reduce the D2 receptor availability in the striatum.


Assuntos
Dopamina , Receptor A2A de Adenosina , Adenosina/metabolismo , Agonistas do Receptor A2 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Animais , Radioisótopos de Carbono , Corpo Estriado/metabolismo , Ligantes , Masculino , Tomografia por Emissão de Pósitrons/métodos , Racloprida , Ratos , Ratos Wistar , Receptor A2A de Adenosina/metabolismo , Receptores Dopaminérgicos/metabolismo , Roedores/metabolismo
18.
Nature ; 608(7922): 374-380, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35831501

RESUMO

Food and water are rewarding in part because they satisfy our internal needs1,2. Dopaminergic neurons in the ventral tegmental area (VTA) are activated by gustatory rewards3-5, but how animals learn to associate these oral cues with the delayed physiological effects of ingestion is unknown. Here we show that individual dopaminergic neurons in the VTA respond to detection of nutrients or water at specific stages of ingestion. A major subset of dopaminergic neurons tracks changes in systemic hydration that occur tens of minutes after thirsty mice drink water, whereas different dopaminergic neurons respond to nutrients in the gastrointestinal tract. We show that information about fluid balance is transmitted to the VTA by a hypothalamic pathway and then re-routed to downstream circuits that track the oral, gastrointestinal and post-absorptive stages of ingestion. To investigate the function of these signals, we used a paradigm in which a fluid's oral and post-absorptive effects can be independently manipulated and temporally separated. We show that mice rapidly learn to prefer one fluid over another based solely on its rehydrating ability and that this post-ingestive learning is prevented if dopaminergic neurons in the VTA are selectively silenced after consumption. These findings reveal that the midbrain dopamine system contains subsystems that track different modalities and stages of ingestion, on timescales from seconds to tens of minutes, and that this information is used to drive learning about the consequences of ingestion.


Assuntos
Dopamina , Área Tegmentar Ventral , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Camundongos , Recompensa , Área Tegmentar Ventral/fisiologia , Água/metabolismo
19.
Nature ; 608(7922): 368-373, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35896744

RESUMO

Ketamine is used clinically as an anaesthetic and a fast-acting antidepressant, and recreationally for its dissociative properties, raising concerns of addiction as a possible side effect. Addictive drugs such as cocaine increase the levels of dopamine in the nucleus accumbens. This facilitates synaptic plasticity in the mesolimbic system, which causes behavioural adaptations and eventually drives the transition to compulsion1-4. The addiction liability of ketamine is a matter of much debate, in part because of its complex pharmacology that among several targets includes N-methyl-D-aspartic acid (NMDA) receptor (NMDAR) antagonism5,6. Here we show that ketamine does not induce the synaptic plasticity that is typically observed with addictive drugs in mice, despite eliciting robust dopamine transients in the nucleus accumbens. Ketamine nevertheless supported reinforcement through the disinhibition of dopamine neurons in the ventral tegmental area (VTA). This effect was mediated by NMDAR antagonism in GABA (γ-aminobutyric acid) neurons of the VTA, but was quickly terminated by type-2 dopamine receptors on dopamine neurons. The rapid off-kinetics of the dopamine transients along with the NMDAR antagonism precluded the induction of synaptic plasticity in the VTA and the nucleus accumbens, and did not elicit locomotor sensitization or uncontrolled self-administration. In summary, the dual action of ketamine leads to a unique constellation of dopamine-driven positive reinforcement, but low addiction liability.


Assuntos
Cocaína , Ketamina , Animais , Cocaína/farmacologia , Dopamina , Neurônios Dopaminérgicos/metabolismo , Ketamina/efeitos adversos , Camundongos , Núcleo Accumbens/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Área Tegmentar Ventral/fisiologia
20.
Nutrients ; 14(14)2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35889920

RESUMO

BACKGROUND: The present study aimed to investigate the rationale and efficacy of using a citicoline, coenzyme Q10 (CAVAQ10) and vitamin B3 fixed combination in combating inflammation and oxidation in neuronal cells exposed to oxidative stress. METHODS: HypoE22 cells and isolated hypothalamic specimens were selected as in vitro models to conduct the experiments. The efficacy of citicoline, CAVAQ10, and vitamin B3, with their fixed combination, were assayed after the exposure of hypothalamic cells to hydrogen peroxide (concentration range 1 nM-10 µM), in order to evaluate the biocompatibility of treatments. The activity of neuroprotective and pro-inflammatory factors, namely, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), involved in the neuronal cell damage in neurodegenerative diseases, were assayed in isolated hypothalamus. RESULTS: Neither citicoline, CAVAQ10, nor vitamin B3 significantly altered hypothalamic cell viability, thus suggesting the biocompatibility of single ingredients and fixed combination in the concentration range considered for the study. In the same condition, citicoline and CAVAQ10 were also effective in reducing the gene expression of monoaminoxidase-B, involved in dopamine degradation. However, only citicoline demonstrated an ability to reduce dopamine levels. Conversely, all compounds were effective in reducing the gene expression of IL-6, and TNFα, and in inducing the gene expression of BDNF, with the co-administration of citicoline/CAVAQ10/vitamin B3 being generally more effective than single ingredients. CONCLUSIONS: The present findings support the beneficial and synergistic effects of citicoline, CAVAQ10, and vitamin B3 in fixed combination in reducing inflammation and oxidation, and in stimulating neurotrophin production in neuronal cells.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Citidina Difosfato Colina , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citidina Difosfato Colina/farmacologia , Dopamina/farmacologia , Humanos , Inflamação , Interleucina-6/genética , Interleucina-6/metabolismo , Niacinamida/farmacologia , Estresse Oxidativo , Fator de Necrose Tumoral alfa/metabolismo , Ubiquinona/análogos & derivados
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