RESUMO
As part of the central nervous system, the optic nerve, composed of axons from retinal ganglion cells (RGCs), generally fails to regenerate on its own when injured in adult mammals. An innovative approach to promoting optic nerve regeneration involves manipulating the interactions between amacrine cells (ACs) and RGCs. Here, we identified a unique AC subtype, dopaminergic ACs (DACs), that responded early after optic nerve crush by down-regulating neuronal activity and reducing retinal dopamine (DA) release. Activating DACs or augmenting DA release with levodopa demonstrated neuroprotective effects and modestly enhanced axon regeneration. Within this context, we pinpointed the DA receptor D1 (DRD1) as a critical mediator of DAC-derived DA and showed that RGC-specific Drd1 overexpression effectively overcame subtype-specific barriers to regeneration. This strategy markedly boosted RGC survival and axon regeneration after crush and preserved vision in a glaucoma model. This study unveils the crucial role of DAC-derived DA signaling in optic nerve regeneration, holding promise for therapeutic insights into neural repair.
Assuntos
Células Amácrinas , Dopamina , Regeneração Nervosa , Nervo Óptico , Células Ganglionares da Retina , Transdução de Sinais , Animais , Células Amácrinas/metabolismo , Dopamina/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Nervo Óptico/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/efeitos dos fármacos , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/patologia , Camundongos , Axônios/metabolismo , Axônios/fisiologia , Receptores de Dopamina D1/metabolismo , Visão Ocular/fisiologia , Modelos Animais de DoençasRESUMO
Endothelial dysfunction may contribute to pathogenesis of Takotsubo cardiomyopathy, but mechanism underlying endothelial dysfunction in the setting of catecholamine excess has not been clarified. The study reports that D1/D5 dopamine receptor signaling and small conductance calcium-activated potassium channels contribute to high concentration catecholamine induced endothelial cell dysfunction. For mimicking catecholamine excess, 100 µM epinephrine (Epi) was used to treat human cardiac microvascular endothelial cells. Patch clamp, FACS, ELISA, PCR, western blot and immunostaining analyses were performed in the study. Epi enhanced small conductance calcium-activated potassium channel current (ISK1-3) without influencing the channel expression and the effect was attenuated by D1/D5 receptor blocker. D1/D5 agonists mimicked the Epi effect, suggesting involvement of D1/D5 receptors in Epi effects. The enhancement of ISK1-3 caused by D1/D5 activation involved roles of PKA, ROS and NADPH oxidases. Activation of D1/D5 and SK1-3 channels caused a hyperpolarization, reduced NO production and increased ROS production. The NO reduction was membrane potential independent, while ROS production was increased by the hyperpolarization. ROS (H2O2) suppressed NO production. The study demonstrates that high concentration catecholamine can activate D1/D5 and SK1-3 channels through NADPH-ROS and PKA signaling and reduce NO production, which may facilitate vasoconstriction in the setting of catecholamine excess.
Assuntos
Células Endoteliais , Epinefrina , Espécies Reativas de Oxigênio , Transdução de Sinais , Humanos , Transdução de Sinais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Óxido Nítrico/metabolismo , Catecolaminas/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/efeitos dos fármacos , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , NADPH Oxidases/metabolismo , Receptores de Dopamina D5/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMO
BACKGROUND: We recently reported that the dopamine (DA) analogue CA140 modulates neuroinflammatory responses in lipopolysaccharide-injected wild-type (WT) mice and in 3-month-old 5xFAD mice, a model of Alzheimer's disease (AD). However, the effects of CA140 on Aß/tau pathology and synaptic/cognitive function and its molecular mechanisms of action are unknown. METHODS: To investigate the effects of CA140 on cognitive and synaptic function and AD pathology, 3-month-old WT mice or 8-month-old (aged) 5xFAD mice were injected with vehicle (10% DMSO) or CA140 (30 mg/kg, i.p.) daily for 10, 14, or 17 days. Behavioral tests, ELISA, electrophysiology, RNA sequencing, real-time PCR, Golgi staining, immunofluorescence staining, and western blotting were conducted. RESULTS: In aged 5xFAD mice, a model of AD pathology, CA140 treatment significantly reduced Aß/tau fibrillation, Aß plaque number, tau hyperphosphorylation, and neuroinflammation by inhibiting NLRP3 activation. In addition, CA140 treatment downregulated the expression of cxcl10, a marker of AD-associated reactive astrocytes (RAs), and c1qa, a marker of the interaction of RAs with disease-associated microglia (DAMs) in 5xFAD mice. CA140 treatment also suppressed the mRNA levels of s100ß and cxcl10, markers of AD-associated RAs, in primary astrocytes from 5xFAD mice. In primary microglial cells from 5xFAD mice, CA140 treatment increased the mRNA levels of markers of homeostatic microglia (cx3cr1 and p2ry12) and decreased the mRNA levels of a marker of proliferative region-associated microglia (gpnmb) and a marker of lipid-droplet-accumulating microglia (cln3). Importantly, CA140 treatment rescued scopolamine (SCO)-mediated deficits in long-term memory, dendritic spine number, and LTP impairment. In aged 5xFAD mice, these effects of CA140 treatment on cognitive/synaptic function and AD pathology were regulated by dopamine D1 receptor (DRD1)/Elk1 signaling. In primary hippocampal neurons and WT mice, CA140 treatment promoted long-term memory and dendritic spine formation via effects on DRD1/CaMKIIα and/or ERK signaling. CONCLUSIONS: Our results indicate that CA140 improves neuronal/synaptic/cognitive function and ameliorates Aß/tau pathology and neuroinflammation by modulating DRD1 signaling in primary hippocampal neurons, primary astrocytes/microglia, WT mice, and aged 5xFAD mice.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Camundongos Transgênicos , Doenças Neuroinflamatórias , Receptores de Dopamina D1 , Transdução de Sinais , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Peptídeos beta-Amiloides/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Receptores de Dopamina D1/metabolismo , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Cognição/efeitos dos fármacos , Dopamina/metabolismo , Camundongos Endogâmicos C57BL , Masculino , HumanosRESUMO
Alloparenting refers to the practice of caring for the young by individuals other than their biological parents. The relationship between the dynamic changes in psychological functions underlying alloparenting and the development of specific neuroreceptors remains unclear. Using a classic 10-day pup sensitization procedure, together with a pup preference and pup retrieval test on the EPM (elevated plus maze), we showed that both male and female adolescent rats (24 days old) had significantly shorter latency than adult rats (65 days old) to be alloparental, and their motivation levels for pups and objects were also significantly higher. In contrast, adult rats retrieved more pups than adolescent rats even though they appeared to be more anxious on the EPM. Analysis of mRNA expression using real-time-PCR revealed a higher dopamine D2 receptor (DRD2) receptor expression in adult hippocampus, amygdala, and ventral striatum, along with higher dopamine D1 receptor (DRD1) receptor expression in ventral striatum compared to adolescent rats. Adult rats also showed significantly higher levels of 5-hydroxytryptamine receptor 2A (HTR2A) receptor expression in the medial prefrontal cortex, amygdala, ventral striatum, and hypothalamus. These results suggest that the faster onset of alloparenting in adolescent rats compared to adult rats, along with the psychological functions involved, may be mediated by varying levels of dopamine DRD1, DRD2, and HTR2A in different forebrain regions.
Assuntos
Prosencéfalo , RNA Mensageiro , Receptor 5-HT2A de Serotonina , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Animais , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Masculino , Ratos , Feminino , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/genética , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/genética , Prosencéfalo/metabolismo , Empatia/fisiologia , Fatores Etários , Caracteres Sexuais , Ratos Sprague-Dawley , Comportamento Animal/fisiologia , Tonsila do Cerebelo/metabolismoRESUMO
The kidney and brain play critical roles in the regulation of blood pressure. Neuropeptide FF (NPFF), originally isolated from the bovine brain, has been suggested to contribute to the pathogenesis of hypertension. However, the roles of NPFF and its receptors, NPFF-R1 and NPFF-R2, in the regulation of blood pressure, via the kidney, are not known. In this study, we found that the transcripts and proteins of NPFF and its receptors, NPFF-R1 and NPFF-R2, were expressed in mouse and human renal proximal tubules (RPTs). In mouse RPT cells (RPTCs), NPFF, but not RF-amide-related peptide-2 (RFRP-2), decreased the forskolin-stimulated cAMP production in a concentration- and time-dependent manner. Furthermore, dopamine D1-like receptors colocalized and co-immunoprecipitated with NPFF-R1 and NPFF-R2 in human RPTCs. The increase in cAMP production in human RPTCs caused by fenoldopam, a D1-like receptor agonist, was attenuated by NPFF, indicating an antagonistic interaction between NPFF and D1-like receptors. The renal subcapsular infusion of NPFF in C57BL/6 mice decreased renal sodium excretion and increased blood pressure. The NPFF-mediated increase in blood pressure was prevented by RF-9, an antagonist of NPFF receptors. Taken together, our findings suggest that autocrine NPFF and its receptors in the kidney regulate blood pressure, but the mechanisms remain to be determined.
Assuntos
Comunicação Autócrina , Pressão Sanguínea , AMP Cíclico , Oligopeptídeos , Transdução de Sinais , Animais , Humanos , Camundongos , AMP Cíclico/metabolismo , Oligopeptídeos/farmacologia , Oligopeptídeos/metabolismo , Receptores de Neuropeptídeos/metabolismo , Túbulos Renais Proximais/metabolismo , Masculino , Rim/metabolismo , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/metabolismoRESUMO
BACKGROUND: The transition from childhood to adulthood, or adolescence, a developmental stage, is characterized by psychosocial and biological changes. The nucleus accumbens (NAc), a striatal brain region composed of the core (NAcC) and shell (NAcSh), has been linked to risk-taking behavior and implicated in reward seeking and evaluation. Most neurons in the NAc are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1R +) and/or dopamine D2 receptors (D2R +). Changes in dopaminergic and glutamatergic systems occur during adolescence and converge in the NAc. While there are previous investigations into sex differences in membrane excitability and synaptic glutamate transmission in both subdivisions of the NAc, to our knowledge, none have specified NAcSh D1R + MSNs from mice during pre- and mid-adolescence. METHODS: Sagittal brain slices containing the NAc were prepared from B6.Cg-Tg(Drd1a-tdTomato)6Calak/J mice of both sexes from postnatal days 21-25 and 35-47, representing pre- and mid-adolescence, respectively. Whole-cell electrophysiology recordings were collected from NAcSh D1R + MSNs in the form of membrane-voltage responses to current injections, to assess membrane properties and action potential waveform characteristics, and spontaneous excitatory postsynaptic currents (sEPSCs) to assess glutamatergic synaptic activity. RESULTS: Relative to pre-adolescent males, pre-adolescent female NAcSh D1R + MSNs exhibited a less hyperpolarized resting membrane potential, increased input resistance, and smaller action potential afterhyperpolarization amplitudes. During mid-adolescence, decreased input resistance and a shorter action potential duration in females were the only sex differences observed. CONCLUSIONS: Taken together, our results indicate that NAcSh D1R + MSNs in mice exhibit sex differences in membrane properties and AP waveform during pre-adolescence that are overall indicative of increased cellular excitability in females and are suggestive of possible sex differences in glycine receptors, inwardly-rectifying potassium channels, and large conductance voltage-gated potassium channels. These differences do not appear to persist into mid-adolescence, when sex was observed to affect input resistance oppositely to that of pre-adolescence and AP waveform in a manner suggestive of differences in voltage-gated potassium channels.
Adolescence marks a period of substantial changes in both the mind and body, where alterations in the brain's structure can influence behavior. One change in behavior exhibited by many adolescents is an increased tendency to take risks, particularly in males. While taking risks can result in positive outcomes, like learning new skills, it can also lead to reckless behaviors that may result in negative outcomes. The nucleus accumbens, a brain region tied to risk-taking and reward perception, is not well-studied during the transition from childhood to adulthood, particularly in terms of sex differences. To fill this gap in understanding, this study examined a specific type of brain cell in the nucleus accumbens of pre- and mid-adolescent male and female mice. We measured the electrical properties of these cells and assessed how they responded to manipulation of their electrical state. We also measured how much and how often excitatory electrical information is sent to these cells from other brain regions. Our results suggest that in pre-adolescent females, these brain cells are more excited by manipulations of their electrical state and that these brain cells in mid-adolescent males may take longer to communicate information to other brain regions than in similarly aged females. Understanding these intricacies of brain cell communication sheds light on potential sex-specific vulnerabilities during the transition from childhood to adulthood.
Assuntos
Neurônios , Núcleo Accumbens , Receptores de Dopamina D1 , Caracteres Sexuais , Animais , Receptores de Dopamina D1/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Núcleo Accumbens/citologia , Feminino , Masculino , Neurônios/metabolismo , Neurônios/fisiologia , Camundongos , Potenciais da Membrana , Camundongos Endogâmicos C57BL , Potenciais Pós-Sinápticos Excitadores , Camundongos TransgênicosRESUMO
Synaptic plasticity in the mesolimbic dopamine (DA) system contributes to the neural adaptations underlying addictive behaviors and relapse. However, the specific behavioral relevance of glutamatergic excitatory drive onto dopamine D1 receptor (D1R)-expressing neurons in mediating the reinforcing effect of cocaine remains unclear. Here, we investigated how midbrain AMPAR and NMDAR function modulate cocaine reward-related behavior using mutant mouse lines lacking the glutamate receptor genes Gria1 or Grin1 in D1R-expressing neurons (GluA1D1CreERT2 or GluN1D1CreERT2, respectively). We found that conditional genetic deletion of either GluA1 or GluN1 within this neuronal sub-population did not impact the ability of acute cocaine injection to increase intracranial self-stimulation (ICSS) ratio or reduced brain reward threshold compared to littermate controls. Additionally, our data demonstrate that deletion of GluA1 and GluN1 receptor subunits within D1R-expressing neurons did not affect cocaine reinforcement in an operant self-administration paradigm, as mutant mice showed comparable cocaine responses and intake to controls. Given the pivotal role of glutamate receptors in mediating relapse behavior, we further explored the impact of genetic deletion of AMPAR and NMDAR onto D1R-expressing neurons on cue-induced reinstatement following extinction. Surprisingly, deletion of AMPAR and NMDAR onto these neurons did not impair cue-induced reinstatement of cocaine-seeking behavior. These findings suggest that glutamatergic activity via NMDAR and AMPAR in D1R-expressing neurons may not exclusively mediate the reinforcing effects of cocaine and cue-induced reinstatement.
Assuntos
Cocaína , Receptores de AMPA , Receptores de Dopamina D1 , Receptores de N-Metil-D-Aspartato , Recompensa , Autoadministração , Animais , Cocaína/farmacologia , Cocaína/administração & dosagem , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de AMPA/genética , Receptores de AMPA/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Camundongos , Masculino , Mesencéfalo/metabolismo , Mesencéfalo/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Camundongos Knockout , Inibidores da Captação de Dopamina/farmacologia , Camundongos Endogâmicos C57BL , Reforço Psicológico , Proteínas do Tecido NervosoRESUMO
Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell-type-selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons, or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain.
Assuntos
Astrócitos , Potenciação de Longa Duração , Receptores de Dopamina D1 , Receptores de Dopamina D5 , Sinapses , Animais , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/genética , Potenciação de Longa Duração/fisiologia , Astrócitos/metabolismo , Astrócitos/fisiologia , Camundongos , Masculino , Receptores de Dopamina D5/metabolismo , Receptores de Dopamina D5/agonistas , Receptores de Dopamina D5/genética , Feminino , Sinapses/fisiologia , Sinapses/metabolismo , Gânglios Espinais/citologia , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/citologia , Camundongos Transgênicos , Camundongos Endogâmicos C57BLRESUMO
Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions.NEW & NOTEWORTHY Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions.
Assuntos
Dopamina , Receptores de GABA-A , Células Ganglionares da Retina , Animais , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Dopamina/metabolismo , Dopamina/farmacologia , Receptores de GABA-A/metabolismo , Camundongos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Receptores Opioides mu/metabolismo , Masculino , Potenciais Pós-Sinápticos Inibidores/fisiologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Feminino , Agonistas de Dopamina/farmacologiaRESUMO
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) with autoimmune mechanism of development. The investigation of neuroimmune interaction is one of the most developing directions in MS pathogenesis study. Catecholamines are direct mediators of this interaction and can be involved in the pathogenesis of MS by modulating cells of both innate and adaptive immune systems. The aim of this study was to investigate the influence of dopamine and norepinephrine on the ability of monocytes of patients with relapsing-remitting MS, to induce Th17- and Th1-immune response, which play a crucial role in the autoimmunity of the CNS. We found, that both dopamine and norepinephrine modulate the production of Th17- (IL-23, IL-1ß, and IL-6) and Th1-promoting (IL-12p70) cytokines by activated peripheral blood mononuclear cells or CD14+ monocytes in patients with MS and in healthy subjects. We also found the inhibitory effect of dopamine and norepinephrine on monocyte-induced production of IL-17 and IFN-γ by autologous CD4+ T-cells in both groups. Finally, the multidirectional role of D1- and D2-like dopaminergic receptors in the modulatory effect of dopamine on the ability of CD14+ monocytes to activate CD4+ T-cells was established, expanding the potential role of dopamine in the neuroimmune interaction.
Assuntos
Dopamina , Monócitos , Norepinefrina , Células Th1 , Células Th17 , Humanos , Dopamina/metabolismo , Monócitos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Adulto , Masculino , Feminino , Norepinefrina/farmacologia , Esclerose Múltipla Recidivante-Remitente/imunologia , Células Cultivadas , Citocinas/metabolismo , Citocinas/imunologia , Adulto Jovem , Pessoa de Meia-Idade , Receptores de Dopamina D1/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Esclerose Múltipla/imunologia , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/imunologiaRESUMO
Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade-off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu-opioids (oprm1a), and kappa-opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC-NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long-term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade-off associated with increased emotional investment in offspring, while also maintaining a pair bond.
Assuntos
Arvicolinae , Comportamento Materno , Núcleo Accumbens , Ligação do Par , Receptores Opioides mu , Animais , Feminino , Arvicolinae/genética , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Comportamento Materno/fisiologia , Núcleo Accumbens/metabolismo , Gravidez , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Giro do Cíngulo/metabolismo , Área Pré-Óptica/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismoRESUMO
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.
Assuntos
Benzazepinas , Giro Denteado , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Estresse Psicológico , Sulpirida , Animais , Masculino , Ratos , Analgesia/métodos , Benzazepinas/farmacologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Dor/metabolismo , Dor/tratamento farmacológico , Dor/fisiopatologia , Medição da Dor/métodos , Medição da Dor/efeitos dos fármacos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Sulpirida/farmacologiaRESUMO
Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.
Assuntos
Apoptose , Cisplatino , Microbioma Gastrointestinal , Neoplasias Ovarianas , Receptores de Dopamina D1 , Animais , Cisplatino/farmacologia , Feminino , Apoptose/efeitos dos fármacos , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Microbioma Gastrointestinal/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Antineoplásicos/farmacologia , Humanos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Xantinas/farmacologia , MetabolômicaRESUMO
Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated with positive effects while solitary drinking is linked to negative effects. However, the neurobiological mechanism by which the social environment during alcohol intake impacts on behavioural responses remains poorly understood. We investigated whether distinct social environments affect behavioural responses to ethanol and the role of the dopamine system in this phenomenon in the fruit fly Drosophila melanogaster. The wild-type Canton-S (CS) flies showed higher locomotor response when exposed to ethanol in a group setting than a solitary setting, and there was no difference in females and males. Dopamine signalling is crucial for the locomotor stimulating effect of ethanol. When subjected to ethanol exposure alone, the dopamine transport mutant flies fumin (fmn) with hyper dopamine displayed the locomotor response similar to CS. When subjected to ethanol in a group setting, however, the fmn's response to the locomotor stimulating effect was substantially augmented compared with CS, indicating synergistic interaction of dopamine signalling and social setting. To identify the dopamine signalling pathway important for the social effect, we examined the flies defective in individual dopamine receptors and found that the D1 receptor dDA1/Dop1R1 is the major receptor mediating the social effect. Taken together, this study underscores the influence of social context on the neural and behavioural responses to ethanol.
Assuntos
Dopamina , Proteínas de Drosophila , Drosophila melanogaster , Etanol , Animais , Etanol/farmacologia , Dopamina/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Masculino , Feminino , Proteínas de Drosophila/genética , Receptores de Dopamina D1/efeitos dos fármacos , Meio Social , Transdução de Sinais/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores Dopaminérgicos/metabolismo , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Comportamento Social , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Atividade Motora/efeitos dos fármacosRESUMO
Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2's effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc.
Assuntos
Tecido Adiposo , Metabolismo Energético , Receptor alfa de Estrogênio , Núcleo Accumbens , Receptores de Dopamina D1 , Animais , Feminino , Masculino , Camundongos , Tecido Adiposo/metabolismo , Tecido Adiposo Marrom/metabolismo , Encéfalo/metabolismo , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Técnicas de Silenciamento de Genes , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/genética , Proteína Desacopladora 1/metabolismo , Proteína Desacopladora 1/genéticaRESUMO
Impulsive decision-making has been linked to impulse control disorders and substance use disorders. However, the neural mechanisms underlying impulsive choice are not fully understood. While previous PET imaging and autoradiography studies have shown involvement of dopamine and D2/3 receptors in impulsive behavior, the roles of distinct D1, D2, and D3 receptors in impulsive decision-making remain unclear. In this study, we used a food reward delay-discounting task (DDT) to identify low- and high-impulsive rats, in which low-impulsive rats exhibited preference for large delayed reward over small immediate rewards, while high-impulsive rats showed the opposite preference. We then examined D1, D2, and D3 receptor gene expression using RNAscope in situ hybridization assays. We found that high-impulsive male rats exhibited lower levels of D2 and D3, and particularly D3, receptor expression in the nucleus accumbens (NAc), with no significant changes in the insular, prelimbic, and infralimbic cortices. Based on these findings, we further explored the role of the D3 receptor in impulsive decision-making. Systemic administration of a selective D3 receptor agonist (FOB02-04) significantly reduced impulsive choices in high-impulsive rats but had no effects in low-impulsive rats. Conversely, a selective D3 receptor antagonist (VK4-116) produced increased both impulsive and omission choices in both groups of rats. These findings suggest that impulsive decision-making is associated with a reduction in D3 receptor expression in the NAc. Selective D3 receptor agonists, but not antagonists, may hold therapeutic potentials for mitigating impulsivity in high-impulsive subjects.
Assuntos
Comportamento de Escolha , Tomada de Decisões , Desvalorização pelo Atraso , Comportamento Impulsivo , Receptores de Dopamina D2 , Receptores de Dopamina D3 , Animais , Masculino , Receptores de Dopamina D3/metabolismo , Comportamento Impulsivo/efeitos dos fármacos , Comportamento Impulsivo/fisiologia , Ratos , Desvalorização pelo Atraso/efeitos dos fármacos , Desvalorização pelo Atraso/fisiologia , Receptores de Dopamina D2/metabolismo , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Recompensa , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Antagonistas de Dopamina/farmacologia , Ratos Sprague-DawleyRESUMO
Loss-of-function mutations of the gene encoding the trafficking protein particle complex subunit 9 (Trappc9) cause autosomal recessive intellectual disability and obesity by unknown mechanisms. Genome-wide analysis links Trappc9 to nonalcoholic fatty liver disease (NAFLD). Trappc9-deficient mice have been shown to appear overweight shortly after weaning. Here, we analyzed serum biochemistry and histology of adipose and liver tissues to determine the incidence of obesity and NAFLD in Trappc9-deficient mice and combined transcriptomic and proteomic analyses, pharmacological studies, and biochemical and histological examinations of postmortem mouse brains to unveil mechanisms involved. We found that Trappc9-deficient mice presented with systemic glucose homeostatic disturbance, obesity, and NAFLD, which were relieved upon chronic treatment combining dopamine receptor D2 (DRD2) agonist quinpirole and DRD1 antagonist SCH23390. Blood glucose homeostasis in Trappc9-deficient mice was restored upon administering quinpirole alone. RNA-sequencing analysis of DRD2-containing neurons and proteomic study of brain synaptosomes revealed signs of impaired neurotransmitter secretion in Trappc9-deficient mice. Biochemical and histological studies of mouse brains showed that Trappc9-deficient mice synthesized dopamine normally, but their dopamine-secreting neurons had a lower abundance of structures for releasing dopamine in the striatum. Our study suggests that Trappc9 loss of function causes obesity and NAFLD by constraining dopamine synapse formation.
Assuntos
Dopamina , Camundongos Knockout , Animais , Camundongos , Dopamina/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/genética , Obesidade/metabolismo , Obesidade/genética , Encéfalo/metabolismo , Encéfalo/patologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/patologia , Masculino , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Benzazepinas/farmacologia , Benzazepinas/uso terapêutico , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/genética , Modelos Animais de Doenças , Transmissão Sináptica/efeitos dos fármacosRESUMO
The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.
Assuntos
Dopamina , Transtornos da Memória , Raios Ultravioleta , Animais , Dopamina/metabolismo , Raios Ultravioleta/efeitos adversos , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Camundongos , Masculino , Neurogênese/efeitos da radiação , Plasticidade Neuronal/efeitos da radiação , Hipocampo/metabolismo , Hipocampo/efeitos da radiação , Pele/metabolismo , Pele/efeitos da radiação , Transdução de Sinais , Camundongos Endogâmicos C57BL , Receptores de Dopamina D1/metabolismo , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/efeitos da radiaçãoRESUMO
Dopamine D1 receptor agonists improve spatial working memory, but their effects on temporal order memory, particularly prone to the effects of aging, have not been studied. Two D1 agonists, PF6256142 (PF) and 2-methyldihydrexidine (2MDHX), were examined for their effects in a rodent temporal order recognition task. Our results are consistent with the hypothesis that there is an age-related decline in rodent temporal order memory. The data also show that either agonist rescues the poor memory performance with a large effective size. Interestingly, the optimal effective dose varied among individual rats of different age groups. PF showed greater potency for older rats, whereas 2MDHX showed better overall population effectiveness. Both PF and 2MDHX have high intrinsic activity at rodent D1-mediated cAMP synthesis. Conversely, at D1-mediated ß-arrestin recruitment, PF has essentially no intrinsic activity, whereas 2MDHX is a super-agonist. These findings suggest that D1 agonists have potential to treat age-related cognitive decline, and the pattern of functional selectivity may be useful for developing drugs with an improved therapeutic index.
Assuntos
Envelhecimento , Agonistas de Dopamina , Receptores de Dopamina D1 , Animais , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Masculino , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Agonistas de Dopamina/farmacologia , Ratos , Fenantridinas/farmacologia , Relação Dose-Resposta a Droga , Reconhecimento Psicológico/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Endogâmicos F344 , AMP Cíclico/metabolismoRESUMO
Systemic manipulations that enhance dopamine (DA) transmission around the time of fear extinction can strengthen fear extinction and reduce conditioned fear relapse. Prior studies investigating the brain regions where DA augments fear extinction focus on targets of mesolimbic and mesocortical DA systems originating in the ventral tegmental area, given the role of these DA neurons in prediction error. The dorsal striatum (DS), a primary target of the nigrostriatal DA system originating in the substantia nigra (SN), is implicated in behaviors beyond its canonical role in movement, such as reward and punishment, goal-directed action, and stimulus-response associations, but whether DS DA contributes to fear extinction is unknown. We have observed that chemogenetic stimulation of SN DA neurons during fear extinction prevents the return of fear in contexts different from the extinction context, a form of relapse called renewal. This effect of SN DA stimulation is mimicked by a DA D1 receptor (D1R) agonist injected into the DS, thus implicating DS DA in fear extinction. Different DS subregions subserve unique functions of the DS, but it is unclear where in the DS D1R agonist acts during fear extinction to reduce renewal. Furthermore, although fear extinction increases neural activity in DS subregions, whether neural activity in DS subregions is causally involved in fear extinction is unknown. To explore the role of DS subregions in fear extinction, adult, male Long-Evans rats received microinjections of either the D1R agonist SKF38393 or a cocktail consisting of GABAA/GABAB receptor agonists muscimol/baclofen selectively into either dorsomedial (DMS) or dorsolateral (DLS) DS subregions immediately prior to fear extinction, and extinction retention and renewal were subsequently assessed drug-free. While increasing D1R signaling in the DMS during fear extinction did not impact fear extinction retention or renewal, DMS inactivation reduced later renewal. In contrast, DLS inactivation had no effect on fear extinction retention or renewal but increasing D1R signaling in the DLS during extinction reduced fear renewal. These data suggest that DMS and DLS activity during fear extinction can have opposing effects on later fear renewal, with the DMS promoting renewal and the DLS opposing renewal. Mechanisms through which the DS could influence the contextual gating of fear extinction are discussed.