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1.
Life Sci ; 284: 119923, 2021 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-34481865

RESUMEN

AIMS: Levetiracetam (LEV) is a broad-spectrum antiepileptic drug with neuroprotective properties and novel mechanisms of action. Some evidence suggests that LEV may impact adult neurogenesis, but the results are controversial. The present study was aimed to evaluate the effects of LEV on the proliferation and differentiation of rat embryonic neural stem cells (NSCs) and to explore the role of GABAB or NMDA receptors. MAIN METHODS: NSCs were isolated from rat fetal ganglionic eminence at embryonic day 14.5. The effects of LEV on viability, proliferation, neurosphere formation, and neuronal or astroglial differentiation of NSCs were assessed using resazurin, BrdU incorporation, immunocytochemistry, quantitative real-time PCR, and western blotting. Additionally, we addressed the relationship between treatment with NMDA and GABAB receptor antagonists (MK801 and saclofen, respectively) in combination with LEV on these parameters. KEY FINDINGS: The data showed that LEV (50 µM) significantly increased the number (p < 0.01) and diameter of neurospheres (p < 0.05), enhanced proliferation (p < 0.01), and promoted neuronal differentiation, as revealed by significantly increased expressions of DCX and NeuN. The expressions of astroglial markers, GFAP and Olig2, were markedly reduced. The addition of MK801 (10 µM) significantly diminished neurospheres growth (p < 0.001), decreased the number of proliferating cells (p < 0.01), and reduced the number of new neurons (p < 0.001) but increased the astroglial cells (p < 0.001) induced by LEV. Co-treatment with saclofen (25 µM) did not significantly affect LEV-induced NSCs proliferation and differentiation. SIGNIFICANCE: Our findings suggest that LEV may enhance rat embryonic neurogenesis mainly through an NMDA receptor-mediated mechanism.


Asunto(s)
Embrión de Mamíferos/fisiología , Levetiracetam/farmacología , Neurogénesis/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Proteína Doblecortina , Femenino , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas Wistar , Esferoides Celulares/citología , Esferoides Celulares/efectos de los fármacos
2.
Biomed Pharmacother ; 140: 111786, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34144406

RESUMEN

There is substantial evidence that GABAB agonist, baclofen, prevents somatic and motivational responses induced by nicotine withdrawal and may target drug cue vulnerabilities in humans. In this context, we explored different aspects associated with the possible mechanisms whereby the GABAB receptors might influence nicotine withdrawal. Male mice received nicotine (2.5 mg/kg, s.c.) 4 times daily, for 7 consecutive days. Nicotine-treated mice received the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC, 2 or 3.5 mg/kg, s.c.), to precipitate the withdrawal state. A second group of dependent mice received 2-hydroxysaclofen (GABAB receptor antagonist, 1 mg/kg, s.c.) before MEC-precipitated abstinence. Somatic signs of nicotine withdrawal were measured for 30 min. Anxiogenic-like response associated to nicotine withdrawal was assessed by the elevated plus maze test. The dysphoric/aversive effect induced by nicotine withdrawal was evaluated using conditioned place aversion paradigm. Dopamine, serotonin and its metabolites concentrations were determined by HPLC in the striatum, cortex and hippocampus. Finally, α4ß2 nicotinic acetylcholine receptor density was determined in several brain regions using autoradiography assays. The results showed that MEC-precipitated nicotine withdrawal induced somatic manifestations, anxiogenic-like response and dysphoric/aversive effect, and 2-hydroxysaclofen potentiated these behavioral responses. Additionally, 2-hydroxysaclofen was able to change striatal dopamine levels and α4ß2 nicotinic acetylcholine receptor density, both altered by MEC-precipitated nicotine withdrawal. These findings provide important contributions to elucidate neurobiological mechanisms implicated in nicotine withdrawal. We suggest that GABAB receptor activity is necessary to control alterations induced by nicotine withdrawal, which supports the idea of targeting GABAB receptors to treat tobacco addiction in humans.


Asunto(s)
Receptores de GABA-B/metabolismo , Síndrome de Abstinencia a Sustancias/metabolismo , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Dopamina/metabolismo , Antagonistas de Receptores de GABA-B/farmacología , Masculino , Mecamilamina/farmacología , Ratones , Nicotina/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo
3.
Behav Brain Res ; 409: 113313, 2021 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-33891976

RESUMEN

MK-801 (dizocilpine) is a potent non-competitive N-methyl-[D]-aspartate (NMDA) receptor antagonist that affects cognitive function, learning, and memory. As we know, NMDA receptors are significantly involved in memory function, as well as GABA (Gamma-Aminobutyric acid) receptors. In this study, we aimed to discover the effect of GABA-B receptors in the basolateral amygdala (BLA) on MK-801-induced memory impairment. We used 160 male Wistar rats. The shuttle box was used to evaluate passive avoidance memory and locomotion apparatus was used to evaluate locomotor activity. MK-801 (0.125, 0.25, and 0.5 µg/rat), baclofen (GABA-B agonist, 0.0001, 0.001, and 0.01 µg/rat) and phaclofen (GABA-B antagonist, 0.0001, 0.001, and 0.01 µg/rat) were injected intra-BLA, after the training. The results showed that MK-801 at the dose of 0.5 µg/rat, baclofen at the doses of 0.001 and 0.01 µg/rat, and phaclofen at the doses of 0.001 and 0.01 µg/rat, impaired passive avoidance memory. Locomotor activity did not alter in all groups. Furthermore, the subthreshold dose of both baclofen (0.0001 µg/rat) and phaclofen (0.0001 µg/rat) restored the impairment effect of MK-801 (0.5 µg/rat) on memory. Also, both baclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 µg/rat) and phaclofen (0.0001 µg/rat) potentiated the impairment effect of MK-801 (0.125 and 0.25 µg/rat) on passive avoidance memory. In conclusion, our results indicated that BLA GABA-B receptors can alter the effect of NMDA inactivation on passive avoidance memory.


Asunto(s)
Reacción de Prevención/efectos de los fármacos , Complejo Nuclear Basolateral/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Agonistas de Receptores GABA-B/administración & dosificación , Antagonistas de Receptores de GABA-B/administración & dosificación , Masculino , Ratas , Ratas Wistar
4.
Blood ; 137(6): 775-787, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-32881992

RESUMEN

Hematopoietic and nervous systems are linked via innervation of bone marrow (BM) niche cells. Hematopoietic stem/progenitor cells (HSPCs) express neurotransmitter receptors, such as the γ-aminobutyric acid (GABA) type B receptor subunit 1 (GABBR1), suggesting that HSPCs could be directly regulated by neurotransmitters like GABA that directly bind to GABBR1. We performed imaging mass spectrometry and found that the endogenous GABA molecule is regionally localized and concentrated near the endosteum of the BM niche. To better understand the role of GABBR1 in regulating HSPCs, we generated a constitutive Gabbr1-knockout mouse model. Analysis revealed that HSPC numbers were significantly reduced in the BM compared with wild-type littermates. Moreover, Gabbr1-null hematopoietic stem cells had diminished capacity to reconstitute irradiated recipients in a competitive transplantation model. Gabbr1-null HSPCs were less proliferative under steady-state conditions and upon stress. Colony-forming unit assays demonstrated that almost all Gabbr1-null HSPCs were in a slow or noncycling state. In vitro differentiation of Gabbr1-null HSPCs in cocultures produced fewer overall cell numbers with significant defects in differentiation and expansion of the B-cell lineage. To determine whether a GABBR1 agonist could stimulate human umbilical cord blood (UCB) HSPCs, we performed brief ex vivo treatment prior to transplant into immunodeficient mice, with significant increases in long-term engraftment of HSPCs compared with GABBR1 antagonist or vehicle treatments. Our results indicate a direct role for GABBR1 in HSPC proliferation, and identify a potential target to improve HSPC engraftment in clinical transplantation.


Asunto(s)
Células Madre Hematopoyéticas/citología , Receptores de GABA-B/fisiología , Animales , Linfocitos B/patología , Baclofeno/análogos & derivados , Baclofeno/farmacología , Médula Ósea/inervación , Médula Ósea/metabolismo , Trasplante de Médula Ósea , División Celular , Linaje de la Célula , Femenino , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/trasplante , Humanos , Linfopenia/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Quimera por Radiación , Receptores de GABA-B/deficiencia , Receptores de GABA-B/genética , Nicho de Células Madre
5.
J Biochem Mol Toxicol ; 34(5): e22473, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32048404

RESUMEN

γ-Aminobutyrate (GABA) is commonly used as a food supplement and a health care product by young females, due to its positive roles in relieving stress, alleviating anxiety, and improving sleep. However, its recommended daily dose in different products varies widely. Besides, it is unknown whether, and how, GABA consumption during early pregnancy influences pregnancy establishment. In this study, we found that when pregnant mice were treated with a high (12.5 mg/g) dose of GABA (orally) during preimplantation, there was a reduction in the number of implantation sites on day 5 of pregnancy. Also, among these unimplanted embryos, most exhibited morphological degeneration and developmental retardation, and only a few of them developed into blastocysts but could not implant into the uterus. Moreover, the expression of uterine receptivity-related factors-LIF, E-cadherin, and HOXA10-were all downregulated, while the number of uterine glands was reduced in the high GABA dose group. Finally, in vitro results demonstrated that GABA (ranging from 10 to 50 µg/µL) markedly inhibited preimplantation embryo development in a dose-response manner. However, this inhibitory effect was not observed when the embryos were pretreated with 40 µΜ 2-hydroxysaclofen, a GABAB antagonist, indicating that GABA exerts its inhibitory effects via its B-type receptor. Our results suggest that exposure to certain GABA concentrations, during early pregnancy, can impair preimplantation embryo development via its B-type receptor, and endometrial receptivity, which greatly disturbs early embryo implantation in mice. These findings could raise concerns about GABA consumption during the early stages of pregnancy.


Asunto(s)
Implantación del Embrión/efectos de los fármacos , Desarrollo Embrionario/efectos de los fármacos , Endometrio/efectos de los fármacos , Ácido gamma-Aminobutírico/administración & dosificación , Administración Oral , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Cadherinas/metabolismo , Relación Dosis-Respuesta a Droga , Endometrio/metabolismo , Femenino , Antagonistas de Receptores de GABA-B/farmacología , Proteínas Homeobox A10/metabolismo , Factor Inhibidor de Leucemia/metabolismo , Ratones , Embarazo , Transducción de Señal/efectos de los fármacos
6.
Bull Exp Biol Med ; 168(1): 24-27, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31745683

RESUMEN

The respiratory effects of microinjections of baclofen and 2-hydroxysaclofen into the parafacial respiratory group were studied in experiments on rats. It was shown that activation of GABAB receptors of the parafacial respiratory group suppressed external respiration due to a decrease in the tidal volume and inspiratory flow rate. In parallel, we observed a decrease in the amplitude and an increase in the duration of inspiratory bursts of the diaphragm. Injection of GABAB receptor blocker into the parafacial respiratory group increased pulmonary ventilation due to an increase in volumetric parameters of the inspiratory phase. This effect was accompanied by prolongation of expiration and lengthening of the intervals between the inspiratory bursts of the diaphragm. These results suggest that GABAB receptors of the parafacial respiratory group are an important element of the central mechanisms regulating the volumetric respiratory parameters and are involved in the regulation of the phases of the respiratory cycle.


Asunto(s)
Baclofeno/farmacología , Agonistas de Receptores GABA-B/farmacología , Receptores de GABA-B/metabolismo , Respiración/efectos de los fármacos , Animales , Baclofeno/análogos & derivados , Electroencefalografía , Ventilación Pulmonar/efectos de los fármacos , Ratas , Volumen de Ventilación Pulmonar/efectos de los fármacos
7.
J Neurosci ; 39(42): 8398-8407, 2019 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-31451579

RESUMEN

Binocular rivalry is a classic experimental tool to probe the neural machinery of perceptual awareness. During rivalry, perception alternates between the two eyes, and the ebb and flow of perception is modeled to rely on the strength of inhibitory interactions between competitive neuronal populations in visual cortex. As a result, rivalry has been suggested as a noninvasive perceptual marker of inhibitory signaling in visual cortex, and its putative disturbance in psychiatric conditions, including autism. Yet, direct evidence causally implicating inhibitory signaling in the dynamics of binocular rivalry is currently lacking. We previously found that people with higher GABA levels in visual cortex, measured using magnetic resonance spectroscopy, have stronger perceptual suppression during rivalry. Here, we present direct causal tests of the impact of GABAergic inhibition on rivalry dynamics, and the contribution of specific GABA receptors to these dynamics. In a crossover pharmacological design with male and female adult participants, we found that drugs that modulate the two dominant GABA receptor types in the brain, GABAA (clobazam) and GABAB (arbaclofen), increase perceptual suppression during rivalry relative to a placebo. Crucially, these results could not be explained by changes in reaction times or response criteria, as determined through rivalry simulation trials, suggesting a direct and specific influence of GABA on perceptual suppression. A full replication study of the GABAB modulator reinforces these findings. These results provide causal evidence for a link between the strength of inhibition in the brain and perceptual suppression during rivalry and have implications for psychiatric conditions including autism.SIGNIFICANCE STATEMENT How does the brain accomplish perceptual gating? Here we use a direct and causal pharmacological manipulation to present insight into the neural machinery of a classic illusion of perceptual awareness: binocular rivalry. We show that drugs that increase GABAergic inhibition in the brain, clobazam (GABAA modulator) and arbaclofen (GABAB modulator), increase perceptual suppression during rivalry relative to a placebo. These results present the first causal link between GABAergic inhibition and binocular rivalry in humans, complementing classic models of binocular rivalry, and have implications for our understanding of psychiatric conditions, such as autism, where binocular rivalry is posited as a behavioral marker of disruptions in inhibitory signaling in the brain.


Asunto(s)
Baclofeno/análogos & derivados , Clobazam/farmacología , Agonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores GABA-B/farmacología , Visión Binocular/efectos de los fármacos , Percepción Visual/efectos de los fármacos , Adolescente , Adulto , Concienciación/efectos de los fármacos , Baclofeno/farmacología , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Adulto Joven
8.
Pharmacol Biochem Behav ; 180: 11-21, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30851293

RESUMEN

Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABAB receptors in the antinociceptive responses induced by MOR (1, 3 and 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 mg/kg, intra cisterna magna) and genetic approaches (GABAB1 knockout mice; GABAB1 KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABAB1 KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABAB1 subunit of the GABAB receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABAB receptors are involved in the MOR antinociceptive effect of both male and female mice.


Asunto(s)
Analgésicos/farmacología , Morfina/farmacología , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Analgésicos/administración & dosificación , Animales , Baclofeno/administración & dosificación , Baclofeno/análogos & derivados , Baclofeno/farmacología , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/farmacología , Técnicas de Inactivación de Genes , Genes fos/genética , Genotipo , Giro del Cíngulo/efectos de los fármacos , Giro del Cíngulo/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Morfina/administración & dosificación , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/inmunología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Factores Sexuales , Transducción de Señal/efectos de los fármacos
9.
Neurosci Lett ; 699: 189-194, 2019 04 23.
Artículo en Inglés | MEDLINE | ID: mdl-30753913

RESUMEN

Tonic immobility (TI) is a temporary state of profound motor inhibition associated with great danger as the attack of a predator. Previous studies carried out in our laboratory evidenced high Fos-IR in the posteroventral region of the medial nucleus of the amygdala (MEA) after induction of the TI response. Here, we investigated the effects of GABAA and GABAB of the MEA on TI duration. Intra-MEA injections of the GABAA agonist muscimol and GABAB agonist baclofen reduced TI response, while intra-MEA injections of the GABAA antagonist bicuculline and GABAB antagonist phaclofen increased the TI response. Moreover, the effects observed with muscimol and baclofen administrations into MEA were blocked by pretreatment with bicuculline and phaclofen (at ineffective doses per se). Finally, the activation of GABAA and GABAB receptors in the MEA did not alter the spontaneous motor activity in the open field test. These data support the role of the GABAergic system of the MEA in the modulation of innate fear.


Asunto(s)
Complejo Nuclear Corticomedial/fisiología , Agonistas de Receptores de GABA-A/fisiología , Agonistas de Receptores GABA-B/fisiología , Pérdida de Tono Postural/fisiología , Animales , Baclofeno/administración & dosificación , Baclofeno/análogos & derivados , Baclofeno/antagonistas & inhibidores , Baclofeno/farmacología , Bicuculina/administración & dosificación , Bicuculina/farmacología , Complejo Nuclear Corticomedial/efectos de los fármacos , Agonistas de Receptores de GABA-A/administración & dosificación , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/administración & dosificación , Antagonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores GABA-B/administración & dosificación , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/administración & dosificación , Antagonistas de Receptores de GABA-B/farmacología , Cobayas , Pérdida de Tono Postural/efectos de los fármacos , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Muscimol/administración & dosificación , Muscimol/antagonistas & inhibidores , Muscimol/farmacología
10.
Synapse ; 73(4): e22081, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30450777

RESUMEN

Cholinergic neurons in the nucleus accumbens contain GABAA and GABAB receptors that are thought to inhibit neural activity. We analyzed the roles of GABAA and GABAB receptors in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. The effects of GABA receptor ligands on the accumbal dopamine efflux were also analyzed because accumbal cholinergic and dopaminergic neurons could mutually interact. Drugs were applied intracerebrally through the dialysis probe. Doses of compounds indicate total amount administered (mol) during 30-60 min infusions. To monitor basal acetylcholine, a low concentration of physostigmine (50 nM) was added to the perfusate. GABAA receptor agonist muscimol (3 and 30 pmol) induced a dose-related decrease in accumbal acetylcholine. GABAB receptor agonist baclofen (30 and 300 pmol) also produced a dose-related decrease in acetylcholine. GABAA receptor antagonist bicuculline (60 pmol) which failed to alter baseline acetylcholine counteracted the muscimol (30 pmol)-induced decrease in acetylcholine. GABAB receptor antagonist 2-hydroxysaclofen (12 nmol) which failed to change baseline acetylcholine, counteracted the baclofen (300 pmol)-induced decrease in acetylcholine. Neither muscimol (30 pmol) nor baclofen (300 pmol) which reduced accumbal acetylcholine altered baseline accumbal dopamine. Neither bicuculline (60 pmol) nor 2-hydroxysaclofen (12 nmol) also affected the baseline dopamine. These results show that GABAA and GABAB receptors each exert inhibitory roles in the regulation of accumbal cholinergic neural activity. The present results also provides in vivo neurochemical evidence that stimulation of GABAA and GABAB receptors each reduce acetylcholine efflux without affecting dopamine efflux in the nucleus accumbens of freely moving rats.


Asunto(s)
Acetilcolina/metabolismo , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Núcleo Accumbens/metabolismo , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/farmacología , Dopamina/metabolismo , Masculino , Movimiento , Muscimol/farmacología , Núcleo Accumbens/efectos de los fármacos , Ratas , Ratas Sprague-Dawley
11.
Arab J Gastroenterol ; 19(2): 51-55, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29935866

RESUMEN

BACKGROUND AND STUDY AIMS: Several studies have demonstrated the superiority of proton-pump inhibitors (PPIs) in resolving erosive gastro-oesophageal reflux disease (GORD). However, this first line of treatment can fail to control symptoms in around 30% of cases, especially in the presence of non-erosive GORD. In situations where the first line of treatment fails, there is a lack of concordance regarding the best strategy to apply. This study presents a systematic review of the trials which have tested second-line treatments after PPI failure. METHODS: The study was conducted according to the PRISMA statement. The systematic review included medical trials written in English which were published between 2000 and 2016 and were retrieved from PubMed and Scopus using the keywords 'PPI-resistant gastro-oesophageal reflux', 'alginate AND gastro-oesophageal reflux', 'hyaluronic acid AND gastro-oesophageal reflux', 'prokinetics AND gastro-oesophageal reflux', 'sucralfate AND gastro-oesophageal reflux' and 'baclofen AND gastro-oesophageal reflux'. RESULTS: Ten randomised and non-randomised studies were included, which included 1515 patients of both sexes (mean age = 49.19 years, age range = 18-85, males = 700; 46.2%). CONCLUSIONS: A personalised choice of the best treatment for PPI-resistant GORD should be based on the results of an upper endoscopy and pH/MII monitoring. For patients in situations where the first line of treatment fails, we encourage the execution of trials for testing double doses of PPIs against alternative medicaments.


Asunto(s)
Baclofeno/análogos & derivados , Reflujo Gastroesofágico/tratamiento farmacológico , Inhibidores de la Bomba de Protones/uso terapéutico , Baclofeno/uso terapéutico , Benzamidas/uso terapéutico , Sulfatos de Condroitina/uso terapéutico , Domperidona/uso terapéutico , Combinación de Medicamentos , Quimioterapia Combinada , Monitorización del pH Esofágico , Fármacos Gastrointestinales/uso terapéutico , Humanos , Ácido Hialurónico/uso terapéutico , Morfolinas/uso terapéutico , Inhibidores de la Bomba de Protones/administración & dosificación , Insuficiencia del Tratamiento
12.
Addict Biol ; 23(1): 230-246, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28419642

RESUMEN

It has been demonstrated that GABAB receptors modulate nicotine (NIC) reward effect; nevertheless, the mechanism implicated is not well known. In this regard, we evaluated the involvement of GABAB receptors on the behavioral, neurochemical, biochemical and molecular alterations associated with the rewarding effects induced by NIC in mice, from a pharmacological and genetic approach. NIC-induced rewarding properties (0.5 mg/kg, subcutaneously, sc) were evaluated by conditioned place preference (CPP) paradigm. CPP has three phases: preconditioning, conditioning and postconditioning. GABAB receptor antagonist 2-hydroxysaclofen (0.25, 0.5 and 1 mg/kg; intraperitoneally, ip) or the GABAB receptor agonist baclofen (3 mg/kg; ip) was injected before NIC during the conditioning phase. GABAB1 knockout (GABAB1 KO) mice received NIC during the conditioning phase. Vehicle and wild-type controls were employed. Neurochemical (dopamine, serotonin and their metabolites), biochemical (nicotinic receptor α4ß2, α4ß2nAChRs) and molecular (c-Fos) alterations induced by NIC were analyzed after the postconditioning phase by high-performance liquid chromatography (HPLC), receptor-ligand binding assays and immunohistochemistry, respectively, in nucleus accumbens (Acb), prefrontal cortex (PFC) and ventral tegmental area (VTA). NIC induced rewarding effects in the CPP paradigm and increased dopamine levels in Acb and PFC, α4ß2nAChRs density in VTA and c-Fos expression in Acb shell (AcbSh), VTA and PFC. We showed that behavioral, neurochemical, biochemical and molecular alterations induced by NIC were prevented by baclofen. However, in 2-hydroxysaclofen pretreated and GABAB1 KO mice, these alterations were potentiated, suggesting that GABAB receptor activity is necessary to control alterations induced by NIC-induced rewarding effects. Therefore, the present findings provided important contributions to the mechanisms implicated in NIC-induced rewarding effects.


Asunto(s)
Encéfalo/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptores de GABA-B/efectos de los fármacos , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Encéfalo/metabolismo , Dopamina/metabolismo , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Masculino , Ratones , Ratones Noqueados , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores de GABA-B/genética , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/metabolismo , Recompensa , Serotonina/metabolismo , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo
13.
Brain Res ; 1678: 164-173, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29038006

RESUMEN

To investigate the interaction between hippocampal γ-aminobutyric acid GABAA receptor (GABAAR) or GABAB receptor (GABABR) and N-methyl-D-aspartate receptor (NMDAR) in the acquisition of passive avoidance memory in rats, we used GABAA or GABAB agents, D-AP5 (as a NMDAR antagonist), and a combination of the mentioned drugs in a step-through task. All agents were microinjected into the intra-CA1 regions at a volume of 1 µl/rat, prior to training. GABAAR agonist muscimol (0.2 µg/rat), selective GABABR agonist baclofen (0.5 µg/rat) or NMDAR antagonist D-AP5 (0.25 µg/rat) decreased step-through latency, indicating a memory retention impairment. Neither GABAAR antagonist bicuculline (0.0625-0.25 µg/rat) nor GABABR antagonist phaclofen (0.1-0.5 µg/rat) altered memory retrieval by itself. Moreover, the lower dose of muscimol (0.05 µg/rat) decreased D-AP5 (0.125 µg/rat) response on memory acquisition, but bicuculline did not alter the D-AP5 response. Furthermore, baclofen and phaclofen at the dose of 0.1 µg/rat potentiated D-AP5 response at the doses of 0.0625 and 0.125 µg/rat, but abolished memory impairment induced by D-AP5 at the higher dose (0.25 µg/rat). The results suggest that the microinjection of GABAA and GABAB agents into the CA1 region differently affects memory acquisition deficit induced by D-AP5. The activation of GABAARs increased the impairment effect of D-AP5 on passive avoidance memory, but their blockade did not have an effect. Also, the activation or blockade of GABABRs induced a similar and dual effect.


Asunto(s)
Reacción de Prevención/efectos de los fármacos , Trastornos de la Memoria/metabolismo , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/farmacología , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Hipocampo/efectos de los fármacos , Masculino , Memoria/fisiología , Muscimol/farmacología , Ratas , Ratas Wistar , Receptores de GABA-B/efectos de los fármacos , Receptores de GABA-B/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Ácido gamma-Aminobutírico/farmacología
14.
Cereb Cortex ; 28(1): 1-8, 2018 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29253248

RESUMEN

The amygdala receives cortical inputs from the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) that are believed to affect emotional control and cue-outcome contingencies, respectively. Although mPFC impact on the amygdala has been studied, how the OFC modulates mPFC-amygdala information flow, specifically the infralimbic (IL) division of mPFC, is largely unknown. In this study, combined in vivo extracellular single-unit recordings and pharmacological manipulations were used in anesthetized rats to examine how OFC modulates amygdala neurons responsive to mPFC activation. Compared with basal condition, pharmacological (N-Methyl-D-aspartate) or electrical activation of the OFC exerted an inhibitory modulation of the mPFC-amygdala pathway, which was reversed with intra-amygdala blockade of GABAergic receptors with combined GABAA and GABAB antagonists (bicuculline and saclofen). Moreover, potentiation of the OFC-related pathways resulted in a loss of OFC control over the mPFC-amygdala pathway. These results show that the OFC potently inhibits mPFC drive of the amygdala in a GABA-dependent manner; but with extended OFC pathway activation this modulation is lost. Our results provide a circuit-level basis for this interaction at the level of the amygdala, which would be critical in understanding the normal and pathophysiological control of emotion and contingency associations regulating behavior.


Asunto(s)
Amígdala del Cerebelo/fisiología , Lóbulo Frontal/fisiología , Inhibición Neural/fisiología , Neuronas/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Anestesia , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/farmacología , Estimulación Eléctrica , Emociones/fisiología , Agonistas de Aminoácidos Excitadores/farmacología , Lóbulo Frontal/efectos de los fármacos , Antagonistas del GABA/farmacología , Masculino , Microelectrodos , N-Metilaspartato/farmacología , Inhibición Neural/efectos de los fármacos , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Neuronas/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de GABA/metabolismo , Ácido gamma-Aminobutírico/metabolismo
15.
Addict Biol ; 23(1): 165-181, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28271626

RESUMEN

There is growing public interest in alternative approaches to addiction treatment and scientific interest in elucidating the neurobiological underpinnings of acupuncture. Our previous studies showed that acupuncture at a specific Shenmen (HT7) points reduced dopamine (DA) release in the nucleus accumbens (NAc) induced by drugs of abuse. The present study was carried out to evaluate the effects of HT7 acupuncture on γ-aminobutyric acid (GABA) neuronal activity in the ventral tegmental area (VTA) and the reinstatement of cocaine-seeking behavior. Using microdialysis and in vivo single-unit electrophysiology, we evaluated the effects of HT7 acupuncture on VTA GABA and NAc DA release and VTA GABA neuronal activity in rats. Using a within-session reinstatement paradigm in rats self-administering cocaine, we evaluated the effects of HT7 stimulation on cocaine-primed reinstatement. Acupuncture at HT7 significantly reduced cocaine suppression of GABA release and GABA neuron firing rates in the VTA. HT7 acupuncture attenuated cocaine-primed reinstatement, which was blocked by VTA infusions of the selective GABAB receptor antagonist 2-hydroxysaclofen. HT7 stimulation significantly decreased acute cocaine-induced DA release in the NAc, which was also blocked by 2-hydroxysaclofen. HT7 acupuncture also attenuated cocaine-induced sensitization of extracellular DA levels in the NAc. Moreover, HT7 acupuncture reduced both locomotor activity and neuronal activation in the NAc induced by acute cocaine in a needle-penetration depth-dependent fashion. These results suggest that acupuncture may suppress cocaine-induced DA release in the NAc and cocaine-seeking behavior through activation of VTA GABA neurons. Acupuncture may be an effective therapy to reduce cocaine relapse by enhancing GABAergic inhibition in the VTA.


Asunto(s)
Acupuntura , Conducta Animal , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Comportamiento de Búsqueda de Drogas , Locomoción , Área Tegmental Ventral/metabolismo , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Dopamina/metabolismo , Fenómenos Electrofisiológicos , Antagonistas de Receptores de GABA-B/farmacología , Neuronas GABAérgicas/metabolismo , Microdiálisis , Núcleo Accumbens/citología , Núcleo Accumbens/metabolismo , Ratas , Área Tegmental Ventral/citología , Ácido gamma-Aminobutírico/metabolismo
16.
Psychopharmacology (Berl) ; 234(20): 3117-3128, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28779310

RESUMEN

RATIONALE: Previous studies have postulated functional links between GABA and cannabinoid systems in the hippocampus. The aim of the present study was to investigate any possible interaction between these systems in spatial change and object novelty discrimination memory consolidation in the dorsal hippocampus (CA1 region) of NMRI mice. METHODS: Assessment of the spatial change and object novelty discrimination memory function was carried out in a non-associative task. The experiment comprised mice exposure to an open field containing five objects followed by the examination of their reactivity to object displacement (spatial change) and object substitution (object novelty) after three sessions of habituation. RESULTS: Our results showed that the post-training intraperitoneal administration of the higher dose of ACPA (0.02 mg/kg) impaired both spatial change and novelty discrimination memory functions. Meanwhile, the higher dose of GABA-B receptor agonist, baclofen, impaired the spatial change memory by itself. Moreover, the post-training intra-CA1 microinjection of a subthreshold dose of baclofen increased the ACPA effect on spatial change and novelty discrimination memory at a lower and higher dose, respectively. On the other hand, the lower and higher but not mid-level doses of GABA-B receptor antagonist, phaclofen, could reverse memory deficits induced by ACPA. However, phaclofen at its mid-level dose impaired the novelty discrimination memory and whereas the higher dose impaired the spatial change memory. CONCLUSIONS: Based on our findings, GABA-B receptors in the CA1 region appear to modulate the ACPA-induced cannabinoid CB1 signaling upon spatial change and novelty discrimination memory functions.


Asunto(s)
Hipocampo/metabolismo , Memoria/fisiología , Receptor Cannabinoide CB1/metabolismo , Receptores de Cannabinoides/metabolismo , Receptores de GABA-B/metabolismo , Conducta Espacial/fisiología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Aprendizaje Discriminativo/fisiología , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Agonistas de Receptores GABA-B/farmacología , Antagonistas de Receptores de GABA-B/farmacología , Hipocampo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Microinyecciones , Conducta Espacial/efectos de los fármacos
17.
Neuroscience ; 362: 127-140, 2017 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-28827179

RESUMEN

Oligodendrocyte progenitor cells (OPC) are glial cells that differentiate into myelinating oligodendrocytes during early stages of post-natal life. However, OPCs persist beyond developmental myelination and represent an important population of cycling cells in the gray and white matter of the adult brain. While adult OPCs form unique territories that are maintained through self-avoidance, some cortical OPCs appear to position their cell body very close to that of a neuron, forming what are known as OPC-neuron pairs. We used unbiased systematic stereological analysis of the NG2-CreERTM:EYFP reporter mouse to determine that close to 170,000 OPC-neuron pairs can be found in the dorsal portion of the adult neocortex, with approximately 40% of OPCs and 4% of neurons in pairs. Through stereological analysis, we also determined that reference memory training does not change the prevalence of OPC-neuron pairs or the proportion of OPCs and neurons that form them. GABAergic agent administration did not affect the proportion of OPCs and neurons that can be found in pairs. However, the GABAB-receptor agonist baclofen and the GABAA receptor antagonist picrotoxin significantly increased the estimated number of pairs when compared to the control group and the GABAB-receptor antagonist (i.e. saclofen) group. Density of OPC-neuron pairs was increased by the GABAA receptor antagonist picrotoxin. Finally, histological analysis of OPC-neuron pairs suggested that in the dorsal portion of the cortex, GABAergic interneurons represent the most common neuronal component of the pairs, and that calbindin, calretinin and parvalbumin GABAergic interneurons found in the cortex take part in these pairs. Using previous estimates of the number of GABAergic neurons in the rodent cortex, we estimate that roughly one in four GABAergic neurons are paired with an OPC.


Asunto(s)
Neuronas GABAérgicas/citología , Neocórtex/citología , Células Precursoras de Oligodendrocitos/citología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Recuento de Células , GABAérgicos/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/fisiología , Aprendizaje/fisiología , Memoria/fisiología , Ratones Endogámicos C57BL , Ratones Transgénicos , Neocórtex/efectos de los fármacos , Neocórtex/fisiología , Plasticidad Neuronal , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Células Precursoras de Oligodendrocitos/fisiología , Picrotoxina/farmacología , Receptores de GABA-A/metabolismo , Receptores de GABA-B/metabolismo
18.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 515-524, 2017 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-28800869

RESUMEN

Glutamatergic and GABAergic systems play key roles in the hippocampus and affect the pathogenesis of anxiety- and memory-related processes. Some investigations have assessed the role of balancing the function of these two systems in different areas of the central nervous system (CNS) as an approach to manage the related disorders. We investigated the anxiety and avoidance memory states using the test-retest protocol in the elevated plus maze to understand the role of GABAB receptors (GABABRs) in relation to the NMDA receptor blockade by D-AP5 (an NMDA receptor antagonist). Also, we examined the function of Ca2+ ions by blocking its entrance to the cell using SKF96365 (a Ca2+ channel blocker). The drugs were injected into the CA3 region before the test. Our data showed that D-AP5 induced anxiolytic-like behaviors and impaired the avoidance memory. Injection of baclofen (a GABABR agonist), but not phaclofen (a GABABR antagonist) induced anxiolytic-like behaviors. Neither baclofen nor phaclofen altered avoidance memory-related behaviors. When baclofen was injected before D-AP5, it potentiated the anxiolytic-like behaviors induced by D-AP5, but counteracted its effect on avoidance memory. Phaclofen pretreatment attenuated D-AP5-induced anxiolytic-like behaviors, but potentiated its effect on avoidance memory. The effect of baclofen application before D-AP5 on anxiety and phaclofen application before D-AP5 on avoidance memory at the heist doses were accompanied by a decrease in locomotion. The application of SKF96365 did not alter anxiety-like behaviors but induced avoidance memory impairment. SKF96365 application before the combination of baclofen and D-AP5 counteracted the effects produced by the combination of baclofen and D-AP5 on anxiety and memory states. Our findings showed that the CA3 GABABRs had a critical role in anxiolytic-like behaviors and avoidance memory deficit induced by D-AP5 and confirmed the role of Ca2+ ions in the observed results.


Asunto(s)
Ansiedad/metabolismo , Reacción de Prevención/fisiología , Región CA3 Hipocampal/metabolismo , Calcio/metabolismo , Trastornos de la Memoria/metabolismo , Receptores de GABA-B/metabolismo , 2-Amino-5-fosfonovalerato , Animales , Ansiedad/tratamiento farmacológico , Reacción de Prevención/efectos de los fármacos , Baclofeno/análogos & derivados , Baclofeno/farmacología , Región CA3 Hipocampal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Cationes Bivalentes/metabolismo , Modelos Animales de Enfermedad , Antagonistas del GABA/farmacología , Agonistas de Receptores GABA-B/farmacología , Imidazoles/farmacología , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Psicotrópicos/farmacología , Distribución Aleatoria , Ratas Wistar , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo
19.
Int J Neuropsychopharmacol ; 20(7): 602-610, 2017 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-28444246

RESUMEN

Background: The basolateral complex of the amygdala receives inputs from neocortical areas, including the medial prefrontal cortex and lateral orbitofrontal cortex. Earlier studies have shown that lateral orbitofrontal cortex activation exerts an inhibitory gating on medial prefrontal cortex-amygdala information flow. Here we examined the individual role of GABAA and GABAB receptors in this process. Methods: In vivo extracellular single-unit recordings were done in anesthetized rats. We searched amygdala neurons that fire in response to medial prefrontal cortex activation, tested lateral orbitofrontal cortex gating at different delays (lateral orbitofrontal cortex-medial prefrontal cortex delays: 25, 50, 100, 250, 500, and 1000 milliseconds), and examined differential contribution of GABAA and GABAB receptors with iontophoresis. Results: Relative to baseline, lateral orbitofrontal cortex stimulation exerted an inhibitory modulatory gating on the medial prefrontal cortex-amygdala pathway and was effective up to a long delay of 500 ms (long-delay latencies at 100, 250, and 500 milliseconds). Moreover, blockade of intra-amygdala GABAA receptors with bicuculline abolished the lateral orbitofrontal cortex inhibitory gating at both short- (25 milliseconds) and long-delay (100 milliseconds) intervals, while blockade of GABAB receptors with saclofen reversed the inhibitory gating at long delay (100 milliseconds) only. Among the majority of the neurons examined (8 of 9), inactivation of either GABAA or GABAB receptors during baseline did not change evoked probability per se, suggesting that local feed-forward inhibitory mechanism is pathway specific. Conclusions: Our results suggest that the effect of lateral orbitofrontal cortex inhibitory modulatory gating was effective up to 500 milliseconds and that intra-amygdala GABAA and GABAB receptors differentially modulate the short- and long-delay lateral orbitofrontal cortex inhibitory gating on the medial prefrontal cortex-amygdala pathway.


Asunto(s)
Amígdala del Cerebelo/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Receptores de GABA-B/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/administración & dosificación , Estimulación Eléctrica , Antagonistas del GABA/farmacología , Iontoforesis , Masculino , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Neuronas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/fisiología , Receptores de GABA-A , Filtrado Sensorial/fisiología , Factores de Tiempo
20.
Neuroreport ; 28(9): 485-491, 2017 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-28419057

RESUMEN

Experiments using in-vivo microdialysis methods were conducted to investigate whether blood pressure changes cause an alteration in the release of noradrenaline (NA) in the median preoptic nucleus (MnPO) and whether the γ-aminobutyric acid (GABA) receptor mechanism is involved in the modulation of the pressure response-induced alteration in the NA release. In urethane-anesthetized male rats, intravenous administration of metaraminol, an α-agonist, significantly produced an increase in dialysate NA concentration in the MnPO area accompanied by an elevation in the mean arterial pressure (MAP). Perfusion with GABA (10 µM) through the dialysis probe elicited a significant decrease in either MAP or the NA concentration in the MnPO area. Similar perfusion with either the GABAA receptor antagonist bicuculline (10 µM) or the GABAB receptor antagonist phaclofen (10 µM) caused a significant increase in both MAP and the NA release in the MnPO area. Either bicuculline or phaclofen administered together with the metaraminol further enhanced the metaraminol-induced MAP and NA release in the MnPO area. The degree of increases in the both MAP of the NA release was significantly greater in the bicuculline-treated group than in the phaclofen-treated group. These results suggest that the NA release in the MnPO area may be potentiated during an elevation in arterial pressure caused by the metaraminol injection and imply that the NA release may be mediated through GABAA receptors rather than GABAB receptors in the MnPO area.


Asunto(s)
Presión Sanguínea/fisiología , Norepinefrina/metabolismo , Área Preóptica/efectos de los fármacos , Área Preóptica/metabolismo , Ácido gamma-Aminobutírico/farmacología , Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Baclofeno/análogos & derivados , Baclofeno/farmacología , Bicuculina/farmacología , Presión Sanguínea/efectos de los fármacos , Antagonistas del GABA/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Masculino , Metaraminol/farmacología , Microdiálisis , Ratas , Ratas Wistar
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