RESUMEN
Omeprazole, a drug of choice for the management of gastric hyperacidity, influences serotonergic neurotransmission in brain regions and its long-term use is known to cause stress-related behavioral deficits including anxiety. Aim of the current study was to explore the effects of omeprazole treatment on immobilization-induced anxiety in rats, specifically on the role of serotonin (5-HT). In view of the role of serotonin-1A (5-HT1A) autoreceptor in the availability of 5-HT in brain regions, mRNA expression of this autoreceptor was performed in raphe nuclei. Similarly, because of the role of hippocampal 5-HT neurotransmission in anxiety-like disorders, expression of the 5-HT1A heteroreceptors was determined in this region. We found that the treatment with omeprazole reduces anxiety-like behavior in rats, increases the expression of 5-HT1A autoreceptor in the raphe and decreases the hippocampal expression of 5-HT1A heteroreceptor. This suggests a role of 5-HT1A receptor types in omeprazole-induced behavioral changes. It also indicates a potential role of omeprazole in the management of serotonergic disorders.
Asunto(s)
Ansiedad , Modelos Animales de Enfermedad , Hipocampo , Omeprazol , Receptor de Serotonina 5-HT1A , Estrés Psicológico , Animales , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Omeprazol/farmacología , Masculino , Ratas , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Estrés Psicológico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratas Wistar , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Serotonina/metabolismo , Núcleos del Rafe/metabolismo , Núcleos del Rafe/efectos de los fármacos , ARN Mensajero/metabolismo , Restricción Física , InmovilizaciónRESUMEN
The head-twitch response (HTR) in mice is considered a behavioral assay for activation of 5-HT 2A receptors in rodents. It can be evoked by direct-acting 5-HT 2A receptor agonists such as (±)-2,5-dimethoxy-4-iodoamphetamine, 5-hydroxytryptamine precursors [e.g. 5-hydroxytryptophan (5-HTP)], and selective 5-hydroxytryptamine releasers (e.g. d -fenfluramine). The nonselective monoamine releaser methamphetamine by itself does not produce the HTR but can suppress both (±)-2,5-dimethoxy-4-iodoamphetamine- and d -fenfluramine-evoked HTRs across ages via concomitant activation of the inhibitory serotonergic 5-HT 1A or adrenergic α 2 receptors. Currently, we investigated: (1) the ontogenic development of 5-HTP-induced HTR in 20-, 30-, and 60-day-old mice; (2) whether pretreatment with ultra-low doses of methamphetamine (0.1, 0.25, and 0.5â mg/kg, intraperitoneally) can suppress the frequency of 5-HTP-induced HTR at different ages; and (3) whether the inhibitory serotonergic 5-HT 1A or adrenergic α 2 receptors may account for the potential inhibitory effect of methamphetamine on 5-HTP-induced HTR. In the presence of a peripheral decarboxylase inhibitor (carbidopa), 5-HTP produced maximal frequency of HTRs in 20-day-old mice which rapidly subsided during aging. Methamphetamine dose-dependently suppressed 5-HTP-evoked HTR in 20- and 30-day-old mice. The selective 5-HT 1A -receptor antagonist WAY 100635 reversed the inhibitory effect of methamphetamine on 5-HTP-induced HTR in 30-day-old mice, whereas the selective adrenergic α 2 -receptor antagonist RS 79948 failed to reverse methamphetamine's inhibition at any tested age. These findings suggest an ontogenic rationale for methamphetamine's inhibitory 5-HT 1A receptor component of action in its suppressive effect on 5-HTP-induced HTR during development which is not maximally active at a very early age.
Asunto(s)
5-Hidroxitriptófano , Envejecimiento , Metanfetamina , Animales , Metanfetamina/farmacología , Ratones , Envejecimiento/efectos de los fármacos , 5-Hidroxitriptófano/farmacología , Masculino , Relación Dosis-Respuesta a Droga , Movimientos de la Cabeza/efectos de los fármacos , Ratones Endogámicos C57BL , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismoRESUMEN
As a subtype of the 5-hydroxytryptamine (5-HT) receptor, 5-HT1A receptors are involved in the pathological process of psychiatric disorders and is an important target for antidepressants. The research groups focus on these area have tried to design novel compounds to alleviate depression by targeting 5-HT1A receptor. The heterocyclic structures is an important scaffold to enhance the antidepressant activity of ligands, including piperazine, piperidine, benzothiazole, and pyrrolidone. The current review highlights the function and significance of nitrogen-based heterocyclics 5-HT1AR represented by piperazine, piperidine, benzothiazole, and pyrrolidone in the development of antidepressant.
Asunto(s)
Antidepresivos , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1 , Humanos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Piperazinas/farmacología , Piperazinas/química , Benzotiazoles/farmacología , Benzotiazoles/química , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/uso terapéutico , Piperidinas/farmacología , Piperidinas/uso terapéutico , Piperidinas/química , Pirrolidinonas/farmacología , Pirrolidinonas/uso terapéutico , Pirrolidinonas/química , Depresión/tratamiento farmacológicoRESUMEN
BACKGROUND: The highly selective 5-HT1A serotonin receptor "biased" agonists NLX-101 and NLX-204 display, like ketamine, potent and efficacious rapid-acting antidepressant (RAAD) activity in the rat chronic mild stress (CMS) model with systemic (i.p.) administration. They rapidly (within 1 day) reverse anhedonia (i.e., CMS-induced sucrose consumption deficit), attenuate working memory deficit (novel object recognition: NOR), and decrease anxiety behavior in the elevated-plus maze (EPM). AIMS: Here, we sought to explore the contribution of prefrontal cortex (PFC) 5-HT1A receptor activation in the RAAD activity of NLX compounds. RESULTS/OUTCOMES: In male Wistar rats, unilateral PFC microinjections of NLX-204 and NLX-101 (16 µg), like ketamine (10 µg), reproduced the effects of their systemic administration: they reversed CMS-induced sucrose consumption deficit, attenuated anxiety (EPM), and reduced working memory deficits (NOR). In addition, unilateral PFC microinjections of the selective 5-HT1A antagonist, WAY-100,635 (2 µg), attenuated the beneficial effects of systemic NLX-204 and NLX-101 (0.16 mg/kg i.p.) in the sucrose intake and NOR models, indicating that these compounds exert their RAAD activity specifically through activation of PFC 5-HT1A receptors. CONCLUSIONS/INTERPRETATION: These data indicate that 5-HT1A receptor biased agonists share with ketamine a common neuroanatomical site for RAAD activity, which can be obtained not only by targeting glutamatergic/NMDA neurotransmission (ketamine's primary mechanism of action) but also by activating 5-HT1A receptors, as is the case for the NLX compounds. The present observations also reinforce the notion that biased agonism at 5-HT1A receptors constitutes a promising strategy to achieve RAAD effects, with additional benefits against cognitive deficits and anxiety in depressed patients, without ketamine's troublesome side effects.
Asunto(s)
Antidepresivos , Modelos Animales de Enfermedad , Ketamina , Ratas Wistar , Receptor de Serotonina 5-HT1A , Agonistas del Receptor de Serotonina 5-HT1 , Estrés Psicológico , Animales , Ketamina/farmacología , Ketamina/administración & dosificación , Masculino , Ratas , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Anhedonia/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Piridinas/farmacología , Memoria a Corto Plazo/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/administración & dosificación , Depresión/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Piperidinas , PirimidinasRESUMEN
Recent studies have shown that the 5-HT1a receptor (5-HT1aR) in the central 5-HT (Serotonergic) system is involved in the pathophysiology of schizophrenia through its various receptors, and the dysfunction of the ventral hippocampus may be a key causative factor in schizophrenia. To date, whether the 5-HT1a receptor is involved in ventral hippocampal dysfunction and its internal mechanism remain unclear. In this study, schizophrenia-like animal model was induced by intraperitoneal injection of aspartate receptor antagonist MK-801 in male Sprague Dawley rats, and the role of 5-HT1aR in this animal model was investigated by bilaterally micro-infusing the 5-HT1aR antagonist WAY100635 into the ventral subiculum (vSub) of the hippocampus of rats. Behavioral experiments such as open field test (OFT) and prepulse inhibition (PPI) were performed. The results showed that MK-801 induced hyperactivity and impaired prepulse inhibition in rats, whereas, micro-infusion of 5-HT1aR antagonist WAY100635 into the vSub ameliorated these phenomena. Immunofluorescence analysis revealed that WAY100635 significantly increased the c-Fos expression in vSub. Western blot and immunohistochemical analysis showed that MK-801 induced up-regulation of 5-HT1aR and phospho-extracellular regulated protein kinase (p-ERK) pathway, while micro-infusion of the WAY100635 down-regulated 5-HT1aR and p-ERK in the vSub. Therefore, the results of the present study suggested that in vSub, the 5-HT1aR antagonist WAY100635 may attenuate MK-801-induced schizophrenia-like activity by modulating excitatory neurons and downregulating p-ERK.
Asunto(s)
Maleato de Dizocilpina , Hipocampo , Piperazinas , Piridinas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A , Esquizofrenia , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Maleato de Dizocilpina/farmacología , Masculino , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Piperazinas/farmacología , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Piridinas/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Ratas , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Inhibición Prepulso/efectos de los fármacos , MicroinyeccionesRESUMEN
Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HT1AR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HT2AR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3â¯mg/kg), WAY100,635 (0.4â¯mg/kg), DOI (0.1â¯mg/kg), ALT (1â¯mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[123I]iodophenyl)-nortropane ([123I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HT1AR inhibition and 5-HT2AR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.
Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Conducta Exploratoria , Reconocimiento en Psicología , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Masculino , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Emociones/efectos de los fármacos , Emociones/fisiología , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratas WistarRESUMEN
BACKGROUND: Yokukansan, a traditional Japanese medicine (Kampo), has been widely used to treat neurosis, dementia, and chronic pain. Previous in vitro studies have suggested that Yokukansan acts as a partial agonist of the 5-HT1A receptor, resulting in amelioration of chronic pain through inhibition of nociceptive neuronal activity. However, its effectiveness for treating postoperative pain remains unknown, although its analgesic mechanism of action has been suggested to involve serotonin and glutamatergic neurotransmission. This study aimed to investigate the effect of Yokukansan on postoperative pain in an animal model. METHODS: A mouse model of postoperative pain was created by plantar incision, and Yokukansan was administered orally the day after paw incision. Pain thresholds for mechanical and heat stimuli were examined in a behavioral experiment. In addition, to clarify the involvement of the serotonergic nervous system, we examined the analgesic effects of Yokukansan in mice that were serotonin-depleted by para-chlorophenylalanine (PCPA) treatment and intrathecal administration of NAN-190, 5-HT1A receptor antagonist. RESULTS: Orally administered Yokukansan increased the pain threshold dose-dependent in postoperative pain model mice. Pretreatment of para-chlorophenylalanine dramatically suppressed serotonin immunoreactivity in the spinal dorsal horn without changing the pain threshold after the paw incision. The analgesic effect of Yokukansan tended to be attenuated by para-chlorophenylalanine pretreatment and significantly attenuated by intrathecal administration of 2.5 µg of NAN-190 compared to that in postoperative pain model mice without para-chlorophenylalanine treatment and NAN-190 administration. CONCLUSION: This study demonstrated that oral administration of Yokukansan has acute analgesic effects in postoperative pain model mice. Behavioral experiments using serotonin-depleted mice and mice intrathecally administered with a 5-HT1A receptor antagonist suggested that Yokukansan acts as an agonist at the 5-HT1A receptor, one of the serotonin receptors, to produce analgesia.
Asunto(s)
Analgésicos , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos , Dolor Postoperatorio , Animales , Ratones , Medicamentos Herbarios Chinos/farmacología , Masculino , Dolor Postoperatorio/tratamiento farmacológico , Analgésicos/farmacología , Serotonina/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Administración Oral , Ratones Endogámicos ICRRESUMEN
Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.
Asunto(s)
Ratones Endogámicos C57BL , Paroxetina , Inhibidores Selectivos de la Recaptación de Serotonina , Serotonina , Síndrome de Abstinencia a Sustancias , Animales , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Paroxetina/farmacología , Serotonina/metabolismo , Masculino , Síndrome de Abstinencia a Sustancias/metabolismo , Ratones , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Ácido Hidroxiindolacético/metabolismo , Microdiálisis , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismoRESUMEN
OBJECTIVES: The serotonin (5-hydroxytryptamine, 5-HT) receptor 1A (5-HT1AR) is closely associated with serotonergic neurotransmission in the brain, being the most prevalent and widely distributed receptor of its kind. The purpose of this study is to investigate the regulation mechanism of 5-HT1AR by GSK4716. METHODS: To investigate the mechanism of GSK4716-mediated 5-HT1AR regulation, we used hippocampus-derived HT22 cells expressing 5-HT1AR. The expression level of 5-HT1AR and associated proteins, were detected by reporter gene assay and western blotting. RESULTS: GSK4716, an estrogen-related receptor gamma agonist increased 5-HT1AR expression by interacting with the GR, a repressor of 5-HT1AR transcription. Dexamethasone, a GR agonist, decreased the GSK4716-induced increase in 5-HT1AR, which was associated with an alteration in nuclear GR. Furthermore, GR antagonist RU486 reversed the effects induced by dexamethasone, including the elevation of nuclear GR levels and the reduction of 5-HT1AR transcription and expression. CONCLUSION: The results could provide insight into the potential applications of small molecules, such as GSK4716, in the regulation of 5-HT1AR expression, which plays a role in serotonergic neurotransmission.
Asunto(s)
Hipocampo , Receptor de Serotonina 5-HT1A , Receptores de Glucocorticoides , Animales , Ratones , Línea Celular , Dexametasona/farmacología , Estrógenos/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Mifepristona/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Schizophrenia is a psychotic disorder with an increasing prevalence and incidence over the last two decades. The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N-methyl-D-aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU-580), an analogue of CBDA known to act as an agonist of the serotonin-1A receptor (5-HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK-801, .3 mg/kg) once daily for 17 days. After 7 days, they were concurrently given HU-580 (.01 or .05 µg/kg) for 10 days. Behavioural deficits were assessed at two time points. We conducted enzyme-linked immunosorbent assays to measure the concentration of PFC 5-HT1AR and CB1R. We found that MK-801 effectively induced schizophrenia-related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low-dose HU-580 (.01 µg/kg), but not the high dose (.05 µg/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK-801 downregulated both CB1R and 5-HT1AR, an effect that was blocked by both low- and high-dose HU-580. This study sheds light on the potential antipsychotic properties of HU-580, particularly in the context of NMDAR-induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU-580 and related compounds in alleviating symptoms.
Asunto(s)
Modelos Animales de Enfermedad , Maleato de Dizocilpina , Ratones Endogámicos C57BL , Receptor Cannabinoide CB1 , Receptor de Serotonina 5-HT1A , Esquizofrenia , Animales , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/inducido químicamente , Esquizofrenia/metabolismo , Maleato de Dizocilpina/farmacología , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Masculino , Ratones , Femenino , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB1/agonistas , Cannabinoides/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Antipsicóticos/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: Ayahuasca (AYA) is a botanical psychedelic with promising results in observational and small clinical trials for depression, trauma and drug use disorders. Its psychoactive effects primarily stem from N,N-dimethyltryptamine (DMT). However, there is a lack of research on how and where AYA acts in the brain. This study addressed these questions by examining the extinction of aversive memories in AYA-treated rats. EXPERIMENTAL APPROACH: We focused on the 5-HT1A and 5-HT2A receptors, as DMT exhibits a high affinity for both of them, along with the infralimbic cortex in which activity and plasticity play crucial roles in regulating the mnemonic process under analysis. KEY RESULTS: A single oral treatment with AYA containing 0.3 mg·kg-1 of DMT increased the within-session extinction of contextual freezing behaviour without affecting its recall. This protocol, when repeated twice on consecutive days, enhanced extinction recall. These effects were consistent for both 1- and 21-day-old memories in males and females. AYA effects on fear extinction were independent of changes in anxiety and general exploratory activity: AYA- and vehicle-treated animals showed no differences when tested in the elevated plus-maze. The 5-HT2A receptor antagonist MDL-11,939 and the 5-HT1A receptor antagonist WAY-100635 infused into the infralimbic cortex respectively blocked within- and between-session fear extinction effects resulting from repeated oral administration of AYA. CONCLUSION AND IMPLICATIONS: Our findings highlight complementary mechanisms by which AYA facilitates the behavioural suppression of aversive memories in the rat infralimbic cortex. These results suggest potential beneficial effects of AYA or DMT in stress-related disorders.
Asunto(s)
Banisteriopsis , Extinción Psicológica , Miedo , Receptor de Serotonina 5-HT1A , Receptor de Serotonina 5-HT2A , Animales , Miedo/efectos de los fármacos , Miedo/fisiología , Masculino , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Ratas , Banisteriopsis/química , Alucinógenos/farmacología , Alucinógenos/administración & dosificación , Ratas Sprague-Dawley , Conducta Animal/efectos de los fármacos , Piridinas/farmacologíaRESUMEN
INTRODUCTION: Antidepressants increase the level of 5-HT in the somatodendritic region of the serotonergic dorsal raphe nucleus (DRN) neurons in the first few days of their usage, which, in turn, inhibits the serotonergic neurons locally. Pindolol may eliminate this inhibition when used in combination with antidepressants. MATERIAL AND METHODS: We aimed to determine the effect of pindolol on 5-HT1A receptor response in the DRN neurons, using voltage clamp recordings and prove the potentiation of antidepressant effect of venlafaxine by pindolol through behavior experiments. Balb/c mice, 28-35 days-old were used. RESULTS: 5-HT application (25 µM) induced an outward current by 23.36 ± 3.79 pA at the neurons in the dorsal subnucleus of DRN. This effect was inhibited by pre-administration of WAY-100135 (21 µM) and pindolol (10 µM) separately. The current induced by 5-HT and 8-OHDPAT have no statistically significance. 8-OHDPAT (30 µM) induced a 5-HT-like outward current, which was inhibited by pre-administration of pindolol (10 µM). Combination of venlafaxine (20 mg/kg/day) and pindolol (15 mg/kg/day) significantly reduced immobilization time when compared to the control group in tail suspension test and forced swim test without any significant change in locomotor activity. Administration of venlafaxine (20 mg/kg/day) alone or pindolol (15 mg/kg/day) alone did not significantly reduce immobilization time. CONCLUSION: Pindolol has the potential to prevent the inhibition of serotonergic neurons after antidepressant use. Hence, we, for the first time, demonstrated that pindolol can potentiate antidepressant effect of venlafaxine. In the mood disorders, pindolol is likely to increase the effectiveness of antidepressant drugs when given in combination.
Asunto(s)
Antidepresivos/farmacología , Núcleo Dorsal del Rafe/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Pindolol/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Clorhidrato de Venlafaxina/farmacología , Animales , Antidepresivos/administración & dosificación , Conducta Animal/efectos de los fármacos , Sinergismo Farmacológico , Ratones , Ratones Endogámicos BALB C , Pindolol/administración & dosificación , Piperazinas/farmacología , Antagonistas de la Serotonina/administración & dosificación , Clorhidrato de Venlafaxina/administración & dosificaciónRESUMEN
Systemic 8-OH-DPAT (a 5-HT1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT1A receptors induces tachypnea via disinhibition of local GABAA neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 µg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT1A receptor antagonist) or gabazine (a GABAA receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by Ë60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Antagonistas del GABA/farmacología , Hiperventilación/inducido químicamente , Hiperventilación/tratamiento farmacológico , Bulbo Raquídeo/metabolismo , Receptor de Serotonina 5-HT1A/fisiología , Centro Respiratorio/metabolismo , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Agonistas de Receptores de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Modelos Animales de Enfermedad , Masculino , Bulbo Raquídeo/efectos de los fármacos , Piperazinas/farmacología , Piridazinas/farmacología , Ratas , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Centro Respiratorio/efectos de los fármacosRESUMEN
Alcohol exposure alters the signaling of the serotoninergic system, which is involved in alcohol consumption, reward, and dependence. In particular, dysregulation of serotonin receptor type 1A (5-HT1AR) is associated with alcohol intake and withdrawal-induced anxiety-like behavior in rodents. However, how ethanol regulates 5-HT1AR activity and cell surface availability remains elusive. Using neuroblastoma 2a cells stably expressing human 5-HT1ARs tagged with hemagglutinin at the N-terminus, we found that prolonged ethanol exposure (18 h) reduced the basal surface levels of 5-HT1ARs in a concentration-dependent manner. This reduction is attributed to both enhanced receptor internalization and attenuated receptor recycling. Moreover, constitutive 5-HT1AR internalization in ethanol naïve cells was blocked by concanavalin A (ConA) but not nystatin, suggesting clathrin-dependent 5-HT1AR internalization. In contrast, constitutive 5-HT1AR internalization in ethanol-treated cells was blocked by nystatin but not by ConA, indicating that constitutive 5-HT1AR internalization switched from a clathrin- to a caveolin-dependent pathway. Dynasore, an inhibitor of dynamin, blocked 5-HT1AR internalization in both vehicle- and ethanol-treated cells. Furthermore, ethanol exposure enhanced the activity of dynamin I via dephosphorylation and reduced myosin Va levels, which may contribute to increased internalization and reduced recycling of 5-HT1ARs, respectively. Our findings suggest that prolonged ethanol exposure not only alters the endocytic trafficking of 5-HT1ARs but also the mechanism by which constitutive 5-HT1AR internalization occurs.
Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/metabolismo , Línea Celular , Clatrina/metabolismo , Concanavalina A/farmacología , Relación Dosis-Respuesta a Droga , Dinaminas/metabolismo , Endocitosis , Humanos , Hidrazonas/farmacología , Nistatina/farmacología , Antagonistas del Receptor de Serotonina 5-HT1/farmacología , Proteínas de Unión al GTP rab/metabolismoRESUMEN
Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT3 and 5-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Hidrazinas/farmacología , Infarto del Miocardio/complicaciones , Accidente Cerebrovascular/complicaciones , Animales , Antidepresivos/uso terapéutico , Simulación por Computador , Depresión/etiología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hidrazinas/uso terapéutico , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptores de Serotonina 5-HT3/efectos de los fármacos , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT3 , Proteínas de Transporte de Serotonina en la Membrana Plasmática/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
We previously reported that abnormal emotionality in stress-maladaptive mice was ameliorated by chronic treatment with flesinoxan, a 5-HT1A receptor agonist. Furthermore, the maintenance of hippocampal myelination appeared to contribute to the development of stress adaptation in mice. However, the effects of 5-HT1A receptor activation on myelination under the stress-maladaptive situations and the underlying mechanisms remain unknown. In the present study, we examined using flesinoxan whether activation of 5-HT1A receptor can reduce an abnormal emotional response by acting on oligodendrocytes to preserve myelin proteins in stress-maladaptive mice. Mice were exposed to repeated restraint stress for 4 h/day for 14 days as a stress-maladaptive model. Flesinoxan was given intraperitoneally immediately after the daily exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated by the hole-board test. The expression levels of brain-derived neurotrophic factor (BDNF), phosphorylated-extracellular signal-regulated kinase (p-ERK), phosphorylated-cAMP response element-binding protein (p-CREB), myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and oligodendrocyte transcription factor 2 (olig2) in the hippocampus was assessed by western blotting. Hippocampal oligodendrogenesis were examined by immunohistochemistry. Chronic treatment with flesinoxan suppressed the decrease in head-dipping behaviors in stress-maladaptive mice in the hole-board test. Under this condition, the decreases in MAG and MBP in the hippocampus recovered with increase in BDNF, p-ERK, p-CREB, and olig2. Furthermore, hippocampal oligodendrogenesis in stress-maladaptive mice was promoted by chronic treatment with flesinoxan. These findings suggest that 5-HT1A receptor activation may promote oligodendrogenesis and myelination via an ERK/CREB/BDNF signaling pathway in the hippocampus and reduces abnormal emotionality due to maladaptation to excessive stress.
Asunto(s)
Hipocampo/metabolismo , Proteínas de la Mielina/metabolismo , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Estrés Fisiológico/fisiología , Animales , Conducta Exploratoria/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/patología , Masculino , Ratones , Oligodendroglía/metabolismo , Receptor de Serotonina 5-HT1A/metabolismo , Restricción Física/fisiología , Agonistas de Receptores de Serotonina/farmacología , Estrés Fisiológico/efectos de los fármacos , Estrés Psicológico/metabolismoRESUMEN
Glutamate, GABA, acetylcholine, dopamine, and serotonin interact with each other to regulate the flow of neural information in the striatum. Serotonin type 1A receptor (5HT1A) is primarily expressed on glutamatergic nerve terminals, and 5HT1B is expressed on GABAergic medium spiny neurons (MSNs). Zonisamide (ZNS) reportedly improves the off period without worsening levodopa-induced dyskinesia (LID) in patients with advanced Parkinson's disease. In this study, LID model rats were prepared by administrating levodopa to unilaterally 6-OHDA-lesioned rats. We analyzed changes in serotonergic neurotransmission of LID model rats to elucidate the relationship between LID and the serotonergic system and pathomechanism of the anti-dyskinetic effects of ZNS. Abnormal involuntary movements (AIMs) were most severe in intermittently levodopa-treated rats but milder in rats intermittently medicated with levodopa and ZNS. Continuously levodopa-infused rats or intermittently ZNS-injected rats did not develop AIMs, and no differences in the expression of brain-derived neurotrophic factor, 5-HT transporter, 5HT1A, and 5HT1B mRNA between the lesioned striatum and normal side were observed. Expression of 5HT1B mRNA was elevated in the lesioned striatum of intermittently levodopa-treated rats, but this elevation was normalized by concomitant use of ZNS. The severity of AIMs was correlated with the ratio of 5HT1B to 5HT1A mRNA expression in the lesioned striatum, indicating that the anti-LID effect of ZNS is based on inhibition via 5HT1B receptors to direct pathway MSNs sensitized by intermittent levodopa treatment. Selectively acting serotonergic drugs, especially those that lower the 5HT1B to 5HT1A ratio, are promising new therapeutic agents to attenuate LID development.
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Antidiscinéticos/uso terapéutico , Antiparkinsonianos/efectos adversos , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Levodopa/efectos adversos , Neostriado/efectos de los fármacos , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Neuronas Serotoninérgicas/efectos de los fármacos , Zonisamida/uso terapéutico , Animales , Femenino , Neuronas GABAérgicas/efectos de los fármacos , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Serotoninérgicos/uso terapéuticoRESUMEN
Cardamonin, a naturally occurring chalcone isolated from Alpinia species has shown to possess strong anti-inflammatory and anti-nociceptive activities. Previous studies have demonstrated that cardamonin exerts antihyperalgesic and antiallodynic properties in chronic constriction injury (CCI)-induced neuropathic pain animal model. However, the mechanisms underlying cardamonin's effect have yet to be fully understood. The present study aims to investigate the involvement of the serotonergic system in cardamonin induced antihyperalgesic and antiallodynic effects in CCI-induced neuropathic pain mice model. The neuropathic pain symptoms in the CCI mice model were assessed using Hargreaves Plantar test and von-Frey filament test on day 14 post-surgery. Central depletion of serotonin along the descending serotonergic pathway was done using ρ-chlorophenylalanine (PCPA, 100 mg/kg, i.p.), an inhibitor of serotonin synthesis for four consecutive days before cardamonin treatment, and was found to reverse the antihyperalgesic and antiallodynic effect produced by cardamonin. Pretreatment of the mice with several 5-HT receptor subtypes antagonists: methiothepin (5-HT1/6/77 receptor antagonist, 0.1 mg/kg), WAY 100635 (5-HT1A receptor antagonist, 1 mg/kg), isamoltane (5-HT1B receptor antagonist, 2.5 mg/kg), ketanserin (5-HT2A receptor antagonist, 0.3 mg/kg), and ondansetron (5-HT3 receptor antagonist, 0.5 mg/kg) were shown to abolish the effect of cardamonin induced antihyperalgesic and antiallodynic effects. Further evaluation of the 5-HT1A receptor subtype protein expressions reveals that cardamonin significantly upregulated its expression in the brainstem and spinal cord. Our results suggest that the serotonergic pathway is essential for cardamonin to exert its antineuropathic effect in CCI mice through the involvement of the 5-HT1A receptor subtype in the central nervous system.
Asunto(s)
Chalconas/farmacología , Neuralgia/tratamiento farmacológico , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Analgésicos/farmacología , Animales , Chalconas/metabolismo , Modelos Animales de Enfermedad , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos ICR , Receptor de Serotonina 5-HT1A/metabolismo , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/metabolismo , Serotonina/metabolismo , Médula Espinal/efectos de los fármacosRESUMEN
The prelimbic division (PrL) of the medial prefrontal cortex (mPFC) is a cerebral division that is putatively implicated in the chronic pain and depression. We investigated the activity of PrL cortex neurons in Wistar rats that underwent chronic constriction injury (CCI) of sciatic nerve and were further subjected to the forced swimming (FS) test and mechanical allodynia (by von Frey test). The effect of blockade of synapses with cobalt chloride (CoCl2), and the treatment of the PrL cortex with cannabidiol (CBD), the CB1 receptor antagonist AM251 and the 5-HT1A receptor antagonist WAY-100635 were also investigated. Our results showed that CoCl2 decreased the time spent immobile during the FS test but did not alter mechanical allodynia. CBD (at 15, 30 and 60 nmol) in the PrL cortex also decreased the frequency and duration of immobility; however, only the dose of 30 nmol of CBD attenuated mechanical allodynia in rats with chronic NP. AM251 and WAY-100635 in the PrL cortex attenuated the antidepressive and analgesic effect caused by CBD but did not alter the immobility and the mechanical allodynia when administered alone. These data show that the PrL cortex is part of the neural substrate underlying the comorbidity between NP and depression. Also, the previous blockade of CB1 cannabinoid receptors and 5-HT1A serotonergic receptors in the PrL cortex attenuated the antidepressive and analgesics effect of the CBD. They also suggest that CBD could be a potential medicine for the treatment of depressive and pain symptoms in patients with chronic NP/depression comorbidity.
Asunto(s)
Cannabidiol/farmacología , Depresión/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Receptor Cannabinoide CB1/agonistas , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Animales , Cannabidiol/administración & dosificación , Enfermedad Crónica , Cobalto , Depresión/complicaciones , Sistema Límbico , Microinyecciones , Neuralgia/complicaciones , Piperazinas/uso terapéutico , Piperidinas/farmacología , Pirazoles/farmacología , Piridinas/uso terapéutico , Ratas , Ratas Wistar , Ciática/tratamiento farmacológico , Ciática/patología , Antagonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Natación/psicología , Sinapsis/efectos de los fármacosRESUMEN
Serotonin (5-HT) neurotransmission has been associated with reward-related behaviour. Moreover, the serotonergic system modulates the basolateral amygdala (BLA), a structure involved in reward encoding, and reward prediction error. However, the role played by 5-HT on BLA during a reward-driven task has not been fully elucidated. In this paper, we investigated whether serotonergic modulation of the BLA is involved in reward-driven learning. To this end, we trained Long Evans rats in an operant conditioning task, and examined the effects of fluoxetine treatment (a selective serotonin reuptake inhibitor, 10 mg/kg) in combination with BLA lesions with NMDA (20 mg/mL) on extinction learning. We also investigated whether intra-BLA injection of the serotonergic 5-HT1A receptor agonist 8-OH DPAT, or antagonist WAY-100635, alters extinction performance. We found that fluoxetine treatment strongly accelerated extinction learning, while BLA lesions partially reverted this effect and slightly impaired consolidation of extinction. Stimulation and inhibition of 5-HT1A receptors in BLA induced opposite effects to those of fluoxetine, impairing or accelerating extinction performance, respectively. Our findings suggest that 5-HT modulates reward-driven learning, and 5-HT1A receptors located in the BLA are relevant for extinction.