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1.
Neurobiol Learn Mem ; 197: 107709, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36503101

RESUMEN

The present study investigated whether N-methyl-d-aspartate (NMDA) receptors in the dorsolateral striatum (DLS) mediate consolidation and retrieval of habit memory. Adult male Long-Evans rats were trained in a response learning version of a water plus-maze task in which rats were reinforced to make a habitual and consistent body-turn response at the maze choice point in order to mount a hidden escape platform. Prior research indicates that acquisition, consolidation, and retrieval in this task requires DLS function. The present study consisted of two experiments. In Experiment 1, rats received intra-DLS post-training injections of the NMDA receptor antagonist 2-amino-5- phosphonopentanoic acid (AP5; 2 µg/side) to examine the role of NMDA receptors in consolidation of habit memory. In Experiment 2, different groups of rats received a single pre-retrieval injection of AP5 in the DLS (AP5; 2 µg/side) during the last day of maze training to examine the potential role of NMDA receptors in retrieval of habit memory. Results indicated that post-training intra-DLS AP5 injections impaired memory consolidation. However, administration of AP5 at the same dose that impaired consolidation had no effect on memory retrieval. The findings are consistent with previous research indicating a role for NMDA receptors in the DLS in memory consolidation, and suggest that NMDA-dependent synaptic activity in the DLS may not be a critical component of habit memory retrieval.


Asunto(s)
N-Metilaspartato , Receptores de N-Metil-D-Aspartato , Ratas , Masculino , Animales , Receptores de N-Metil-D-Aspartato/fisiología , Ratas Long-Evans , N-Metilaspartato/farmacología , Memoria/fisiología , Hábitos , 2-Amino-5-fosfonovalerato/farmacología
2.
Brain Res ; 1787: 147919, 2022 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-35436447

RESUMEN

A technique combining fluorescence imaging with Ca2+ indicators and single-cell laser scanning photostimulation of caged glutamate (LSPS) allowed identification of functional connections between individual neurons in mixed cultures of rat neocortical cells as well as observation of synchronous spontaneous activity among neurons. LSPS performed on large numbers of neurons yielded maps of functional connections between neurons and allowed calculation of neuronal network parameters. LSPS also provided an indirect measure of excitability of neurons targeted for photostimulation. By repeating LSPS sessions with the same neurons, stability of connections and change in the number and strength of connections were also determined. Experiments were conducted in the presence of bicuculline to study in detail the properties of excitatory neurotransmission. The AMPA receptor inhibitor, 6-Cyano-7-nitroquinoxaline-2,3-dione (CNQX), abolished synchronous neuronal activity but had no effect on connections mapped by LSPS. In contrast, the NMDA receptor inhibitor, 2-Amino-5-phosphono-pentanoic acid (APV), dramatically decreased the number of functional connections between neurons while also affecting synchronous spontaneous activity. Functional connections were also decreased by increasing extracellular Mg2+ concentration. These data demonstrated that LSPS mapping interrogates NMDA receptor-dependent connectivity between neurons in the network. In addition, a GluN2A-specific inhibitor, NVP-AAM077, decreased the number and strength of connections between neurons as well as neuron excitability. Conversely, the GluN2A-specific positive modulator, GNE-0723, increased these same properties. These data showed that LSPS can be used to directly study perturbations in the properties of NMDA receptor-dependent connectivity in neuronal networks. This approach should be applicable in a wide variety of in vitro and in vivo experimental preparations.


Asunto(s)
N-Metilaspartato , Receptores de N-Metil-D-Aspartato , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , N-Metilaspartato/farmacología , Neuronas , Ratas , Receptores AMPA/fisiología
3.
Am J Physiol Heart Circ Physiol ; 321(3): H580-H591, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34355986

RESUMEN

Tumor necrosis factor-α (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFα (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P < 0.0001, n = 10). Given that TNFα can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. When compared with that of vehicle (n = 5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), 2.48 nmol; D-(-)-2-amino-5-phosphonopentanoic acid (APV), 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%), attenuated TNFα-induced SSNA ramping (n = 5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P < 0.0001, n = 5). Whereas separate blockade of PVN AMPA or NMDA receptors (n = 5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n = 5) or PVN inhibition with the GABA-A receptor agonist muscimol (n = 5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.NEW & NOTEWORTHY The proinflammatory cytokine TNFα contributes to heightened SNA in cardiovascular disease models, but mechanisms remain obscure. Here, we demonstrate that TNFα injection into the hypothalamic PVN triggers SNA ramping by mechanisms dependent on local ionotropic glutamate receptor availability, but largely independent of TNFα autoinduction. Continued SNA ramping depends on ionotropic glutamate receptor and neuronal activity in PVN, indicating that strengthening and/or increased efficacy of glutamatergic transmission is necessary for acute sympathoexcitation by PVN TNFα.


Asunto(s)
Núcleo Hipotalámico Paraventricular/metabolismo , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Nervios Esplácnicos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Animales , Antagonistas de Aminoácidos Excitadores/farmacología , Agonistas de Receptores de GABA-A/farmacología , Masculino , Muscimol/farmacología , Núcleo Hipotalámico Paraventricular/fisiología , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de GABA-A/metabolismo , Nervios Esplácnicos/efectos de los fármacos , Nervios Esplácnicos/fisiología
4.
J Neurosci ; 41(35): 7340-7349, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34290083

RESUMEN

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by the accumulation of amyloid-ß (Aß) plaques and neurofibrillary tangles. Aß oligomers cause synaptic dysfunction early in AD by enhancing long-term depression (LTD; a paradigm for forgetfulness) via metabotropic glutamate receptor (mGluR)-dependent regulation of striatal-enriched tyrosine phosphatase (STEP61). Reelin is a neuromodulator that signals through ApoE (apolipoprotein E) receptors to protect the synapse against Aß toxicity (Durakoglugil et al., 2009) Reelin signaling is impaired by ApoE4, the most important genetic risk factor for AD, and Aß-oligomers activate metabotropic glutamate receptors (Renner et al., 2010). We therefore asked whether Reelin might also affect mGluR-LTD. To this end, we induced chemical mGluR-LTD using DHPG (Dihydroxyphenylglycine), a selective mGluR5 agonist. We found that exogenous Reelin reduces the DHPG-induced increase in STEP61, prevents the dephosphorylation of GluA2, and concomitantly blocks mGluR-mediated LTD. By contrast, Reelin deficiency increased expression of Ca2+-permeable GluA2-lacking AMPA receptors along with higher STEP61 levels, resulting in occlusion of DHPG-induced LTD in hippocampal CA1 neurons. We propose a model in which Reelin modulates local protein synthesis as well as AMPA receptor subunit composition through modulation of mGluR-mediated signaling with implications for memory consolidation or neurodegeneration.SIGNIFICANCE STATEMENT Reelin is an important neuromodulator, which in the adult brain controls synaptic plasticity and protects against neurodegeneration. Amyloid-ß has been shown to use mGluRs to induce synaptic depression through endocytosis of NMDA and AMPA receptors, a mechanism referred to as LTD, a paradigm of forgetfulness. Our results show that Reelin regulates the phosphatase STEP, which plays an important role in neurodegeneration, as well as the expression of calcium-permeable AMPA receptors, which play a role in memory formation. These data suggest that Reelin uses mGluR LTD pathways to regulate memory formation as well as neurodegeneration.


Asunto(s)
Depresión Sináptica a Largo Plazo/fisiología , Neuronas/fisiología , Proteínas Tirosina Fosfatasas no Receptoras/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Proteína Reelina/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Calcio/fisiología , Células Cultivadas , Corteza Cerebral/citología , Inducción Enzimática/efectos de los fármacos , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Memoria/fisiología , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Ratones , Degeneración Nerviosa/fisiopatología , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Fosforilación/efectos de los fármacos , Picrotoxina/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores AMPA/metabolismo , Receptores de Glutamato Metabotrópico/agonistas , Proteínas Recombinantes/metabolismo , Proteína Reelina/deficiencia , Proteína Reelina/genética
5.
Mol Brain ; 14(1): 63, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33789707

RESUMEN

Cerebellar granule cells (GCs) relay mossy fiber (MF) inputs to Purkinje cell dendrites via their axons, the parallel fibers (PFs), which are individually located at a given sublayer of the molecular layer (ML). Although a certain degree of heterogeneity among GCs has been recently reported, variability of GC responses to MF inputs has never been associated with their most notable structural variability, location of their projecting PFs in the ML. Here, we utilize an adeno-associated virus (AAV)-mediated labeling technique that enables us to categorize GCs according to the location of their PFs, and compare the Ca2+ responses to MF stimulations between three groups of GCs, consisting of either GCs having PFs at the deep (D-GCs), middle (M-GCs), or superficial (S-GCs) sublayer. Our structural analysis revealed that there was no correlation between position of GC soma in the GC layer and location of its PF in the ML, confirming that our AAV-mediated labeling was important to test the projection-dependent variability of the Ca2+ responses in GCs. We then found that the Ca2+ responses of D-GCs differed from those of M-GCs. Pharmacological experiments implied that the different Ca2+ responses were mainly attributable to varied distributions of GABAA receptors (GABAARs) at the synaptic and extrasynaptic regions of GC dendrites. In addition to GABAAR distributions, amounts of extrasynaptic NMDA receptors appear to be also varied, because Ca2+ responses were different between D-GCs and M-GCs when glutamate spillover was enhanced. Whereas the Ca2+ responses of S-GCs were mostly equivalent to those of D-GCs and M-GCs, the blockade of GABA uptake resulted in larger Ca2+ responses in S-GCs compared with D-GCs and M-GCs, implying existence of mechanisms leading to more excitability in S-GCs with increased GABA release. Thus, this study reveals MF stimulation-mediated non-uniform Ca2+ responses in the cerebellar GCs associated with the location of their PFs in the ML, and raises a possibility that combination of inherent functional variability of GCs and their specific axonal projection contributes to the information processing through the GCs.


Asunto(s)
Señalización del Calcio/fisiología , Corteza Cerebelosa/citología , Vías Nerviosas/fisiología , Neuronas/fisiología , Transmisión Sináptica/fisiología , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Corteza Cerebelosa/ultraestructura , Dependovirus/genética , Genes Reporteros , Vectores Genéticos , Ratones , Fibras Nerviosas/fisiología , Células de Purkinje/fisiología , Receptores de GABA-A/genética , Receptores de GABA-A/fisiología
6.
Psychopharmacology (Berl) ; 237(1): 231-248, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31654083

RESUMEN

RATIONALE: Several findings indicate that early-life dysfunction of N-methyl-D-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. OBJECTIVES: In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). METHODS: Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. RESULTS: The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. CONCLUSIONS: The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.


Asunto(s)
Epigénesis Genética/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Acetilación/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Miedo/fisiología , Histonas/metabolismo , Masculino , Memoria/fisiología , Corteza Prefrontal/metabolismo , Ratas , Esquizofrenia/metabolismo
7.
Neuroscience ; 423: 98-108, 2019 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-31689490

RESUMEN

Non-synaptic transmission is pervasive throughout the nervous system. It appears especially prevalent in peripheral ganglia, where non-synaptic interactions between neighboring cell bodies have been described in both physiological and pathological conditions, a phenomenon referred to as cross-depolarization (CD) and thought to play a role in sensory processing and chronic pain. CD has been proposed to be mediated by a chemical agent, but its identity has remained elusive. Here, we report that in the rat dorsal root ganglion (DRG), the P2Y1 purinergic receptor (P2RY1) plays an important role in regulating CD. The effect of P2RY1 is cell-type specific: pharmacological blockade of P2RY1 inhibited CD in A-type neurons while enhancing it in C-type neurons. In the nodose ganglion of the vagus, CD requires extracellular calcium in a large percentage of cells. In contrast, we show that in the DRG extracellular calcium appears to play no major role, pointing to a mechanistic difference between the two peripheral ganglia. Furthermore, we show that DRG glial cells also play a cell-type specific role in CD regulation. Fluorocitrate-induced glial inactivation had no effect on A-cells but enhanced CD in C-cells. These findings shed light on the mechanism of CD in the DRG and pave the way for further analysis of non-synaptic neuronal communication in sensory ganglia.


Asunto(s)
Comunicación Celular/fisiología , Ganglios Espinales/fisiología , Neuronas/fisiología , Receptores Purinérgicos P2Y1/fisiología , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Potenciales de Acción/fisiología , Adenosina Difosfato/análogos & derivados , Adenosina Difosfato/farmacología , Animales , Bencenosulfonatos/farmacología , Calcio/fisiología , Citratos/farmacología , Estimulación Eléctrica , Masculino , Inhibición Neural/fisiología , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Neuronas/efectos de los fármacos , Ganglio Nudoso/fisiología , Piperazinas/farmacología , Ratas , Receptores Purinérgicos P2Y1/efectos de los fármacos
8.
Behav Neurosci ; 133(4): 428-436, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31294591

RESUMEN

Previous work from our laboratory has indicated that temporary inactivation of the basolateral amygdala (BLA) with bupivacaine blocks acquisition, consolidation, and retrieval of an amphetamine conditioned place preference (CPP). The present study was designed to extend this line of investigation by examining whether N-methyl-D-aspartate (NMDA) receptors in the BLA mediate acquisition and extinction of an amphetamine CPP. Adult male Long-Evans rats received bilateral intra-BLA injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 1.25 µg, 2.5 µg, or 5.0 µg) or saline prior to each session of CPP acquisition (Experiment 1). In addition, separate groups of rats received intra-BLA injections of the sodium channel blocker bupivacaine (Experiment 2), AP5 (1.25 µg, 2.5 µg, or 5.0 µg; Experiment 3), or saline prior to each session of CPP extinction training. Results indicated that intra-BLA injection of bupivacaine or AP5 (2.5 or 5.0 µg) disrupted acquisition of an amphetamine CPP. In addition, neural inactivation of the BLA with bupivacaine blocked extinction of CPP. Finally, intra-BLA AP5 injections (2.5 or 5.0 µg) were sufficient to block CPP extinction. The present findings indicate that NMDA receptor activity in the BLA is critical for acquisition and extinction of an amphetamine CPP and may be relevant to understanding the neural mechanisms underlying some aspects of drug seeking and addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Asunto(s)
Complejo Nuclear Basolateral/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Anfetamina/metabolismo , Anfetamina/farmacología , Amígdala del Cerebelo/fisiología , Animales , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/fisiología , Bupivacaína/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Extinción Psicológica/fisiología , Masculino , Memoria/fisiología , Ratas , Ratas Long-Evans , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo
9.
Eur J Neurosci ; 50(9): 3403-3415, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31340074

RESUMEN

Nucleus accumbens dopamine plays a key role in reward-directed approach. Past findings suggest that dopamine's role in the expression of learned behavior diminishes with extended training. However, little is known about the central substrates that mediate the shift to dopamine-independent reward approach. In the present study, rats approached and inserted the head into a reward compartment in response to a cue signaling food delivery. On days 4 and 5 of 28-trial-per-day sessions, D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) infused to the NAc core reduced the probability and speed of cued approach. The disruptive effect of D1 receptor blockade was specific to the nucleus accumbens core and not seen with drug infusions to nearby dopamine target regions. In rats that received drug infusions after extended training (days 10 or 11), accumbens core D1 receptor blockade produced little effect on the expression of the same behavior. These results could have been due to a continued accumbens mediation of cued approach even after the behavior had become independent of accumbens D1 receptors. However, accumbens core ionotropic glutamate receptor blockade disrupted cued approach during early but not late stages of training, similar to the effects of D1 antagonist infusions. The results suggest that with extended training, a nucleus accumbens D1-dependent behavior becomes less dependent not only on nucleus accumbens D1 transmission but also on excitatory transmission in the nucleus accumbens. These findings fill an important gap in a growing literature on reorganization of striatal function over the course of training.


Asunto(s)
Conducta de Elección/fisiología , Dopamina/fisiología , Aprendizaje/fisiología , Núcleo Accumbens/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , 2-Amino-5-fosfonovalerato/administración & dosificación , 2-Amino-5-fosfonovalerato/farmacología , 6-Ciano 7-nitroquinoxalina 2,3-diona/administración & dosificación , 6-Ciano 7-nitroquinoxalina 2,3-diona/farmacología , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Conducta de Elección/efectos de los fármacos , Dopamina/metabolismo , Aprendizaje/efectos de los fármacos , Masculino , Microinyecciones , Núcleo Accumbens/efectos de los fármacos , Quinpirol/farmacología , Ratas , Recompensa , Factores de Tiempo
10.
Eur J Neurosci ; 50(9): 3454-3471, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31206829

RESUMEN

The activation of N-methyl-D-aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA-related behaviours via the change in postsynaptic DA release. NMDARs are recruited during excitatory synaptic transmission by glutamate release, but the glycine site level of occupancy of these receptors during basal action potential-dependent activity is not known for SNc DA neurons. We explored NMDAR-dependent signals during exogenous applications of co-agonists in midbrain slices from juvenile rats. We found that both glycine and D-serine strengthened the NMDAR-dependent component of excitatory postsynaptic currents (EPSCs) in a concentration-dependent manner. EPSCs were also increased by endogenous glycine via the blockade of the glycine transport. The glycine site of NMDARs contributing to synaptic transmission is therefore subsaturated. The behaviourally relevant burst firing was more sensitive to exogenous D-serine and endogenous glycine than to exogenous glycine. The mechanisms regulating the availability of the co-agonists exert consequently a critical influence on the excitability of DA neurons via NMDARs. The modulation of the phasic firing in DA neurons by ambient NMDAR co-agonists may be important for nigral information processing and downstream motor-related behaviour.


Asunto(s)
Neuronas Dopaminérgicas/fisiología , Potenciales Postsinápticos Excitadores/fisiología , Porción Compacta de la Sustancia Negra/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Relación Dosis-Respuesta a Droga , Agonistas de Aminoácidos Excitadores/farmacología , Glicina/farmacología , Ácido Quinurénico/análogos & derivados , Ácido Quinurénico/farmacología , Ácidos Fosfínicos/farmacología , Propanolaminas/farmacología , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Serina/farmacología
11.
Neuropsychopharmacology ; 44(8): 1464-1475, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30928995

RESUMEN

Rostromedial tegmental nucleus (RMTg) GABA neurons exert a primary inhibitory drive onto midbrain dopamine neurons and are excited by a variety of aversive stimuli. There is, however, little evidence that the RMTg-ventral tegmental area (VTA)-nucleus accumbens shell (Acb) circuit plays a role in the aversive consequences of alcohol withdrawal. This study was performed in adult male Long-Evans rats at 48-h withdrawal from chronic alcohol drinking in the intermittent schedule. These rats displayed clear anhedonia and depression-like behaviors, as measured with the sucrose preference, and forced swimming tests. These aberrant behaviors were accompanied by a substantial increase in cFos expression in the VTA-projecting RMTg neurons, identified by a combination of immunohistochemistry and retrograde-tracing techniques. Pharmacological or chemogenetic inhibition of RMTg neurons mitigated the anhedonia and depression-like behaviors. Ex vivo electrophysiological data showed that chemogenetic inactivation of RMTg neurons reduced GABA release and accelerated spontaneous firings of VTA dopamine neurons. Finally, using a functional hemispheric disconnection procedure, we demonstrated that inhibition of unilateral RMTg, when combined with activation of D1 and D2 dopamine receptors in the contralateral (but not ipsilateral) Acb, mitigated the anhedonia and depression-like behaviors in alcohol-withdrawal rats. These data show that the integrity in the RMTg-VTA-Acb pathway in a single hemisphere is sufficient to elicit depression-like behavior during ethanol-withdrawal. Overall, the present results reveal that the RMTg-VTA-Acb pathway plays a crucial role in the depression-like behavior in animals undergoing alcohol withdrawal, further advocating the RMTg as a potential therapeutic target for alcoholism.


Asunto(s)
Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/psicología , Tegmento Mesencefálico/fisiología , Área Tegmental Ventral/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Conducta Animal/fisiología , Clozapina/análogos & derivados , Clozapina/farmacología , Neuronas Dopaminérgicas/fisiología , Etanol/efectos adversos , Masculino , Microinyecciones , Inhibición Neural/fisiología , Vías Nerviosas/fisiología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Quinoxalinas/farmacología , Quinpirol , Ratas , Tegmento Mesencefálico/efectos de los fármacos , Tegmento Mesencefálico/metabolismo , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/metabolismo
12.
J Neurosci ; 39(23): 4448-4460, 2019 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-30936241

RESUMEN

Striatal output pathways are known to play a crucial role in the control of movement. One possible component for shaping the synaptic output of striatal neuron is the glutamatergic input that originates from cortex and thalamus. Although reports focusing on quantifying glutamatergic-induced morphological changes in striatum exist, the role of glutamatergic input in regulating striatal function remains poorly understood. Using primary neurons from newborn mice of either sex in a reduced two-neuron microcircuit culture system, we examined whether glutamatergic input modulates the output of striatal neurons. We found that glutamatergic input enhanced striatal inhibition in vitro With a glutamatergic partner from either cortex or thalamus, we attributed this potentiation to an increase in the size of quantal IPSC, suggesting a strengthening of the postsynaptic response to GABAergic signaling. Additionally, a differential effect of cortical and thalamic innervation onto striatal GABAergic neurons output was revealed. We observed that cortical, but not thalamic input, enhanced the number of releasable GABAergic synaptic vesicles and morphological synapses. Importantly, these alterations were reverted by blockade of neuronal activity and glutamate receptors, as well as disruption of BDNF-TrkB signaling. Together, our data indicate, for first time, that GABAergic synapse formation in corticostriatal pairs depends on two parallel, but potentially intersecting, signaling pathways that involve glutamate receptor activation in striatal neurons, as well as BDNF signaling. Understanding how cortical and thalamic inputs refine striatal output will pave the way toward dissecting basal ganglia activity in both physiological and pathological conditions.SIGNIFICANCE STATEMENT Striatal GABAergic microcircuits are critical for motor function. However, the mechanisms controlling striatal output, particularly at the level of synaptic strength, are unclear. Using two-neuron culture system, we quantified the synaptic output of individual striatal GABAergic neurons paired with a glutamatergic partner and studied the influence of the excitatory connections that are known to be interregionally formed in vivo We found that glutamatergic input potentiated striatal inhibitory output, potentially involving an increased feedback and/or feedforward inhibition. Moreover, distinct components of glutamatergic innervation, such as firing activity or release of neurotrophic factors were shown to be required for the glutamatergic-induced phenotype. Investigation, therefore, of two-neuron in vitro microcircuits could be a powerful tool to explore synaptic mechanisms or disease pathophysiology.


Asunto(s)
Cuerpo Estriado/fisiología , Neuronas GABAérgicas/fisiología , Ácido Glutámico/fisiología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiología , 2-Amino-5-fosfonovalerato/farmacología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Animales , Anticuerpos Neutralizantes/farmacología , Factor Neurotrófico Derivado del Encéfalo/antagonistas & inhibidores , Factor Neurotrófico Derivado del Encéfalo/farmacología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Células Cultivadas , Corteza Cerebral/citología , Cuerpo Estriado/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Neuronas GABAérgicas/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Potenciales Postsinápticos Inhibidores/fisiología , Masculino , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Potenciales Postsinápticos Miniatura/efectos de los fármacos , Potenciales Postsinápticos Miniatura/fisiología , Proteínas Tirosina Quinasas/fisiología , Quinoxalinas/farmacología , Proteínas Recombinantes/farmacología , Vesículas Sinápticas/fisiología , Tetrodotoxina/farmacología , Tálamo/citología
13.
Sci Rep ; 9(1): 5591, 2019 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-30944364

RESUMEN

The intent of this study was to investigate if cerebrospinal fluid (CSF) from autoimmune encephalitis (AE) patients regulates in vitro neuronal network activity differentially to healthy human control CSF (hCSF). To this end, electrophysiological effects of CSF from AE patients or hCSF were measured by in vitro neuronal network activity (ivNNA) recorded with microelectrode arrays (MEA). CSF from patients with either N-methyl-D-aspartate-receptor-antibody (pCSFNMDAR, n = 7) or Leucine-rich-glioma-inactivated-1-Ab (pCSFLGI1, n = 6) associated AE suppressed global spiking activity of neuronal networks by a factor of 2.17 (p < 0.05) or 2.42 (p < 0.05) compared to hCSF. The former also suppressed synchronous network bursting by a factor of 1.93 (p < 0.05) in comparison to hCSF (n = 13). As a functional diagnostic test, this parameter reached a sensitivity of 86% for NMDAR-Ab- and 100% for LGI1-Ab-associated AE vs. hCSF at a specificity of 85%. To explore if modulation at the NMDAR influences effects of hCSF or pathological CSF, we applied the NMDAR-antagonist 2-Amino-5-phosphono-pentanoic acid (AP5). In CSF from NMDAR-Ab-associated AE patients, spike rate reduction by AP5 was more than 2-fold larger than in hCSF (p < 0.05), and network burst rate reduction more than 18-fold (p < 0.01). Recording ivNNA might help discriminating between functional effects of CSF from AE patients and hCSF, and thus could be used as a functional diagnostic test in AE. The pronounced suppression of ivNNA by CSF from NMDAR-Ab-associated AE patients and simultaneous antagonism at the NMDAR by AP5, particularly in burst activity, compared to hCSF plus AP5, confirms that the former contains additional ivNNA-suppressing factors.


Asunto(s)
Líquido Cefalorraquídeo/fisiología , Encefalitis/diagnóstico , Encefalitis/patología , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/patología , Sistema Nervioso/patología , Neuronas/patología , 2-Amino-5-fosfonovalerato/farmacología , Animales , Encefalitis Antirreceptor N-Metil-D-Aspartato/diagnóstico , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Líquido Cefalorraquídeo/efectos de los fármacos , Encefalitis/tratamiento farmacológico , Encefalitis/metabolismo , Femenino , Enfermedad de Hashimoto/tratamiento farmacológico , Enfermedad de Hashimoto/metabolismo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Sistema Nervioso/efectos de los fármacos , Sistema Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Embarazo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores
14.
Artículo en Inglés | MEDLINE | ID: mdl-30814933

RESUMEN

In natural environments our auditory system is exposed to multiple and diverse signals of fluctuating amplitudes. Therefore, to detect, localize, and single out individual sounds the auditory system has to process and filter spectral and temporal information from both ears. It is known that the overall sound pressure level affects sensory signal transduction and therefore the temporal response pattern of auditory neurons. We hypothesize that the mammalian binaural system utilizes a dynamic mechanism to adjust the temporal filters in neuronal circuits to different overall sound pressure levels. Previous studies proposed an inhibitory mechanism generated by the reciprocally coupled dorsal nuclei of the lateral lemniscus (DNLL) as a temporal neuronal-network filter that suppresses rapid binaural fluctuations. Here we investigated the consequence of different sound levels on this filter during binaural processing. Our in vivo and in vitro electrophysiology in Mongolian gerbils shows that the integration of ascending excitation and contralateral inhibition defines the temporal properties of this inhibitory filter. The time course of this filter depends on the synaptic drive, which is modulated by the overall sound pressure level and N-methyl-D-aspartate receptor (NMDAR) signaling. In psychophysical experiments we tested the temporal perception of humans and show that detection and localization of two subsequent tones changes with the sound pressure level consistent with our physiological results. Together our data support the hypothesis that mammals dynamically adjust their time window for sound detection and localization within the binaural system in a sound level dependent manner.


Asunto(s)
Audición/fisiología , Localización de Sonidos/fisiología , Sonido , 2-Amino-5-fosfonovalerato/farmacología , Estimulación Acústica , Potenciales de Acción/efectos de los fármacos , Animales , Vías Auditivas/fisiología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Gerbillinae , Colículos Inferiores/fisiología , Masculino , Inhibición Neural , Neuronas/efectos de los fármacos , Psicofísica , Quinoxalinas/farmacología , Factores de Tiempo
15.
ACS Chem Biol ; 14(4): 742-750, 2019 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-30830751

RESUMEN

Rhizocticins are phosphono-oligopeptide antibiotics that contain a toxic C-terminal ( Z) -l -2-amino-5-phosphono-3-pentenoic acid (APPA) moiety. APPA is an irreversible inhibitor of threonine synthase (ThrC), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the conversion of O-phospho-l-homoserine to l-threonine. ThrCs are essential for the viability of bacteria, plants, and fungi and are a target for antibiotic development, as de novo threonine biosynthetic pathway is not found in humans. Given the ability of APPA to interfere in threonine metabolism, it is unclear how the producing strain B. subtilis ATCC 6633 circumvents APPA toxicity. Notably, in addition to the housekeeping APPA-sensitive ThrC ( BsThrC), B. subtilis encodes a second threonine synthase (RhiB) encoded within the rhizocticin biosynthetic gene cluster. Kinetic and spectroscopic analyses show that PLP-dependent RhiB is an authentic threonine synthase, converting O-phospho-l-homoserine to threonine with a catalytic efficiency comparable to BsThrC. To understand the structural basis of inhibition, we determined the crystal structure of APPA bound to the housekeeping BsThrC, revealing a covalent complex between the inhibitor and PLP. Structure-based sequence analyses reveal structural determinants within the RhiB active site that contribute to rendering this ThrC homologue resistant to APPA. Together, this work establishes the self-resistance mechanism utilized by B. subtilis ATCC 6633 against APPA exemplifying one of many ways by which bacteria can overcome phosphonate toxicity.


Asunto(s)
2-Amino-5-fosfonovalerato/análogos & derivados , Antibacterianos/metabolismo , Bacillus subtilis/metabolismo , Farmacorresistencia Microbiana , Oligopéptidos/metabolismo , 2-Amino-5-fosfonovalerato/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Antibacterianos/farmacología , Liasas de Carbono-Oxígeno/antagonistas & inhibidores , Liasas de Carbono-Oxígeno/metabolismo , Conformación Proteica
16.
J Pain ; 20(8): 885-897, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30707953

RESUMEN

The present study investigated the role of the amygdala N-methyl-d-aspartate (NMDA) receptors/nitric oxide synthase pathway in morphine-induced anti-allodynia. Concurrently with the bilateral cannulation of the central amygdala, chronic constriction of the sciatic nerve was performed on male Wistar rats. Morphine (3-5 mg/kg) was administered intraperitoneally to induce anti-allodynia. When D-AP5, a selective NMDA receptor antagonist, (.05-.1 µg/rat) or NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME), the nitric oxide synthase inhibitor (.1-.5 µg/rat), were microinjected into the central amygdala, the higher doses potentiated an ineffective dose of morphine (3 mg/kg). Microinjection of the same doses of D-AP5 and L-NAME without morphine had no effect. Comicroinjection of the ineffective doses of L-NAME (.1 µg/rat) and D-AP5 (.05 µg/rat) with a 5-minute interval, enhanced the anti-allodynic effect of morphine (3 mg/kg). Western blot analysis was employed to evaluate the levels of cyclic adenosine monophosphate-response element-binding protein (CREB) and phosphorylated CREB (pCREB) in the amygdala tissues. Our results showed that neuropathic pain increased the pCREB/CREB ratio in the amygdala, and this ratio was decreased after morphine-induced anti-allodynia. The potentiative effect of the coadministration of D-AP5/L-NAME on an ineffective dose of morphine also decreased the amygdala pCREB/CREB levels. Therefore, it seems that the amygdala pCREB/CREB signaling pathway plays a critical role in processing neuropathic pain. Moreover, the glutamate NMDA receptors and nitric oxide system in the amygdala may be involved in morphine-induced anti-allodynia. PERSPECTIVE: Neuropathic pain is difficult to treat and the exact mechanisms remain unknown. This article suggests the importance of the amygdala glutamatergic and nitric oxide systems in morphine-induced anti-allodynia. These findings might be used in clinical studies to reach a better understanding of neuropathic pain mechanisms and treatment.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Hiperalgesia/tratamiento farmacológico , Morfina/uso terapéutico , Neuralgia/tratamiento farmacológico , Óxido Nítrico Sintasa/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , 2-Amino-5-fosfonovalerato/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Hiperalgesia/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacología , Neuralgia/metabolismo , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar
17.
Artículo en Inglés | MEDLINE | ID: mdl-30742862

RESUMEN

Exposure of rats to an environment with low O2 levels evokes a panic-like escape behavior and recruits the dorsal periaqueductal gray (dPAG), which is considered to be a key region in the pathophysiology of panic disorder. The neurochemical basis of this response is, however, currently unknown. We here investigated the role played by nitric oxide (NO) within the dPAG in mediation of the escape reaction induced by hypoxia exposure. The results showed that exposure of male Wistar rats to 7% O2 increased nitrite levels, a NO metabolite, in the dPAG but not in the amygdala or hypothalamus. Nitrite levels in the dPAG were correlated with the number of escape attempts during the hypoxia challenge. Injections of the NO synthesis inhibitor NPA, the NO-scavenger c- PTIO, or the NMDA receptor antagonist AP-7 into the dorsolateral column of the periaqueductal gray (dlPAG) inhibited escape expression during hypoxia, without affecting the rats' locomotion. Intra-dlPAG administration of c-PTIO had no effect on the escape response evoked by the elevated-T maze, a defensive behavior that has also been associated with panic attacks. Altogether, our results suggest that NO plays a critical role in mediation of the panic-like defensive response evoked by exposure to low O2 concentrations.


Asunto(s)
Reacción de Fuga/fisiología , Hipoxia/fisiopatología , Óxido Nítrico/fisiología , Pánico/fisiología , Sustancia Gris Periacueductal/fisiología , 2-Amino-5-fosfonovalerato/administración & dosificación , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Amígdala del Cerebelo/metabolismo , Animales , Arginina/administración & dosificación , Arginina/análogos & derivados , Arginina/farmacología , Reacción de Fuga/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Microinyecciones , Actividad Motora/efectos de los fármacos , Nitritos/metabolismo , Sustancia Gris Periacueductal/metabolismo , Ratas
18.
Mol Pain ; 15: 1744806919832718, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30717631

RESUMEN

The neuropeptide of calcitonin gene-related peptide (CGRP) plays critical roles in chronic pain, especially in migraine. Immunohistochemistry and in situ hybridization studies have shown that CGRP and its receptors are expressed in cortical areas including pain perception-related prefrontal anterior cingulate cortex. However, less information is available for the functional roles of CGRP in cortical regions such as the anterior cingulate cortex (ACC). Recent studies have consistently demonstrated that long-term potentiation is a key cellular mechanism for chronic pain in the ACC. In the present study, we used 64-electrode array field recording system to investigate the effect of CGRP on excitatory transmission in the ACC. We found that CGRP induced potentiation of synaptic transmission in a dose-dependently manner (1, 10, 50, and 100 nM). CGRP also recruited inactive circuit in the ACC. An application of the calcitonin receptor-like receptor antagonist CGRP8-37 blocked CGRP-induced chemical long-term potentiation and the recruitment of inactive channels. CGRP-induced long-term potentiation was also blocked by N-methyl-D-aspartate (NMDA) receptor antagonist AP-5. Consistently, the application of CGRP increased NMDA receptor-mediated excitatory postsynaptic currents. Finally, we found that CGRP-induced long-term potentiation required the activation of calcium-stimulated adenylyl cyclase subtype 1 (AC1) and protein kinase A. Genetic deletion of AC1 using AC1-/- mice, an AC1 inhibitor NB001 or a protein kinase A inhibitor KT5720, all reduced or blocked CGRP-induced potentiation. Our results provide direct evidence that CGRP may contribute to synaptic potentiation in important physiological and pathological conditions in the ACC, an AC1 inhibitor NB001 may be beneficial for the treatment of chronic headache.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Giro del Cíngulo/efectos de los fármacos , Red Nerviosa/efectos de los fármacos , 2-Amino-5-fosfonovalerato/farmacología , Adenilil Ciclasas/deficiencia , Adenilil Ciclasas/genética , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Carbazoles/farmacología , Estimulación Eléctrica , Inhibidores Enzimáticos/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Giro del Cíngulo/metabolismo , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Técnicas de Placa-Clamp , Pirroles/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Transducción de Señal/efectos de los fármacos
19.
Glia ; 67(5): 915-934, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30632636

RESUMEN

Optogenetics has been widely expanded to enhance or suppress neuronal activity and it has been recently applied to glial cells. Here, we have used a new approach based on selective expression of melanopsin, a G-protein-coupled photopigment, in astrocytes to trigger Ca2+ signaling. Using the genetically encoded Ca2+ indicator GCaMP6f and two-photon imaging, we show that melanopsin is both competent to stimulate robust IP3-dependent Ca2+ signals in astrocyte fine processes, and to evoke an ATP/Adenosine-dependent transient boost of hippocampal excitatory synaptic transmission. Additionally, under low-frequency light stimulation conditions, melanopsin-transfected astrocytes can trigger long-term synaptic changes. In vivo, melanopsin-astrocyte activation enhances episodic-like memory, suggesting melanopsin as an optical tool that could recapitulate the wide range of regulatory actions of astrocytes on neuronal networks in behaving animals. These results describe a novel approach using melanopsin as a precise trigger for astrocytes that mimics their endogenous G-protein signaling pathways, and present melanopsin as a valuable optical tool for neuron-glia studies.


Asunto(s)
Astrocitos/metabolismo , Red Nerviosa/metabolismo , Neuronas/metabolismo , Optogenética/métodos , Opsinas de Bastones/metabolismo , 2-Amino-5-fosfonovalerato/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Alanina/análogos & derivados , Alanina/farmacología , Animales , Compuestos Azo/farmacología , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Quelantes/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/citología , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Luz , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacología , Pirimidinas/farmacología , Opsinas de Bastones/genética , Potenciales Sinápticos/fisiología , Triazoles/farmacología , Xantenos/farmacología
20.
Behav Pharmacol ; 30(1): 59-66, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30299277

RESUMEN

The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist - 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist - 1/3/10 nmol/µl) or N-propyl-L-arginine (NPA, nNOS inhibitor - 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.


Asunto(s)
Antidepresivos/uso terapéutico , Capsaicina/análogos & derivados , Depresión/tratamiento farmacológico , Ácido Glutámico/metabolismo , Óxido Nítrico/metabolismo , Natación/psicología , 2-Amino-5-fosfonovalerato/análogos & derivados , 2-Amino-5-fosfonovalerato/farmacología , Animales , Apomorfina/análogos & derivados , Apomorfina/farmacología , Arginina/farmacología , Capsaicina/uso terapéutico , GMP Cíclico/metabolismo , Depresión/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Inhibidores Enzimáticos/farmacología , Conducta Exploratoria/efectos de los fármacos , Masculino , Microinyecciones , Nitroprusiato/metabolismo , Ratas , Receptores de N-Metil-D-Aspartato/metabolismo , Estadísticas no Paramétricas
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