RESUMO
Children who experienced moderate perinatal asphyxia (MPA) are at risk of developing long lasting subtle cognitive and behavioral deficits, including learning disabilities and emotional problems. The prefrontal cortex (PFC) regulates cognitive flexibility and emotional behavior. Neurons that release serotonin (5-HT) project to the PFC, and compounds modulating 5-HT activity influence emotion and cognition. Whether 5-HT dysregulations contribute to MPA-induced cognitive problems is unknown. We established a MPA mouse model, which displays recognition and spatial memory impairments and dysfunctional cognitive flexibility. We found that 5-HT expression levels, quantified by immunohistochemistry, and 5-HT release, quantified by in vivo microdialysis in awake mice, are reduced in PFC of adult MPA mice. MPA mice also show impaired body temperature regulation following injection of the 5-HT1A receptor agonist 8-OH-DPAT, suggesting the presence of deficits in 5-HT auto-receptor function on raphe neurons. Finally, chronic treatment of adult MPA mice with fluoxetine, an inhibitor of 5-HT reuptake transporter, or the 5-HT1A receptor agonist tandospirone rescues cognitive flexibility and memory impairments. All together, these data demonstrate that the development of 5-HT system function is vulnerable to moderate perinatal asphyxia. 5-HT hypofunction might in turn contribute to long-term cognitive impairment in adulthood, indicating a potential target for pharmacological therapies.
Assuntos
Inibidores Seletivos de Recaptação de Serotonina , Serotonina , Humanos , Criança , Camundongos , Animais , Serotonina/metabolismo , Receptor 5-HT1A de Serotonina , Asfixia , Fluoxetina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Receptores de Serotonina , Cognição , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , HipóxiaRESUMO
In the present studies, we assessed the effect of the 5-HT1A receptor (R) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on motor and exploratory behaviors, object and place recognition and dopamine transporter (DAT) and serotonin transporter (SERT) binding in the rat brain. In Experiment I, motor/exploratory behaviors were assessed in an open field after injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle for 30 min without previous habituation to the open field. In Experiment II, rats underwent a 5-min exploration trial in an open field with two identical objects. After injection of either 8-OH-DPAT (0.1 and 3 mg/kg) or vehicle, rats underwent a 5-min test trial with one of the objects replaced by a novel one and the other object transferred to a novel place. Subsequently, N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]FP-CIT; 11 ± 4 MBq) was injected into the tail vein. Regional radioactivity accumulations were determined post mortem with a well counter. In both experiments, 8-OH-DPAT dose-dependently increased ambulation and exploratory head-shoulder motility, whereas rearing was dose-dependently decreased. In the test rial of Experiment II, there were no effects of 8-OH-DPAT on overall activity, sitting and grooming. 8-OH-DPAT dose-dependently impaired recognition of object and place. 8-OH-DPAT (3 mg/kg) increased DAT binding in the dorsal striatum relative to both vehicle and 0.1 mg/kg 8-OH-DPAT. Furthermore, in the ventral striatum, DAT binding was decreased after 3 mg/kg 8-OH-DPAT relative to vehicle. Findings indicate that motor/exploratory behaviors, memory for object and place and regional dopamine function may be modulated by the 5-HT1AR. Since, after 8-OH-DPAT, rats exhibited more horizontal and less (exploratory) vertical motor activity, while overall activity was not different between groups, it may be inferred, that the observed impairment of object recognition was not related to a decrease of motor activity as such, but to a decrease of intrinsic motivation, attention and/or awareness, which are relevant accessories of learning. Furthermore, the present findings on 8-OH-DPAT action indicate associations not only between motor/exploratory behavior and the recognition of object and place but also between the respective parameters and the levels of available DA in dorsal and ventral striatum.
Assuntos
Receptor 5-HT1A de Serotonina , Estriado Ventral , Ratos , Animais , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
It has been recognized that serotonergic blocker showed serious side effects, and that ginsenoside modulated serotonergic system with the safety. However, the effects of ginsenoside on serotonergic impairments remain to be clarified. Thus, we investigated ginsenoside Re (GRe), a major bioactive component in the mountain-cultivated ginseng on (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT), a 5-HT1A receptor agonist. In the present study, we observed that the treatment with GRe resulted in significant inhibition of protein kinase C δ (PKCδ) phosphorylation induced by the 5-HT1A receptor agonist (±)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) in the hypothalamus of the wild-type (WT) mice. The inhibition of GRe was comparable with that of the PKCδ inhibitor rottlerin or the 5-HT1A receptor antagonist WAY100635 (WAY). 8-OH-DPAT-induced significant reduction in nuclear factor erythroid-2-related factor 2 (Nrf2)-related system (i.e., Nrf2 DNA binding activity, γ-glutamylcysteine ligase modifier (GCLm) and γ-glutamylcysteine ligase catalytic (GCLc) mRNA expression, and glutathione (GSH)/oxidized glutathione (GSSG) ratio) was significantly attenuated by GRe, rottlerin, or WAY in WT mice. However, PKCδ gene knockout significantly protected the Nrf2-dependent system from 8-OH-DPAT insult in mice. Increases in 5-hydroxytryptophan (5-HT) turnover rate, overall serotonergic behavioral score, and hypothermia induced by 8-OH-DPAT were significantly attenuated by GRe, rottlerin, or WAY in WT mice. Consistently, PKCδ gene knockout significantly attenuated these parameters in mice. However, GRe or WAY did not provide any additional positive effects on the serotonergic protective potential mediated by PKCδ gene knockout in mice. Therefore, our results suggest that PKCδ is an important mediator for GRe-mediated protective activity against serotonergic impairments/oxidative burden caused by the 5-HT1A receptor.
Assuntos
Ginsenosídeos , Camundongos , Animais , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Ginsenosídeos/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Receptor 5-HT1A de Serotonina/genética , Glutationa , Dissulfeto de Glutationa , Antagonistas da Serotonina , LigasesRESUMO
Anxiety is a mental disorder with a growing worldwide incidence due to the SARS-CoV-2 virus pandemic. Pharmacological therapy includes drugs such as benzodiazepines (BDZs) or azapirones like buspirone (BUSP) or analogs, which unfortunately produce severe adverse effects or no immediate response, respectively. Medicinal plants or their bioactive metabolites are a shared global alternative to treat anxiety. Palmitone is one active compound isolated from Annona species due to its tranquilizing activity. However, its influence on neural activity and possible mechanism of action are unknown. In this study, an electroencephalographic (EEG) spectral power analysis was used to corroborate its depressant activity in comparison with the anxiolytic-like effects of reference drugs such as diazepam (DZP, 1 mg/kg) and BUSP (4 mg/kg) or 8-OH-DPAT (1 mg/kg), alone or in the presence of the GABAA (picrotoxin, PTX, 1 mg/kg) or serotonin 5-HT1A receptor antagonists (WAY100634, WAY, 1 mg/kg). The anxiolytic-like activity was assayed using the behavioral response of mice employing open-field, hole-board, and plus-maze tests. EEG activity was registered in both the frontal and parietal cortex, performing a 10 min baseline and 30 min recording after the treatments. As a result, anxiety-like behavior was significantly decreased in mice administered with palmitone, DZP, BUSP, or 8-OH-DPAT. The effect of palmitone was equivalent to that produced by 5-HT1A receptor agonists but 50% less effective than DZP. The presence of PTX and WAY prevented the anxiolytic-like response of DZP and 8-OH-DPAT, respectively. Whereas only the antagonist of the 5-HT1A receptor (WAY) inhibited the palmitone effects. Palmitone and BUSP exhibited similar changes in the relative power bands after the spectral power analysis. This response was different to the changes induced by DZP. In conclusion, brain electrical activity was associated with the anxiolytic-like effects of palmitone implying a serotoninergic rather than a GABAergic mechanism of action.
Assuntos
Ansiolíticos , COVID-19 , Camundongos , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Buspirona/farmacologia , Diazepam/farmacologia , Receptor 5-HT1A de Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , SARS-CoV-2 , Agonistas do Receptor de Serotonina/farmacologia , EletroencefalografiaRESUMO
The effect of 5-HT1A receptor agonist 8-OH-DPAT (intraperitoneal injection in doses of 1, 2, and 4 mg/kg) on spontaneous alternation behavior of mice in Y-maze was studied without and with habituation procedure and food reward. In the first case, 8-OH-DPAT administration led to a decrease in spontaneous alternation and locomotor activity in mice. At the same time, 8-OH-DPAT treatment after habituation and food deprivation increased repeated choices of goal arms without affecting locomotor activity, which was consistent with perseverative behavior. 8-OH-DPAT-induced decrease in spontaneous alternation behavior in Y-maze in mice with habituation and food reward is the most suitable procedure for experimental modeling of the perseverative behavior and studying the anticompulsive activity of new substances.
Assuntos
Agonistas do Receptor de Serotonina , Camundongos , Animais , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Understanding the neurobiological mechanisms of drug-related learning and memory formation may help the treatment of cognitive disorders. Dysfunction of the cannabinoid and serotonergic systems has been demonstrated in learning and memory disorders. The present paper investigates the phenomenon called state-dependent memory (SDM) induced by ACPA (a selective cannabinoid CB1 receptor agonist) and 8-OH-DPAT (a nonselective 5-HT1A receptor agonist) with special focus on the role of the 5-HT1A receptor in the effects of both ACPA and 8-OH-DPAT SDM and cross state-dependent memory retrieval between ACPA and 8-OH-DPAT in a step-down inhibitory avoidance task. The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended injection sites. A single-trial step-down inhibitory avoidance task was used to assess memory retrieval and state-dependence. Post-training and/or pre-test microinjections of ACPA (1 and 2 ng/mouse) and 8-OH-DPAT (0.5 and 1 µg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of ACPA and 8-OH-DPAT reversed the post-training ACPA- and 8-OH-DPAT-induced amnesia, respectively. This phenomenon has been named SDM. 8-OH-DPAT (1 µg/mouse) reversed the amnesia induced by ACPA (0.5, 1, and 2 ng/mouse) and induced ACPA SDM. ACPA (2 ng/mouse) reversed the amnesia induced by 8-OH-DPAT (0.25, 0.5, and 1 µg/mouse) and induced 8-OH-DPAT SDM. Pre-test administration of a 5-HT1A receptor antagonist, (S)-WAY 100,135 (0.25 and 0.5 µg/mouse), 5 min before ACPA and 8-OH-DPAT dose-dependently inhibited ACPA- and 8-OH-DPAT-induced SDM, respectively. The present study results demonstrated ACPA- and 8-OH-DPAT- induced SDM. Overall, the data revealed that dorsal hippocampal 5-HT1A receptor mechanisms play a pivotal role in modulating cross state-dependent memory retrieval between ACPA and 8-OH-DPAT.
Assuntos
Canabinoides , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Amnésia/induzido quimicamente , Animais , Aprendizagem da Esquiva , Agonistas de Receptores de Canabinoides/farmacologia , Hipocampo , Masculino , Camundongos , Receptor CB1 de Canabinoide , Receptor 5-HT1A de SerotoninaRESUMO
BACKGROUND: Male and female rats were exposed to repeated restraint to determine how changes in serotonin (5-hydroxytryptamine; 5-HT) 1A receptors associate with stress hypothalamic-pituitary-adrenal (HPA) axis habituation. METHODS: In response to 2-hour episodes of restraint, repeated daily for 5 consecutive days, males and females displayed reliable declines in HPA output, indicated by diminished adrenocorticotropin and corticosterone secretory responses. Using the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as a pharmacological challenge for inducing hypothermia and elevations in plasma corticosterone, males displayed sensitized hypothermal responses after repeated restraint, whereas corticosterone responses to 8-OH-DPAT were enhanced in both sexes following single or repeated exposure. RESULTS: Only males showed elevations in 5-HT 1A receptor G-protein coupling responses in the dorsal raphe after repeated restraint, whereas only females showed an increase in 5-HT 1A receptor responses in the hippocampus following single or repeated exposure. G-protein coupling responses within both regions correlated positively with 5-HT 1A receptor binding capacity. Thus, despite expressing similar capacities for stress HPA axis habituation, males and females emerged from repeated restraint to show region-specific changes in 5-HT 1A receptor function that may be explained, at least in part, by changes in receptor availability. CONCLUSIONS: Based on the hypothermal and corticosteroid responses to 8-OH-DPAT, the present data suggest that stress habituation is met by an increase in the sensitivity of presynaptic 5-HT 1A receptors in males and by an increase in the sensitivity of a population of postsynaptic receptors in both sexes.
Assuntos
Sistema Hipotálamo-Hipofisário , Serotonina , Animais , Feminino , Ratos , Masculino , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Serotonina/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Corticosterona , Caracteres Sexuais , Piperazinas/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Hormônio Adrenocorticotrópico/metabolismo , Hormônio Adrenocorticotrópico/farmacologia , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/farmacologiaRESUMO
Psoriasis pain is a common symptom underestimated and rarely evaluated in psoriasis clinical trials. This work aimed to investigate whether the development of secondary chronic allodynia and hyperalgesia in the imiquimod (IMQ)-induced psoriasis mice model could be modulated by anti-inflammatory agents and compound 48/80 (C48/80) and to determine whether the activation of 5-HT1A receptor modulates these nociceptive behaviours. C57BL/6 male mice were treated with 5% IMQ for 7 days. The paw withdrawal responses to von Frey filaments (10 and 250 mN) were used to assess the allodynia and hyperalgesia. Nociceptive behaviours were also evaluated using ketorolac 15 mg/kg s.c., adalimumab 10 mg/kg s.c. and C48/80 10 mg/kg i.p. Then, the serum serotonin and the impact of 8-OH-DPAT (1 mg/kg s.c), a 5-HT1A receptor agonist, on long-lasting pain were examined. Mice receiving IMQ showed enhanced nociception, which decreased with all tested compounds. The serum serotonin in the IMQ group showed a significant decrease (947.042 ng/ml) regarding the control group (1143.68 ng/ml). The pretreatment with 8-OH-DPAT alleviated pain-related behaviours. These results suggest that the long-lasting pain resulting from psoriasis inflammation is also associated with the serotonergic system. The 5-HT1A receptor should be further explored as a potential therapeutic target for psoriasis pain modulation.
Assuntos
Dor Crônica , Psoríase , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/uso terapêutico , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Imiquimode , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/induzido quimicamente , Psoríase/complicações , Psoríase/tratamento farmacológico , Receptor 5-HT1A de Serotonina , Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêuticoRESUMO
Recent evidence indicates that 5-HT1A receptors play a significant role in mediating maternal behavior in rats. Given that they also modulate the mesocortical dopamine system, we hypothesized that 5-HT1A receptors may mediate maternal behavior, possibly by interacting with the D2 receptor. To address this issue, we used a combination of 5-HT1A agonist (8-OH-DPAT, 0.5 mg/kg) and two D2 drugs (an agonist quinpirole, QUIN, 1.0 mg/kg; a potent D2 antagonist haloperidol, HAL, 0.1 mg/kg) on rat maternal behavior in the home-cage maternal behavior and pup preference tests. We replicated the findings that acute QUIN, HAL, and 8-OH-DPAT disrupted home-cage maternal behavior. When administered in combination, pretreatment with HAL and QUIN worsened 8-OH-DPAT-induced maternal disruption and induced a decrease in the pup preference ratio. Accordingly, 8-OH-DPAT enhanced QUIN' and HAL's disruption of pup retrieval and pup preference, reversed the increase in hovering over pups induced by HAL. These findings suggest that activation of 5-HT1A receptors enhances D2-mediated maternal disruption. Furthermore, given that the combination of D2 drugs and 5-HT1A agonists only produced an additive effect on maternal disruption, 5-HT1A receptors may have a direct effect on maternal behavior independent of their interaction with D2 receptors.
Assuntos
Dopamina , Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Feminino , Quimpirol/farmacologia , Ratos , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
Tetrabenazine, a preferential inhibitor of the vesicular monoamine transporter type 2, depletes the brain monoamines dopamine, serotonin and norepinephrine. Tetrabenazine and deutetrabenazine (Austedo ®) are used to treat chorea associated with Huntington's disease. However, both compounds are known to aggravate Parkinsonism and depression observed in Huntington's disease patients. NLX-112 (a.k.a. befiradol/F13640) is a highly selective, potent and efficacious serotonin 5-HT 1A agonist. In animal models, it has robust efficacy in combating other iatrogenic motor disorders such as L-DOPA-induced dyskinesia and has marked antidepressant-like activity in rodent tests. In the present study, we investigated, in rats, the efficacy of NLX-112 to counteract tetrabenazine-induced catalepsy (a model of Parkinsonism) and tetrabenazine-induced potentiation of immobility in the forced swim test (FST, a model to detect antidepressant-like activity). The prototypical 5-HT 1A agonist, (±)8-OH-DPAT, and the 5-HT 1A partial agonist/dopamine D2 receptor blocker, buspirone, were used as comparators. Both NLX-112 and (±)8-OH-DPAT (0.16-2.5 mg/kg p.o. or s.c., respectively) abolished catalepsy induced by tetrabenazine (2 mg/kg i.p.). In comparison, buspirone (0.63-5.0 mg/kg p.o.) was ineffective and even tended to potentiate tetrabenazine-induced catalepsy at 0.63 mg/kg. In the FST, NLX-112 and (±)8-OH-DPAT (0.63 mg/kg) strongly reduced immobility when administered alone but also significantly opposed potentiation of immobility induced by tetrabenazine (1.5 mg/kg i.p.). Buspirone (0.63 and 2.5 mg/kg p.o.) had no effect by itself or against tetrabenazine. These results strongly suggest that selective and highly efficacious 5-HT 1A agonists, such as NLX-112, may be useful in combating tetrabenazine-induced Parkinsonism and/or depression in Huntington's disease patients.
Assuntos
Doença de Huntington , Transtornos Parkinsonianos , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Antidepressivos/farmacologia , Buspirona/farmacologia , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Doença de Huntington/induzido quimicamente , Doença de Huntington/tratamento farmacológico , Piperidinas , Piridinas , Ratos , Receptor 5-HT1A de Serotonina , Serotonina , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , TetrabenazinaRESUMO
The reticular thalamic nucleus (RTn) is a thin shell of GABAergic neurons that covers the dorsal thalamus that regulate the global activity of all thalamic nuclei. RTn controls the flow of information between thalamus and cerebral cortex since it receives glutamatergic information from collaterals of thalamo-cortical (TCs) and cortico-thalamic neurons. It also receives aminergic information from several brain stem nuclei, including serotonergic fibers originated in the dorsal raphe nucleus. RTn neurons express serotonergic receptors including the 5-HT1A subtype, however, the role of this receptor in the RTn electrical activity has been scarcely analyzed. In this work, we recorded in vivo the unitary spontaneous electrical activity of RTn neurons in anesthetized rats; our study aimed to obtain information about the effects of 5-HT1A receptors in RTn neurons. Local application of fluoxetine (a serotonin reuptake inhibitor) increases burst firing index accompanied by a decrease in the basal spiking rate. Local application of different doses of serotonin and 8-OH-DPAT (a specific 5-HT1A receptor agonist) causes a similar response to fluoxetine effects. Local 5-HT1A receptors blockade produces opposite effects and suppresses the effect by 8-OH-DPAT. Our findings indicate the presence of a serotonergic tonic discharge in the RTn that increases the burst firing index and simultaneously decreases the basal spiking frequency through 5-HT1A receptors activation.
Assuntos
Fluoxetina , Receptor 5-HT1A de Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Fluoxetina/farmacologia , Neurônios GABAérgicos , Humanos , Ratos , Núcleos Talâmicos/fisiologiaRESUMO
Severe aggressive behavior of juvenile pufferfish affects economic efficiency and fish welfare in aquaculture. 5-HT plays an important role in regulating the aggressive behavior of fish in aquaculture environment. This study examined the effects of different concentrations (0, 0.25, 0.5, 1 mg/kg) of 8-OH-DPAT, a selective 5-HT1A receptor agonist, on the aggressive behavior of juvenile pufferfish. Forty-five minutes after drug injection, the aggressive behavior of juvenile fish was recorded for 20 min, including the latency to the first attack and the frequency of aggressive behaviors. The results showed no significant differences in the latency to the first attack of juvenile fish among treatment groups. During the first 10 min of the observation period, there was no significant difference in the total aggressive acts and locomotor activity among treatment groups. Total aggressive acts and locomotor activity were the least in the 1 mg/kg 8-OH-DPAT-treated during the 20 min observation period. Both aggressive behavior and locomotor activity were negatively correlated with 8-OH-DPAT treatment overall, respectively. The above results suggested that the serotonergic system activation had suppressive effects on aggressive behavior and locomotor activity in juvenile pufferfish.
Assuntos
Receptor 5-HT1A de Serotonina , Takifugu , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Agressão/fisiologia , Animais , Humanos , Agonistas do Receptor de Serotonina/farmacologiaRESUMO
The neurotransmitter serotonin (5-HT) plays an important role in mood disorders. It has been demonstrated that 5-HT signaling through 5-HT1A receptors (5-HT1A-R) is crucial for early postnatal hippocampal development and later-life behavior. Although this suggests that 5-HT1A-R signaling regulates early brain development, the mechanistic underpinnings of this process have remained unclear. Here we show that stimulation of the 5-HT1A-R at postnatal day 6 (P6) by intrahippocampal infusion of the agonist 8-OH-DPAT (D) causes signaling through protein kinase Cε (PKCε) and extracellular receptor activated kinase ½ (ERK1/2) to boost neuroblast proliferation in the dentate gyrus (DG), as displayed by an increase in bromodeoxy-uridine (BrdU), doublecortin (DCX) double-positive cells. This boost in neuroproliferation was eliminated in mice treated with D in the presence of a 5-HT1A-R antagonist (WAY100635), a selective PKCε inhibitor, or an ERK1/2-kinase (MEK) inhibitor (U0126). It is believed that hippocampal neuro-progenitors undergoing neonatal proliferation subsequently become postmitotic and enter the synaptogenesis phase. Double-staining with antibodies against bromodeoxyuridine (BrdU) and neuronal nuclear protein (NeuN) confirmed that 5-HT1A-R â PKCε â ERK1/2-mediated boosted neuroproliferation at P6 also leads to an increase in BrdU-labeled granular neurons at P36. This 5-HT1A-R-mediated increase in mature neurons was unlikely due to suppressed apoptosis, because terminal deoxynucleotidyl transferase dUTP nick-end labeling analysis showed no difference in DNA terminal labeling between vehicle and 8-OH-DPAT-infused mice. Therefore, 5-HT1A-R signaling through PKCε may play an important role in micro-neurogenesis in the DG at P6, following which many of these new-born neuroprogenitors develop into mature neurons.
Assuntos
Hipocampo/metabolismo , Neurogênese/fisiologia , Proteína Quinase C-épsilon/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Serotonina/metabolismo , Transdução de Sinais/fisiologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Bromodesoxiuridina/farmacologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
The neurotransmitter serotonin (5-HT) reduces aggressive behaviour in a number of vertebrates, and the 5-HT1A receptor is known to be involved in this regulation. However, the role of this receptor in the modulation of sociopositive behaviour remains largely unknown. Here we investigated the role of the 5-HT1A receptor in the regulation of aggressive, submissive and affiliative behaviour in the cooperatively-breeding cichlid Neolamprologus pulcher. In two experiments, we performed intramuscular injections of a 5-HT1A agonist (8-OH-DPAT) and antagonist (Way-100635) followed by recordings of social behaviour of injected fish within their social groups. We determined the concentrations and post-injection times when the drugs had the greatest effect on social behaviour. We recorded spontaneous social behaviour in both experiments. In the second experiment we also recorded behaviour after social groups received a territorial challenge by live presentations of either conspecifics or egg predators. The 5-HT1A agonist caused an increase in aggression and a decrease in submission and affiliation, whereas the antagonist had the opposite effects. Thus, the 5-HT1A receptor plays an important regulatory role not only for aggressive but also sociopositive behaviour.
Assuntos
Ciclídeos , Receptor 5-HT1A de Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Agonistas do Receptor de Serotonina/farmacologia , Comportamento SocialRESUMO
NLX-101 and F13714 are selective, full efficacy, biased agonists of the serotonin (5-HT1A) receptor. NLX-101 preferentially activates cortical postsynaptic 5-HT1A receptors, whereas F13714 preferentially activates raphe nuclei presynaptic 5-HT1A receptors. We compared NLX-101 and F13714 for their efficacy and potency to substitute for the discriminative cue produced by the prototypical, nonbiased 5-HT1A receptor agonist 8-OH-DPAT (racemate). Male and female Sprague-Dawley rats were trained to discriminate 8-OH-DPAT (0.1 mg/kg i.p., 20 min pretreatment) from saline using a classical two-lever drug-discrimination procedure. 8-OH-DPAT (0.01 and 0.05 mg/kg i.p.) dose-dependently substituted for the training dose, with about 50% responding on the 8-OH-DPAT-associated lever at 0.05 mg/kg. F13714 fully and very potently substituted for the training dose of 8-OH-DPAT from 0.018 mg/kg i.p., whereas NLX-101 only achieved full substitution at 0.5 mg/kg i.p., a dose which is known to also activate presynaptic 5-HT1A receptors. The 5-HT1A receptor partial agonist, buspirone, partially substituted (~80%) at 1 and 2 mg/kg i.p., doses which also decreased response rates. F13714 decreased response rates at 0.05 mg/kg. The selective 5-HT1A receptor antagonist WAY-100 635 (1 mg/kg s.c., 40 min pretreatment) elicited almost no responding on the 8-OH-DPAT-associated lever by itself, but blocked the discriminative stimulus effects produced by administration (20 min pretreatment) of 8-OH-DPAT (0.1 mg/kg), F13714 (0.025 mg/kg), NLX-101 (0.5 mg/kg) or buspirone (1 mg/kg). These data suggest that the discriminative cue produced by 0.1 mg/kg i.p. 8-OH-DPAT results from activation of presynaptic 5-HT1A receptors. They also further demonstrate the distinct profiles in behavioral models of 5-HT1A receptor-biased agonists.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Aminopiridinas/farmacologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Aminopiridinas/administração & dosagem , Animais , Buspirona/administração & dosagem , Buspirona/farmacologia , Aprendizagem por Discriminação , Relação Dose-Resposta a Droga , Feminino , Masculino , Piperazinas/farmacologia , Piperidinas/administração & dosagem , Piridinas/farmacologia , Pirimidinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagemRESUMO
The forward (kon) and reverse (koff) rate constants of drug-target interactions have important implications for therapeutic efficacy. Hence, time-resolved assays capable of measuring these binding rate constants may be informative to drug discovery efforts. Here, we used an ion channel activation assay to estimate the kons and koffs of four dopamine D2 receptor (D2R) agonists; dopamine (DA), p-tyramine, (R)- and (S)-5-OH-dipropylaminotetralin (DPAT). We further probed the role of the conserved serine S1935.42 by mutagenesis, taking advantage of the preferential interaction of (S)-, but not (R)-5-OH-DPAT with this residue. Results suggested similar koffs for the two 5-OH-DPAT enantiomers at wild-type (WT) D2R, both being slower than the koffs of DA and p-tyramine. Conversely, the kon of (S)-5-OH-DPAT was estimated to be higher than that of (R)-5-OH-DPAT, in agreement with the higher potency of the (S)-enantiomer. Furthermore, S1935.42A mutation lowered the kon of (S)-5-OH-DPAT and reduced the potency difference between the two 5-OH-DPAT enantiomers. Kinetic Kds derived from the koff and kon estimates correlated well with EC50 values for all four compounds across four orders of magnitude, strengthening the notion that our assay captured meaningful information about binding kinetics. The approach presented here may thus prove valuable for characterizing D2R agonist candidate drugs.
Assuntos
Agonistas de Dopamina/metabolismo , Receptores de Dopamina D2/química , Receptores de Dopamina D2/metabolismo , Serina/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Sequência Conservada , Dopamina/metabolismo , Agonistas de Dopamina/química , Humanos , Cinética , Proteínas Mutantes/metabolismo , Mutação/genética , Fenetilaminas/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Tiramina/metabolismo , Xenopus laevisRESUMO
Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists are neuroprotective in CNS injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), a serotonin receptor (5-HT1A) agonist, in an adult male Wistar rat model of chronic glaucoma model remain unknown. We found that ocular hypertension decreased 5-HT1A receptor expression in rat retinas because the number of retinal ganglion cells (RGCs) was significantly reduced in rats with induced ocular hypertension relative to that in control retinas and 8-OH-DPAT enhanced the RGC viability. The protective effects of 8-OH-DPAT were blocked by intravitreal administration of the selective 5-HT1A antagonist WAY-100635 or the selective GABAA receptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic IPSCs (sIPSCs and mIPSCs, respectively) of RGCs in rat retinal slices were recorded. 8-OH-DPAT significantly increased the frequency and amplitude of GABAergic sIPSCs and mIPSCs in ON- and OFF-type RGCs. Among the signaling cascades mediated by the 5-HT1A receptor, the role of cAMP-protein kinase A (PKA) signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by PKA inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of phosphorylated PKA (p-PKA)/PKA was significantly increased in glaucomatous retinas and 8-OH-DPAT significantly decreased p-PKA/PKA expression, which led to the inhibition of PKA phosphorylation upon relieving neurotransmitter GABA release. These results showed that the activation of 5-HT1A receptors in retinas facilitated presynaptic GABA release functions by suppressing cAMP-PKA signaling and decreasing PKA phosphorylation, which could lead to the de-excitation of RGC circuits and suppress excitotoxic processes in glaucoma.SIGNIFICANCE STATEMENT We found that serotonin (5-HT) receptors in the retina (5-HT1A receptors) were downregulated after intraocular pressure elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic IPSCs (mIPSCs) in ON- and OFF-type retinal ganglion cells (RGCs) and RGCs in normal and glaucomatous retinal slices. Therefore, phosphorylated protein kinase A (PKA) inhibition upon release of the neurotransmitter GABA was eliminated by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), which led to increased levels of GABAergic mIPSCs in ON- and OFF-type RGCs, thus enhancing RGC viability and function. These protective effects were blocked by the GABAA receptor antagonist SR95531 or the 5-HT1A antagonist WAY-100635. This study identified a novel mechanism by which activation of 5-HT1A receptors protects damaged RGCs via the cAMP-PKA signaling pathway that modulates GABAergic presynaptic activity.
Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , AMP Cíclico/fisiologia , Proteínas do Olho/metabolismo , Glaucoma/metabolismo , Receptor 5-HT1A de Serotonina/fisiologia , Células Ganglionares da Retina/metabolismo , Ácido gama-Aminobutírico/metabolismo , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Bucladesina/farmacologia , Proteínas Quinases Dependentes de AMP Cíclico/efeitos dos fármacos , Isoquinolinas/farmacologia , Masculino , Hipertensão Ocular/metabolismo , Fosforilação/efeitos dos fármacos , Piperazinas/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Wistar , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Sistemas do Segundo Mensageiro/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina/farmacologia , Sulfonamidas/farmacologiaRESUMO
Active expiration represents an important mechanism to improve ventilation in conditions of augmented ventilatory demand, such as hypercapnia. While a rostral ventromedullary region, the parafacial respiratory group (pFRG), has been identified as a conditional expiratory oscillator, little is known about how central chemosensitive sites contribute to modulate active expiration under hypercapnia. In this study, we investigated the influence of the medullary raphe in the emergence of phasic expiratory abdominal activity during hypercapnia in unanesthetized adult male rats, in a state-dependent manner. To do so, reverse microdialysis of muscimol (GABAA receptor agonist, 1 mM) or 8-OH-DPAT (5-HT1A agonist, 1 mM) was applied in the MR during sleep and wakefulness periods, both in normocapnic (room air) and hypercapnic conditions (7% CO2). Electromyography (EMG) of diaphragm and abdominal muscles was performed to measure inspiratory and expiratory motor outputs. We found that active expiration did not occur in room air exposure during wakefulness or sleep. However, hypercapnia did recruit active expiration, and differential effects were observed with the drug dialyses in the medullary raphe. Muscimol increased the diaphragm inspiratory motor output and also increased the amplitude and frequency of abdominal expiratory rhythmic activity during hypercapnia in wakefulness periods. On the other hand, the microdialysis of 8-OH-DPAT attenuated hypercapnia-induced active expiration in a state-dependent manner. Our data suggest that the medullary raphe can either inhibit or potentiate respiratory motor activity during hypercapnia, and the balance of these inhibitory or excitatory outputs may determine the expression of active expiration.
Assuntos
Diafragma/fisiopatologia , Expiração , Hipercapnia/fisiopatologia , Núcleos da Rafe/fisiopatologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Músculos Abdominais/inervação , Músculos Abdominais/fisiopatologia , Animais , Diafragma/inervação , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Muscimol/farmacologia , Contração Muscular , Núcleos da Rafe/efeitos dos fármacos , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/farmacologia , Sono , VigíliaRESUMO
BACKGROUND: Depression is one of the most common neuropsychiatric disturbances in Parkinson's disease (PD), but its pathophysiology is not definite. Lines of evidence have indicated that the hippocampus and serotonin 1A (5-HT1A) receptors are related to the regulation of depression. OBJECTIVE: The purpose of the present study was to observe the effect of 5-HT1A receptors in the dorsal hippocampus (dHIP) on PD-related depression in rats. METHODS: Unilateral 6-hydroxydopamine lesioning of the medial forebrain bundle (MFB) was used to establish the hemiparkinsonian rat model. The effects of intra-dHIP injection of the 5-HT1A receptor -agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) or antagonist WAY-100635 on depressive-like behaviors were observed in sucrose preference and forced swim tests in control and lesioned rats. Monoamine levels including dopamine (DA), 5-HT, and noradrenaline (NA) in depression-related brain regions were determined by a neurochemical method in all groups. RESULTS: Behavioral results showed that MFB lesions induced depressive-like behaviors. Intra-dHIP injection of 8-OH-DPAT produced antidepressant effects, while WAY-100635 induced or increased the depressive-like behaviors in both control and the lesioned rats. Neurochemical results found that intra-dHIP injection of 8-OH-DPAT significantly increased DA and 5-HT levels in the medial prefrontal cortex (mPFC), lateral habenula (LHb), ventral hippocampus and amygdala in the lesioned group and decreased NA levels in the mPFC and LHb in the control group. Moreover, after injection of WAY-100635, NA levels in all these regions of the lesioned group were significantly increased. CONCLUSIONS: These findings suggest that hippocampal 5-HT1A receptors regulate depression and PD-related depression by neurochemical mechanisms.
Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Doença de Parkinson/complicações , Receptor 5-HT1A de Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Antagonistas da Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Depressão/etiologia , Depressão/metabolismo , Modelos Animais de Doenças , Habenula/efeitos dos fármacos , Habenula/metabolismo , Masculino , Feixe Prosencefálico Mediano/lesões , Piperazinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Antagonistas da Serotonina/administração & dosagemRESUMO
The essential oil obtained by the fresh fruit of Citrus bergamia Risso et Poiteau is used worldwide in aromatherapy to reduce pain, facilitate sleep induction, and/or minimize the effects of stress-induced anxiety. Preclinical pharmacological data demonstrate that bergamot essential oil (BEO) modulates specific neurotransmissions and shows an anxiolytic-relaxant effect not superimposable to that of the benzodiazepine diazepam, suggesting that neurotransmissions, other than GABAergic, could be involved. Several studies on essential oils indicate a role for serotonergic (5-HT) neurotransmission in anxiety. Interestingly, among serotonergic receptors, the 5-HT1A subtype seems to play a key role in the control of anxiety. Here, we report that modulation of the 5-HT1A receptor by selective agonist ((±)8-OH-DPAT) or antagonist (WAY-100635) may influence some of the anxiolytic-relaxant effects of BEO in Open Field and Elevated Plus Maze tests.