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Emotional arousal is caused by the activity of two parallel ascending systems targeting mostly the subcortical limbic regions and the prefrontal cortex. The aversive, negative arousal system is initiated by the activity of the mesolimbic cholinergic system and the hedonic, appetitive, arousal is initiated by the activity of the mesolimbic dopaminergic system. Both ascending projections have a diffused nature and arise from the rostral, tegmental part of the brain reticular activating system. The mesolimbic cholinergic system originates in the laterodorsal tegmental nucleus and the mesolimbic dopaminergic system in the ventral tegmental area. Cholinergic and dopaminergic arousal systems have converging input to the medial prefrontal cortex. The arousal system can modulate cortical EEG with alpha rhythms, which enhance synaptic strength as shown by an increase in long-term potentiation (LTP), whereas delta frequencies are associated with decreased arousal and a decrease in synaptic strength as shown by an increase in long-term depotentiation (LTD). It is postulated that the medial prefrontal cortex is an adaptable node with decision making capability and may control the switch between positive and negative affect and is responsible for modifying or changing emotional state and its expression.
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Stinels are a novel class of N-methyl-d-aspartate glutamate receptor (NMDAR) positive allosteric modulators. We explored mechanism of action and NR2 subtype specificity of the stinel zelquistinel (ZEL) in HEK 293 cells expressing recombinant NMDARs. ZEL potently enhanced NMDAR current at NR2A (EC50 = 9.9 ± 0.5 nM) and NR2C-containing (EC50 = 9.7 ± 0.6 nM) NMDARs, with a larger ceiling enhancement at NR2B-NMDAR (EC50 = 35.0 ± 0.7 nM), while not affecting NR2D-containing NMDARs. In cells expressing NR2A and NR2C-containing NMDARs, ZEL exhibited an inverted-U dose-response relation, with a low concentration enhancement and high concentration suppression of NMDAR currents. Extracellular application of ZEL potentiated NMDAR receptor activity via prolongation of NMDAR currents. Replacing the slow Ca2+ intracellular chelator EGTA with the fast chelator BAPTA blocked ZEL potentiation of NMDARs, suggesting an action on intracellular Ca2+-calmodulin-dependent inactivation (CDI). Consistent with this mechanism of action, removal of the NR1 intracellular C-terminus, or intracellular infusion of a calmodulin blocking peptide, blocked ZEL potentiation of NMDAR current. In contrast, BAPTA did not prevent high-dose suppression of current, indicating this effect has a different mechanism of action. These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore NMDAR-dependent synaptic plasticity by reducing activity-dependent CDI.
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Cálcio , Receptores de N-Metil-D-Aspartato , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Humanos , Células HEK293 , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Sesterterpenos/farmacologia , AnimaisRESUMO
Positive and negative emotional states in rats can be studied by investigating ultrasonic vocalizations (USVs). Positive affect in rats is indexed by 50 kHz hedonic USVs, and negative affect is indexed by 22 kHz aversive calls. We examined the relationship of emotional states in rats using medial prefrontal cortex (MPFC) quantitative electroencephalograms (qEEG) and found that hedonic USVs were associated with active wake qEEG (high alpha/low delta power), and aversive USVs occurred with groggy wake qEEG (low alpha/high delta). Further, alpha frequency electrical stimulation of the MPFC induces hedonic calls and reward-seeking behavior, whereas delta frequency stimulation produces aversive calls and avoidance behavior. The brain region responsible for generating motor output for USVs, the periaqueductal gray (PAG), shows a motor-evoked potential that is temporally locked to the alpha (hedonic) and delta (aversive) motor-evoked potential. Closed-loop alpha frequency electrical stimulation could prevent delta qEEG and aversive USVs. At the neuronal circuit level, the alpha rhythm was associated with synaptic long-term potentiation (LTP) in the cortex, whereas the delta rhythm was associated with synaptic depotentiation (LTD) in the cortex. At the pharmacological level, NMDAR and growth factor modulation regulated these forms of neuroplasticity. At the single neuron level, excitatory neurons show increased activity in response to alpha frequencies and decreased activity during delta frequencies. In humans, the feeling of joy increased alpha and decreased delta power in frontal scalp qEEG, and the opposite response was seen for sadness. Thus, the synchronization of alpha/delta oscillations through the neuronal circuit responsible for emotional expression coordinates emotional behavior, and the switch between active wake/positive affect and groggy wake/negative affect is under the control of an LTP- LTD synaptic plasticity mechanism.
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We developed an IGFBP2-mimetic peptide fragment, JB2, and showed that it promotes basal synaptic structural and functional plasticity in cultured neurons and mice. We demonstrate that JB2 directly binds to dendrites and synapses, and its biological activity involves NMDA receptor activation, gene transcription and translation, and IGF2 receptors. It is not IGF1 receptor-dependent. In neurons, JB2 induced extensive remodeling of the membrane phosphoproteome. Synapse and cytoskeletal regulation, autism spectrum disorder (ASD) risk factors, and a Shank3-associated protein network were significantly enriched among phosphorylated and dephosphorylated proteins. Haploinsufficiency of the SHANK3 gene on chromosome 22q13.3 often causes Phelan-McDermid Syndrome (PMS), a genetically defined form of autism with profound deficits in motor behavior, sensory processing, language, and cognitive function. We identified multiple disease-relevant phenotypes in a Shank3 heterozygous mouse and showed that JB2 rescued deficits in synaptic function and plasticity, learning and memory, ultrasonic vocalizations, and motor function; it also normalized neuronal excitability and seizure susceptibility. Notably, JB2 rescued deficits in the auditory evoked response latency, alpha peak frequency, and steady-state electroencephalography response, measures with direct translational value to human subjects. These data demonstrate that JB2 is a potent modulator of neuroplasticity with therapeutic potential for the treatment of PMS and ASD.
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Transtorno do Espectro Autista , Transtornos Cromossômicos , Humanos , Camundongos , Animais , Transtorno do Espectro Autista/genética , Proteínas do Tecido Nervoso/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Peptídeos/genética , Modelos Animais de Doenças , Plasticidade Neuronal , Cromossomos Humanos Par 22/metabolismo , Proteínas dos Microfilamentos/genéticaRESUMO
BACKGROUND: The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity. METHODS: NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the chronic social deficit mouse model. Target engagement and the safety/tolerability profile was assessed using phencyclidine-induced hyperlocomotion and rotarod rodent models. RESULTS: Following a single oral dose, zelquistinel (0.1-100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/ cerebrospinal fluid concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting that zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited phencyclidine (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance. CONCLUSIONS: Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation of synaptic transmission.
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Transtorno Depressivo Maior , Receptores de N-Metil-D-Aspartato , Animais , Ratos , Camundongos , Transtorno Depressivo Maior/tratamento farmacológico , Ratos Sprague-Dawley , Antidepressivos/uso terapêutico , Potenciação de Longa Duração/fisiologia , Fenciclidina/farmacologiaRESUMO
BACKGROUND: A novel N-methyl-D-aspartate receptor (NMDAR) allosteric modulator, rapastinel (RAP, formerly GLYX-13), elicits long-lasting antidepressant-like effects by enhancing long-term potentiation (LTP) of synaptic transmission. RAP elicits these effects by binding to a unique site in the extracellular region of the NMDAR complex, transiently enhancing NMDAR-gated current in pyramidal neurons of both hippocampus and medial prefrontal cortex. METHODS: We compared efficacy of RAP in modulating Schaffer collateral-evoked NMDAR-currents as a function of kinetics of the Ca2+ chelator in the intracellular solution, using whole-cell patch-clamp recordings. The intracellular solution contained either the slow Ca2+ chelator EGTA [3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecane-1,14-dioic acid, 0.5 mmol/l] or the 40-500-fold kinetically faster, more selective Ca2+ chelator BAPTA {2,2',2â³,2â´-[ethane-1,2-diylbis(oxy-2,1-phenylenenitrilo)] tetraacetic acid, 5 mmol/l}. NMDAR-gated currents were pharmacologically isolated by bath application of the 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid receptor antagonist 6-nitro-2,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (10 µmol/l) plus the GABA receptor blocker bicuculline (20 µmol/l). RESULTS: When the slow Ca2+ chelator EGTA was in the intracellular solution, RAP elicited significant enhancement of NMDAR-gated current at a 1 µmol/l concentration, and significantly reduced current at 10 µmol/l. In contrast, when recording with the 40-500-fold kinetically faster, more selective Ca2+ chelator BAPTA, NMDAR current increased in magnitude by 84% as BAPTA washed into the cell, and the enhancement of NMDAR current by 1 µmol/l RAP was completely blocked. Interestingly, the reduction in NMDAR current from 10 µmol/l RAP was not affected by the presence of BAPTA in the recording pipette, indicating that this effect is mediated by a different mechanism. CONCLUSION: Extracellular binding of RAP to the NMDAR produces a novel, long-range reduction in affinity of the Ca2+ inactivation site on the NMDAR C-terminus accessible to the intracellular space. This action underlies enhancement in NMDAR-gated conductance elicited by RAP.
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Cálcio , Receptores de N-Metil-D-Aspartato , Quelantes/farmacologia , Ácido Egtázico/farmacologia , Hipocampo/fisiologia , OligopeptídeosRESUMO
Although many neuronal membrane proteins undergo proteolytic cleavage, little is known about the biological significance of neuronal ectodomain shedding (ES). Here, we show that the neuronal sheddome is detectable in human cerebrospinal fluid (hCSF) and is enriched in neurodevelopmental disorder (NDD) risk factors. Among shed synaptic proteins is the ectodomain of CNTNAP2 (CNTNAP2-ecto), a prominent NDD risk factor. CNTNAP2 undergoes activity-dependent ES via MMP9 (matrix metalloprotease 9), and CNTNAP2-ecto levels are reduced in the hCSF of individuals with autism spectrum disorder. Using mass spectrometry, we identified the plasma membrane Ca2+ ATPase (PMCA) extrusion pumps as novel CNTNAP2-ecto binding partners. CNTNAP2-ecto enhances the activity of PMCA2 and regulates neuronal network dynamics in a PMCA2-dependent manner. Our data underscore the promise of sheddome analysis in discovering neurobiological mechanisms, provide insight into the biology of ES and its relationship with the CSF, and reveal a mechanism of regulation of Ca2+ homeostasis and neuronal network synchrony by a shed ectodomain.
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Transtorno do Espectro Autista , Proteínas de Membrana , Proteínas do Tecido Nervoso , ATPases Transportadoras de Cálcio da Membrana Plasmática , Transtorno do Espectro Autista/líquido cefalorraquidiano , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Membrana Celular/metabolismo , Homeostase , Humanos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , ATPases Transportadoras de Cálcio da Membrana Plasmática/líquido cefalorraquidiano , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Transdução de SinaisRESUMO
Since the realization that human emotional experiences and behavior evolved from mammalian ancestors and are evolutionary continuations of animal emotional behavior [...].
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STUDY OBJECTIVES: The present studies examine the effects of NMDAR activation by NYX-2925 diurnal rhythmicity of both sleep and wake as well as emotion. METHODS: Twenty-four-hour sleep EEG recordings were obtained in sleep-deprived and non-sleep-deprived rats. In addition, the day-night cycle of both activity and mood was measured using home cage ultrasonic-vocalization recordings. RESULTS: NYX-2925 significantly facilitated non-REM (NREM) sleep during the lights-on (sleep) period, and this effect persisted for 3 days following a single dose in sleep-deprived rats. Sleep-bout duration and REM latencies were increased without affecting total REM sleep, suggesting better sleep quality. In addition, delta power during wake was decreased, suggesting less drowsiness. NYX-2925 also rescued learning and memory deficits induced by sleep deprivation, measured using an NMDAR-dependent learning task. Additionally, NYX-2925 increased positive affect and decreased negative affect, primarily by facilitating the transitions from sleep to rough-and-tumble play and back to sleep. In contrast to NYX-2925, the NMDAR antagonist ketamine acutely (1-4 hours post-dosing) suppressed REM and non-REM sleep, increased delta power during wake, and blunted the amplitude of the sleep-wake activity rhythm. DISCUSSION: These data suggest that NYX-2925 could enhance behavioral plasticity via improved sleep quality as well as vigilance during wake. As such, the facilitation of sleep by NYX-2925 has the potential to both reduce symptom burden on neurological and psychiatric disorders as well as serve as a biomarker for drug effects through restoration of sleep architecture.
Assuntos
Afeto/fisiologia , Ritmo Circadiano/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Privação do Sono/fisiopatologia , Sono/fisiologia , Compostos de Espiro/farmacologia , Afeto/efeitos dos fármacos , Animais , Ritmo Circadiano/efeitos dos fármacos , Eletroencefalografia/métodos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistas , Sono/efeitos dos fármacos , Privação do Sono/tratamento farmacológico , Compostos de Espiro/uso terapêutico , Vigília/efeitos dos fármacos , Vigília/fisiologiaRESUMO
BACKGROUND: NYX-2925 is a novel N-methyl-D-aspartate receptor (NMDAR) modulator that has been shown to facilitate both NMDAR-dependent long-term potentiation (LTP) in vitro and learning and memory in vivo. OBJECTIVE: The present studies examine the effects of NYX-2925 on NMDAR-dependent auditory LTP (aLTP) in vivo. METHODS: NMDAR-dependent aLTP and NMDAR-dependent auditory mismatch negativity (MMN) was measured, as well as changes in resting-state qEEG power. RESULTS: NYX-2925 (1, 10 mg/kg PO) increased aLTP 1 h after auditory tetanus measured by the post- minus pre-tetanus difference waveform 140-180 ms post tone onset. NYX-2925 (0.1, 1 mg/kg PO) facilitated MMN measured by the difference waveform (i.e., deviant minus standard tones). NYX-2925 (0.1, 1, 10 mg/kg PO) also enhanced resting-state alpha qEEG power. Conversely, the NMDAR glutamate site antagonist CPP (10 mg/kg IP) reduces alpha power and MMN and produces an opposite effect as NYX-2925 on aLTP. CONCLUSIONS: Together, these data suggest that the activation of the NMDAR by NYX-2925 enhances synaptic plasticity in vivo, which may both reduce symptoms of neurological disorders and serve as a biomarker for drug effects. This is the first demonstration of a long-lasting (1-h post-tetanus) effect of NMDAR modulation on synaptic plasticity processes in vivo using a noninvasive technique in freely behaving animals.
Assuntos
Eletroencefalografia/métodos , Plasticidade Neuronal/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Compostos de Espiro/farmacologia , Pesquisa Translacional Biomédica/métodos , Animais , Eletroencefalografia/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/agonistasRESUMO
In humans, chronic pain is often expressed as a spontaneous emotional response which can lead to fragmented sleep. Rat 50-kHz and 20-kHz ultrasonic vocalizations are well-established measures of positive and negative emotional states, respectively. The rat chronic constriction injury model was used to induce chronic pain, and ultrasonic vocalizations were measured in both the heterospecific rough-and-tumble play (i.e. tickling) test as well as during 24-hour home cage recordings. Rates of hedonic 50-kHz ultrasonic vocalizations during the non-stimulus periods of the tickling test, as well as the rewarding value of tickling, were reduced in chronic constriction injury rats compared to sham controls. In the 24-hour home cage recording study, chronic constriction injury animals showed a reduced amplitude in circadian activity, as well as reduced hedonic 50-kHz ultrasonic vocalizations and increased evoked and spontaneous aversive 20-kHz ultrasonic vocalizations. These data demonstrate that rat ultrasonic vocalizations can be used to capture core symptoms of chronic pain and may be useful in the elucidation of the neuronal mechanisms that underlie the affective component of pain.
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Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Emoções/fisiologia , Ondas Ultrassônicas , Vocalização Animal/fisiologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Neuropatia Ciática/fisiopatologia , Neuropatia Ciática/psicologiaRESUMO
NYX-2925 [(2S,3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide] is a novel N-methyl-d-aspartate (NMDA) receptor modulator that is currently being investigated in phase 2 clinical studies for the treatment of painful diabetic peripheral neuropathy and fibromyalgia. Previous studies demonstrated that NYX-2925 is a member of a novel class of NMDA receptor-specific modulators that affect synaptic plasticity processes associated with learning and memory. Studies here examined NYX-2925 administration in rat peripheral chronic constriction nerve injury (CCI) and streptozotocin-induced diabetic mechanical hypersensitivity. Additionally, NYX-2925 was examined in formalin-induced persistent pain model and the tail flick test of acute nociception. Oral administration of NYX-2925 resulted in rapid and long-lasting analgesia in both of the neuropathic pain models and formalin-induced persistent pain, but was ineffective in the tail flick model. The analgesic effects of NYX-2925 were blocked by the systemic administration of NMDA receptor antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid. Microinjection of NYX-2925 into the medial prefrontal cortex of CCI rats resulted in analgesic effects similar to those observed following systemic administration, whereas intrathecal administration of NYX-2925 was ineffective. In CCI animals, NYX-2925 administration reversed deficits seen in a rat model of rough-and-tumble play. Thus, it appears that NYX-2925 may have therapeutic potential for the treatment of neuropathic pain, and the data presented here support the idea that NYX-2925 may act centrally to ameliorate pain and modulate negative affective states associated with chronic neuropathic pain.
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Analgésicos/farmacologia , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Compostos de Espiro/farmacologia , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-Dawley , Compostos de Espiro/uso terapêutico , Vocalização Animal/efeitos dos fármacosRESUMO
Background: N-methyl-D-aspartate receptors are one member of a family of ionotropic glutamate receptors that play a pivotal role in synaptic plasticity processes associated with learning and have become attractive therapeutic targets for diseases such as depression, anxiety, schizophrenia, and neuropathic pain. NYX-2925 ((2S, 3R)-3-hydroxy-2-((R)-5-isobutyryl-1-oxo-2,5-diazaspiro[3.4]octan-2-yl)butanamide) is one member of a spiro-ß-lactam-based chemical platform that mimics some of the dipyrrolidine structural features of rapastinel (formerly GLYX-13: threonine-proline-proline-threonine) and is distinct from known N-methyl-D-aspartate receptor agonists or antagonists such as D-cycloserine, ketamine, MK-801, kynurenic acid, or ifenprodil. Methods: The in vitro and in vivo pharmacological properties of NYX-2925 were examined. Results: NYX-2925 has a low potential for "off-target" activity, as it did not exhibit any significant affinity for a large panel of neuroactive receptors, including hERG receptors. NYX-2925 increased MK-801 binding to human N-methyl-D-aspartate receptor NR2A-D subtypes expressed in HEK cells and enhanced N-methyl-D-aspartate receptor current and long-term potentiation (LTP) in rat hippocampal slices (100-500 nM). Single dose ex vivo studies showed increased metaplasticity in a hippocampal LTP paradigm and structural plasticity 24 hours after administration (1 mg/kg p.o.). Significant learning enhancement in both novel object recognition and positive emotional learning paradigms were observed (0.01-1 mg/kg p.o.), and these effects were blocked by the N-methyl-D-aspartate receptor antagonist CPP. NYX-2925 does not show any addictive or sedative/ataxic side effects and has a therapeutic index of >1000. NYX-2925 (1 mg/kg p.o.) has a cerebrospinal fluid half-life of 1.2 hours with a Cmax of 44 nM at 1 hour. Conclusions: NYX-2925, like rapastinel, activates an NMDA receptor-mediated synaptic plasticity process and may have therapeutic potential for a variety of NMDA receptor-mediated central nervous system disorders.
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Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Oligopeptídeos/farmacologia , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Emoções/efeitos dos fármacos , Fármacos Atuantes sobre Aminoácidos Excitatórios/líquido cefalorraquidiano , Fármacos Atuantes sobre Aminoácidos Excitatórios/química , Células HEK293 , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Estrutura Molecular , Plasticidade Neuronal/fisiologia , Oligopeptídeos/líquido cefalorraquidiano , Oligopeptídeos/química , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Pirazinas/farmacologia , Ratos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Positive emotions have been shown to induce resilience to stress in humans, as well as increase cognitive abilities (learning, memory, and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic vocalizations (hedonic 50 kHz) reflect a positive affective state and are best elicited by rough-and-tumble play. A well-established rat chronic unpredictable stress paradigm was used to produce a robust and long-lasting decrease in positive affect, increase in negative affect, and learned helplessness in Sprague-Dawley rats. Rough-and-tumble play (3 min every 3 days) reversed stress-induced effects of chronic unpredictable stress in the Porsolt forced swim test, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays compared with a light touch control group. These data demonstrate that positive affect induces resilience to stress effects in rats, and that rough-and-tumble play can be used to explore the biological basis of resilience that may lead to the development of new therapeutics for stress-related disorders.
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Resiliência Psicológica , Comportamento Social , Estresse Psicológico , Afeto , Animais , Sacarose Alimentar , Comportamento Alimentar , Desamparo Aprendido , Masculino , Atividade Motora , Ratos Sprague-Dawley , Percepção Gustatória , Ultrassom , Incerteza , Vocalização AnimalRESUMO
Background: Posttraumatic stress disorder is an anxiety disorder characterized by deficits in the extinction of aversive memories. Insulin-like growth factor 1 (IGF1) is the only growth factor that has shown anxiolytic and antidepressant properties in human clinical trials. In animal studies, insulin-like growth factor binding protein 2 (IGFBP2) shows both IGF1-dependent and IGF1-independent pharmacological effects, and IGFBP2 expression is upregulated by rough-and-tumble play that induces resilience to stress. Methods: IGFBP2 was evaluated in Porsolt, contextual fear conditioning, and chronic unpredictable stress models of posttraumatic stress disorder. The dependence of IGFBP2 effects on IGF1- and AMPA-receptor activation was tested using selective receptor antagonists. Dendritic spine morphology was measured in the dentate gyrus and the medial prefrontal cortex 24 hours after in vivo dosing. Results: IGFBP2 was 100 times more potent than IGF1 in the Porsolt test. Unlike IGF1, effects of IGFBP2 were not blocked by the IGF1-receptor antagonist JB1, or by the AMPA-receptor antagonist 2,3-Dioxo-6-nitro-1,2,3,4 tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) in the Porsolt test. IGFBP2 (1 µg/kg) and IGF1 (100 µg/kg i.v.) each facilitated contextual fear extinction and consolidation. Using a chronic unpredictable stress paradigm, IGFBP2 reversed stress-induced effects in the Porsolt, novelty-induced hypophagia, sucrose preference, and ultrasonic vocalization assays. IGFBP2 also increased mature dendritic spine densities in the medial prefrontal cortex and hippocampus 24 hours postdosing. Conclusions: These data suggest that IGFBP2 has therapeutic-like effects in multiple rat models of posttraumatic stress disorder via a novel IGF1 receptor-independent mechanism. These data also suggest that the long-lasting effects of IGFBP2 may be due to facilitation of structural plasticity at the dendritic spine level. IGFBP2 and mimetics may have therapeutic potential for the treatment of posttraumatic stress disorder.
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Espinhas Dendríticas/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Psicotrópicos/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Animais , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/administração & dosagem , Fator de Crescimento Insulin-Like I/administração & dosagem , Fator de Crescimento Insulin-Like I/metabolismo , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Ratos Sprague-Dawley , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/patologiaRESUMO
BACKGROUND: Positive emotions have been shown to induce resilience to depression and anxiety in humans, as well as increase cognitive abilities (learning, memory and problem solving) and improve overall health. In rats, frequency modulated 50-kHz ultrasonic vocalizations (Hedonic 50-kHz USVs) reflect a positive affective state and are best elicited by rough-and-tumble play. METHODS: The effect of positive affect induced by rough-and tumble play was examined on models of depression and learning and memory. The molecular and pharmacological basis of play induced positive affect was also examined. RESULTS: Rough-and-tumble play induced Hedonic 50-kHz USVs, lead to resilience to depression and anxiety, and facilitation of learning and memory. These effects are mediated, in part, by increased NMDAR expression and activation in the medial prefrontal cortex. CONCLUSIONS: We hypothesize that positive affect induces resilience to depression by facilitating NMDAR-dependent synaptic plasticity in the medial prefrontal cortex. Targeting MPFC synaptic plasticity may lead to novel treatments for depression.
Assuntos
Ansiedade/etiologia , Depressão/etiologia , Emoções/fisiologia , Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Emoções/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Receptores de N-Metil-D-Aspartato/genética , Vocalização Animal/efeitos dos fármacos , Vocalização Animal/fisiologiaRESUMO
BACKGROUND: Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. METHODS: Rapastinel was derived from a monoclonal antibody, B6B21, is a tetrapeptide (threonine-proline-proline-threonine-amide) obtained from amino acid sequence information obtained from sequencing one of the hypervariable regions of the light chain of B6B21. The in-vivo and in-vitro pharmacology of rapastinel was examined. RESULTS: Rapastinel was found to be a robust cognitive enhancer in a variety of learning and memory paradigms and shows marked antidepressant-like properties in multiple models including the forced swim (Porsolt), learned helplessness and chronic unpredictable stress. Rapastinel's rapid-acting antidepressant properties appear to be mediated by its ability to activate NMDA receptors leading to enhancement in synaptic plasticity processes associated with learning and memory. This is further substantiated by the increase in mature dendritic spines found 24 hrs after rapastinel treatment in both the rat dentate gyrus and layer five of the medial prefrontal cortex. Moreover, ex vivo LTP studies showed that the effects of rapastinel persisted at least two weeks post-dosing. CONCLUSION: These data suggest that rapastinel has significant effects on metaplasticity processes that may help explain the long lasting antidepressant effects of rapastinel seen in the human clinical trial results.
Assuntos
Depressão/tratamento farmacológico , Oligopeptídeos/farmacologia , Oligopeptídeos/uso terapêutico , Fatores Etários , Animais , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Depressão/patologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Comportamento Exploratório/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Oligopeptídeos/química , Ratos , Receptores de N-Metil-D-Aspartato/metabolismo , Natação , Sinapses/efeitos dos fármacos , Sinapses/ultraestrutura , Vocalização Animal/efeitos dos fármacosRESUMO
GLYX-13 (rapastinel), a tetrapeptide (Thr-Pro-Pro-Thr-amide), has been reported to have fast acting antidepressant properties in man based upon its N-methyl-D-aspartate receptor (NMDAR) glycine site functional partial agonism. Ketamine, a non-competitive NMDAR antagonist, also reported to have fast acting antidepressant properties, produces cognitive impairment in rodents and man, whereas rapastinel has been reported to have cognitive enhancing properties in rodents, without impairing cognition in man, albeit clinical testing has been limited. The goal of this study was to compare the cognitive impairing effects of rapastinel and ketamine in novel object recognition (NOR), a measure of declarative memory, in male C57BL/6J mice treated with phencyclidine (PCP), another NMDAR noncompetitive antagonist known to severely impair cognition, in both rodents and man. C57BL/6J mice given a single dose or subchronic ketamine (30 mg/kg.i.p.) showed acute or persistent deficits in NOR, respectively. Acute i.v. rapastinel (1.0 mg/kg), did not induce NOR deficit. Pre-treatment with rapastinel significantly prevented acute ketamine-induced NOR deficit. Rapastinel (1.0 mg/kg, but not 0.3 mg/kg, iv) significantly reversed both subchronic ketamine- and subchronic PCP-induced NOR deficits. Rapastinel also potentiated the atypical antipsychotic drug with antidepressant properties, lurasidone, to restore NOR in subchronic ketamine-treated mice. These findings indicate that rapastinel, unlike ketamine, does not induce a declarative memory deficit in mice, and can prevent or reverse the ketamine-induced NOR deficit. Further study is required to determine if these differences translate during clinical use of ketamine and rapastinel as fast acting antidepressant drugs and if rapastinel could have non-ionotropic effects as an add-on therapy with antipsychotic/antidepressant medications.
Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Transtornos da Memória/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Ketamina , Masculino , Transtornos da Memória/induzido quimicamente , Camundongos , Camundongos Endogâmicos C57BL , Fenciclidina , Reconhecimento Psicológico/fisiologiaRESUMO
BACKGROUND: Growth factors play an important role in regulating neurogenesis and synapse formation and may be involved in regulating the antidepressant response to conventional antidepressants. To date, Insulin-like growth factor I (IGFI) is the only growth factor that has shown antidepressant properties in human clinical trials. However, its mechanism of action remains unclear. METHODS: The antidepressant-like effect of a single IV dose of IGFI was determined using a chronic unpredictable stress paradigm in the rat Porsolt, sucrose preference, novelty-induced hypophagia, and ultrasonic vocalization models. The dependence of the medial prefrontal cortex for these effects was determined by direct medial prefrontal cortex injection followed by Porsolt testing as well as IGFI receptor activation in the medial prefrontal cortex following an optimal IV antidepressant-like dose of IGFI. The effect of IGFI on synaptic transmission and long-term potentiation (LTP) of synaptic strength was assessed in the hippocampus and medial prefrontal cortex. The dependence of these effects on IGFI and AMPA receptor activation and protein synthesis were also determined. RESULTS: IGFI produced a rapid-acting and long-lasting antidepressant-like effect in each of the depression models. These effects were blocked by IGFI and AMPA receptor antagonists, and medial prefrontal cortex was localized. IGFI robustly increased synaptic strength in the hippocampus and medial prefrontal cortex and these effects were IGFI receptor and protein synthesis-dependent but N-methyl-d-aspartate receptor independent. IGFI also robustly facilitated hippocampal metaplasticity 24 hours postdosing. CONCLUSIONS: These data support the conclusion that the antidepressant-like effects of IGFI are mediated by a persistent, LTP-like enhancement of synaptic strength requiring both IGFIR activation and ongoing protein synthesis.
Assuntos
Antidepressivos/administração & dosagem , Hipocampo/fisiologia , Fator de Crescimento Insulin-Like I/administração & dosagem , Potenciação de Longa Duração/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Relação Dose-Resposta a Droga , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Microinjeções , Técnicas de Cultura de Órgãos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Contextual fear extinction (CFE) in rodents has been well characterized and used extensively as a model to study the neurobiological mechanisms of post-traumatic stress disorder (PTSD). Since CFE is NMDA receptor modulated and neural circuitry in the medial prefrontal cortex (MPFC) regulates both depression and PTSD, studies were undertaken to examine the effects of rapastinel for its therapeutic potential in PTSD and to use rapastinel as a tool to study its underlying glutamatergic mechanisms. A 21-day chronic mild unpredictable stress (CUS) rat model was used to model depression and PTSD. The effects of CUS alone compared to No CUS controls, and the effects of rapastinel (3 mg/kg IV) on CUS-treated animals were examined. The effect of rapastinel was first assessed using CUS-treated rats in three depression models, Porsolt, sucrose preference, and novelty-induced hypophagia tests, and found to produce a complete reversal of the depressive-like state in each model. Rapastinel was then assessed in a MPFC-dependent positive emotional learning paradigm and in CFE and again a reversal of the impairments induced by CUS treatment was observed. Both synaptic plasticity and metaplasticity, as measured by the induction of long-term potentiation in rat MPFC slice preparations, was found to be markedly impaired in CUS-treated animals. This impairment was reversed when CUS-treated rats were administered rapastinel and tested 24 h later. Transcriptomic analysis of MPFC mRNA expression in CUS-treated rats corroborated the link between rapastinel's behavioral effects and synaptic plasticity. A marked enrichment in both the LTP and LTD connectomes in rapastinel-treated CUS rats was observed compared to CUS-treated controls. The effects of rapastinel on depression models, PEL, and most importantly on CFE demonstrate the therapeutic potential of rapastinel for the treatment of PTSD. Moreover, rapastinel appears to elicit its therapeutic effects through a NMDA receptor-mediated, LTP-like, metaplasticity process in the MPFC.