Cortex Slices Research Articles

3,4-Methylenedioxymethamphetamine, mephedrone, and β-phenylethylamine release dopamine from the cytoplasm by means of transporters and keep the concentration high and constant by blocking reuptake

The addiction-related behavioural effects of drugs of abuse are mediated by the mesocorticolimbic monoamine systems. We investigated the effects of 3,4-methylenedioxymethamphetamine (MDMA), mephedrone, β-phenylethylamine (β-PEA) methylphenidate (MPH) on dopamine release from mouse perfused nucleus accumbens and prefrontal cortex slices. The fractional release of [3H]-dopamine was measured at rest and in response to field stimulation. The distributions of [3H]-dopamine and its metabolites were determined using high-pressure liquid chromatography. The effect of drugs on [3H]-dopamine uptake was measured in synaptosomal P2 preparations from the frontal cortex and striatum. Similar to MDMA, mephedrone β-PEA increased the resting release of [3H]-dopamine from the nucleus accumbens and prefrontal cortex in a [Ca2+]o-independent manner, and the stimulation-evoked release was also augmented. In contrast, MPH failed to affect the resting release but potentiated the release in response to axonal activity. Similar to dopamine transporter antagonist GBR 12909, mephedrone, MDMA and MPH biphasically inhibited the [3H]-dopamine uptake. The administration of GBR 12909 and nisoxetine, or lowering the bath temperature prevented MDMA, mephedrone and β-PEA from enhancing the resting, cytoplasmic release of [3H]-dopamine, indicating the role of transporters in the release process. We conclude that amphetamine-like drugs of abuse and the trace amine β-PEA excessively increase the [Ca2+]o-independent, non-vesicular release of dopamine from the cytoplasm into the extrasynaptic space and inhibit the high-affinity transporters, thereby maintaining a high ambient, non-synaptic concentration of dopamine that may tonically control the activity of neurons equipped with dopamine receptors and is likely involved in the reinforcing effects and abusive potential of amphetamines.

Beta-adrenergic receptor activation increases GABA uptake in adolescent mice frontal cortex: Modulation by cannabinoid receptor agonist WIN55,212-2

GABA transporters regulate synaptic GABA levels and dysfunctions in this system might result in psychiatric disorders. The endocannabinoid system (ECS) is the main circuit breaker in the nervous system and may alter noradrenaline (NA) communication, which in turn modulates the release of GABA. However, a close relationship between these systems has not been recognized. We asked whether NA and ECS might control extracellular GABA levels in slices of frontal cortex (FC) of adolescent Swiss mice with 40 days after birth (PN40). Here we show that NA and isoproterenol (ISO), a beta-adrenergic agonist, increased [3H]-GABA uptake in mice FC, while alpha1-adrenergic agonist phenylephrine had no effect. As GAT-1 is expressed and fully functional at the FC, addition of NO-711, a GAT-1 inhibitor, dose dependently blocked [3H]-GABA uptake. The increase of [3H]-GABA uptake induced by ISO was also blocked by NO-711. [3H]-GABA release induced by 80 mM KCl was reduced by NO-711, but not by removal of Ca2+. ISO also increased cyclic AMP (cAMP) levels and addition of WIN 55,212-2, a mixed CB1/CB2 receptor agonist, inhibited the effect of ISO in GABA uptake increase, GAT-1 expression and cAMP levels compared to control. Our data show that GABA transport increased by NA and ISO is negatively regulated by cannabinoid receptor agonist WIN55,212-2.

Contradictory effects of erythropoietin on inhibitory synaptic transmission in left and right prelimbic cortex of mice

Erythropoietin (EPO) has been shown to improve cognitive function in mammals as well as in patients of psychiatric diseases by directly acting on the brain. In addition, EPO attenuates the synaptic transmission and enhances short- and long-term synaptic plasticity in hippocampus of mice, although there are still many discrepancies between different studies. It has been suggested that the divergences of different studies take root in different in-vivo application schemata or in long-term trophic effects of EPO. In the current study, we investigated the direct effects of EPO in slices of prelimbic cortex (PrL) by acute ex-vivo application of EPO, so that the erythropoietic or other trophic effects could be entirely excluded. Our results showed that the EPO effects were contradictory between the left and the right PrL. It enhanced the inhibitory transmission in the left and depressed the inhibitory transmission in the right PrL. Strikingly, this lateralized effect of EPO could be consistently found in individual bi-lateral PrL of all tested mice. Thus, our data suggest that EPO differentially modulates the inhibitory synaptic transmission of neuronal networks in the left and the right PrL. We hypothesize that such lateralized effects of EPO contribute to the development of the lateralization of stress reaction in PFC and underlie the altered bilateral GAGAergic synaptic transmission and oscillation patterns under stress that impact the central emotional and cognitive control in physiology as well as in pathophysiology.

Multiphoton imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule

Kidney proximal tubules (PTs) are densely packed with mitochondria, and defects in mitochondrial function are implicated in many kidney diseases. However, little is known about intrinsic mitochondrial function within PT cells. Here, using intravital multiphoton microscopy and live slices of mouse kidney cortex, we show that autofluorescence signals provide important functional readouts of redox state and substrate metabolism and that there are striking axial differences in signals along the PT. Mitochondrial NAD(P)H intensity was similar in both PT segment (S)1 and S2 and was sensitive to changes in respiratory chain (RC) redox state, whereas cytosolic NAD(P)H intensity was significantly higher in S2. Mitochondrial NAD(P)H increased in response to lactate and butyrate but decreased in response to glutamine and glutamate. Cytosolic NAD(P)H was sensitive to lactate and pyruvate and decreased dramatically in S2 in response to inhibition of glucose metabolism. Mitochondrial flavoprotein (FP) intensity was markedly higher in S2 than in S1 but was insensitive to changes in RC redox state. Mitochondrial FP signal increased in response to palmitate but decreased in response to glutamine and glutamate. Fluorescence lifetime decays were similar in both S1 and S2, suggesting that intensity differences are explained by differences in abundance of the same molecular species. Expression levels of known fluorescent mitochondrial FPs were higher in S2 than S1. In summary, substantial metabolic information can be obtained in kidney tissue using a label-free live imaging approach, and our findings suggest that metabolism is tailored to the specialized functions of S1 and S2 PT segments.

Neuroprotective Effects of Melissa officinalis on Oxygen and Glucose Deficiency Induced Damage in Rat’s Brain Cortex Slices

Neuroprotective Effects of Melissa officinalis on Oxygen and Glucose Deficiency Induced Damage in Rat’s Brain Cortex Slices

Beta and Gamma Oscillations in Prefrontal Cortex During NMDA Hypofunction: An In Vitro Model of Schizophrenia Features

NMDA receptor (NMDAr) hypofunction has been widely used as a schizophrenia model. Decreased activation of NMDAr is associated with a disrupted excitation/inhibition balance in the prefrontal cortex and with alterations in gamma synchronization. Our aim was to investigate whether this phenomenon could be reproduced in the spontaneous oscillatory activity generated by the local prefrontal network in vitro and, if so, to explore the effects of antipsychotics on the resulting activity. Extracellular recordings were obtained from prefrontal cortex slices bathed in in vivo-like ACSF solution. Slow (<1 Hz) oscillations consisting of interspersed Up (active) and Down (silent) states spontaneously emerged. Fast-frequency oscillations (15–90 Hz) occurred during Up states. We explored the effects of the NMDAr antagonist MK-801 on the spontaneously generated activity. Bath-applied MK-801 induced a dose-dependent decrease in Up-state duration and in the frequency of Up states. However, the beta/gamma power during Up states significantly increased; this increase was in turn prevented by the antipsychotic drug clozapine. The increased beta/gamma power with NMDAr blockade implies that NMDAr activation in physiological conditions prevents hypersynchronization in this frequency range. High-frequency hypersynchronization following NMDAr blockade occurring in cortical slices suggests that—at least part of—the underlying mechanisms of this schizophrenia feature persist in the local cortical circuit, even in the absence of long-range cortical or subcortical inputs. The observed action of clozapine decreasing hypersynchronization in the local circuit may be one of the mechanisms of action of clozapine in preventing schizophrenia symptoms derived from NMDA hypofunction.

Cyproheptadine Regulates Pyramidal Neuron Excitability in Mouse Medial Prefrontal Cortex.

Cyproheptadine (CPH), a first-generation antihistamine, enhances the delayed rectifier outward K+ current (IK) in mouse cortical neurons through a sigma-1 receptor-mediated protein kinase A pathway. In this study, we aimed to determine the effects of CPH on neuronal excitability in current-clamped pyramidal neurons in mouse medial prefrontal cortex slices. CPH (10 µmol/L) significantly reduced the current density required to generate action potentials (APs) and increased the instantaneous frequency evoked by a depolarizing current. CPH also depolarized the resting membrane potential (RMP), decreased the delay time to elicit an AP, and reduced the spike threshold potential. This effect of CPH was mimicked by a sigma-1 receptor agonist and eliminated by an antagonist. Application of tetraethylammonium (TEA) to block IK channels hyperpolarized the RMP and reduced the instantaneous frequency of APs. TEA eliminated the effects of CPH on AP frequency and delay time, but had no effect on spike threshold or RMP. The current-voltage relationship showed that CPH increased the membrane depolarization in response to positive current pulses and hyperpolarization in response to negative current pulses, suggesting that other types of membrane ion channels might also be affected by CPH. These results suggest that CPH increases the excitability of medial prefrontal cortex neurons by regulating TEA-sensitive IK channels as well as other TEA-insensitive K+ channels, probably ID and inward-rectifier Kir channels. This effect of CPH may explain its apparent clinical efficacy as an antidepressant and antipsychotic.

Cephalosporin antibiotics are weak blockers of GABAa receptor-mediated synaptic transmission in rat brain slices

Cephalosporins are beta-lactam antibiotics that are extensively used in medical practice and are reported to cause epileptic seizures in some patients. The primary cause of cephalosporin-induced convulsions is believed to be their ability to block GABAa receptors. However, direct evidence for the involvement of this mechanism has not yet been provided. The present study aims to investigate the ability of two cephalosporins – cefepime and ceftriaxone – to block inhibitory synaptic transmission in entorhinal cortex slices of rats. Using the whole-cell patch-clamp method, we found that millimolar concentrations of cefepime (IC50 = 1.6 ± 0.1 mM) and ceftriaxone (2.0 ± 0.1 mM) were required to block the evoked inhibitory postsynaptic currents (IPSCs). These concentrations are almost two orders of magnitude higher than cerebrospinal fluid concentrations of antibiotics achieved during treatment. We also found that while ceftriaxone did not affect the IPSC decay kinetics, cefepime significantly slowed the decays of the evoked currents, which may be attributed to the diverse mechanisms of the GABAa receptor inhibition of cefepime and ceftriaxone. The experiments involving the fast application of GABA at various concentrations to isolated neurons suggests that cefepime blocks receptors competitively, while ceftriaxone does so noncompetitively. Cefepime, at a concentration of up to 4 mM, was unable to produce seizure-like events in brain slices. However, this antibiotic could induce epileptiform activity in combination with the altered ionic composition of the perfusing media, which may be the case for patients with renal insufficiency. Our results suggest that cefepime and ceftriaxone are weak GABAa receptor blockers and that it is unlikely that the inhibition of GABAa receptors by antibiotics is the primary cause of the seizures.

Targeted Blockade of TARP-γ8-Associated AMPA Receptors: Anticonvulsant Activity with the Selective Antagonist LY3130481 (CERC-611).

6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]- 3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient. Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.

T-2 Mycotoxin Treatment of Newborn Rat Pups does not Significantly Affect Nervous System Functions in Adulthood

T-2 toxin is primarily produced by Fusarium sp. abundant under temperate climatic conditions. Its main harmful effect is the inhibition of protein synthesis. Causing oxidative stress, it also promotes lipid peroxidation and changes plasma membrane phospholipid composition; this may lead to nervous system alterations. The aim of the present study was to examine whether a single dose of T-2 toxin administered at newborn age has any long-lasting effects on nervous system functions. Rat pups were treated on the frst postnatal day with a single intraperitoneal dose of T-2 toxin (0.2 mg/bwkg). Body weight of treated pups was lower during the second and third week of life, compared to littermates; later, weight gain was recovered. At young adulthood, behavior was tested in the open feld, and no difference was observed between treated and control rats. Field potential recordings from somatosensory cortex and hippocampus slices did not reveal any signifcant difference in neuronal network functions. In case of neocortical feld EPSP, the shape was slightly different in treated pups. Long-term synaptic plasticity was also comparable in both groups. Seizure susceptibility of the slices was not different, either. In conclusion, T-2 toxin did not signifcantly affect basic nervous system functions at this dose.

A neural circuit for gamma-band coherence across the retinotopic map in mouse visual cortex.

Cortical gamma oscillations have been implicated in a variety of cognitive, behavioral, and circuit-level phenomena. However, the circuit mechanisms of gamma-band generation and synchronization across cortical space remain uncertain. Using optogenetic patterned illumination in acute brain slices of mouse visual cortex, we define a circuit composed of layer 2/3 (L2/3) pyramidal cells and somatostatin (SOM) interneurons that phase-locks ensembles across the retinotopic map. The network oscillations generated here emerge from non-periodic stimuli, and are stimulus size-dependent, coherent across cortical space, narrow band (30 Hz), and depend on SOM neuron but not parvalbumin (PV) neuron activity; similar to visually induced gamma oscillations observed in vivo. Gamma oscillations generated in separate cortical locations exhibited high coherence as far apart as 850 μm, and lateral gamma entrainment depended on SOM neuron activity. These data identify a circuit that is sufficient to mediate long-range gamma-band coherence in the primary visual cortex.

Preferential cholinergic excitation of corticopontine neurons.

Phasic activation of M1 muscarinic receptors generates transient inhibition followed by longer lasting excitation in neocortical pyramidal neurons. Corticopontine neurons in the mouse prefrontal cortex exhibit weaker cholinergic inhibition, but more robust and longer lasting excitation, than neighbouring callosal projection neurons. Optogenetic release of endogenous ACh in response to single flashes of light (5ms) preferentially enhances the excitability of corticopontine neurons for many tens of seconds. Cholinergic excitation of corticopontine neurons involves at least three ionic mechanisms: suppression of KV 7 currents, activation of the calcium-dependent non-specific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable non-specific cation conductance. Preferential cholinergic excitation of prefrontal corticopontine neurons may facilitate top-down attentional processes and behaviours. Pyramidal neurons in layer 5 of the neocortex comprise two broad classes of projection neurons: corticofugal neurons, including corticopontine (CPn) neurons, and intratelencephalic neurons, including commissural/callosal (COM) neurons. These non-overlapping neuron subpopulations represent discrete cortical output channels contributing to perception, decision making and behaviour. CPn and COM neurons have distinct morphological and physiological characteristics, and divergent responses to modulatory transmitters such as serotonin and acetylcholine (ACh). To better understand how ACh regulates cortical output, in slices of mouse prefrontal cortex (PFC) we compared the responsivity of CPn and COM neurons to transient exposure to exogenous or endogenous ACh. In both neuron subtypes, exogenous ACh generated qualitatively similar biphasic responses in which brief hyperpolarization was followed by longer lasting enhancement of excitability. However, cholinergic inhibition was more pronounced in COM neurons, while excitatory responses were larger and longer lasting in CPn neurons. Similarly, optically triggered release of endogenous ACh from cholinergic terminals preferentially and persistently (for ∼40s) enhanced the excitability of CPn neurons, but had little impact on COM neurons. Cholinergic excitation of CPn neurons involved at least three distinct ionic mechanisms: suppression of KV 7 channels (the 'M-current'), activation of the calcium-dependent non-specific cation conductance underlying afterdepolarizations, and activation of what appears to be a calcium-sensitive but calcium-permeable non-specific cation conductance. Our findings demonstrate projection-specific selectivity in cholinergic signalling in the PFC, and suggest that transient release of ACh during behaviour will preferentially promote corticofugal output.

Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia; a study in rats.

In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9–11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage.

Insular cortex mediates approach and avoidance responses to social affective stimuli.

Social animals detect the affective states of conspecifics and utilize this information to orchestrate social interactions. In a novel social affective preference text in which experimental adult male rats could interact with either naive or stressed conspecifics, the experimental rats either approached or avoided the stressed conspecific, depending upon the age of the conspecific. Specifically, experimental rats approached stressed juveniles but avoided stressed adults. Inhibition of insular cortex, which is implicated in social cognition, and blockade of insular oxytocin receptors disrupted the social affective behaviors. Oxytocin application increased intrinsic excitability and synaptic efficacy in acute insular cortex slices, and insular oxytocin administration recapitulated the behaviors observed toward stressed conspecifics. Network analysis of Fos immunoreactivity in 29 regions identified functional connectivity between insular cortex, prefrontal cortex, amygdala and the social decision-making network. These results implicate insular cortex as a key component in the circuit underlying age-dependent social responses to stressed conspecifics.

Neonatal Hypoxia-Ischemia Causes Functional Circuit Changes in Subplate Neurons.

Neonatal hypoxia-ischemia (HI) in the preterm human results in damage to subcortical developing white matter and cognitive impairments. Subplate neurons (SPNs) are among the first-born cortical neurons and are necessary for normal cerebral development. While moderate or severe HI at P1 in rats leads to SPN loss, it is unclear if HI, esp. forms not associated with overt cell loss lead to altered SPN circuits. Thus, we used two HI models with different severities in P1 rats. Cauterization of the common carotid artery (CCA) causes a largely transient and thus milder ischemia (HI-Caut) while CCA ligation causes more severe ischemia (HI-Lig). While HI-Lig caused subplate damage, HI-Caut did not cause overt histological damage on the light microscopic level. We used laser-scanning photostimulation (LSPS) in acute thalamocortical slices of auditory cortex during P5-10 to study the functional connectivity of SPNs. Both HI categories resulted in hyperconnectivity of excitatory and inhibitory circuits to SPNs. Thus, alterations on the circuit level are present in the absence of cell loss. Our results show that SPN circuits are uniquely susceptible to HI. Given the key developmental role of SPNs, our results suggest that altered SPN circuits might underlie the abnormal development of cortical function after HI.

Alzheimer's Disease Mutant Mice Exhibit Reduced Brain Tissue Stiffness Compared to Wild-type Mice in both Normoxia and following Intermittent Hypoxia Mimicking Sleep Apnea.

Evidence from patients and animal models suggests that obstructive sleep apnea (OSA) may increase the risk of Alzheimer's disease (AD) and that AD is associated with reduced brain tissue stiffness. To investigate whether intermittent hypoxia (IH) alters brain cortex tissue stiffness in AD mutant mice exposed to IH mimicking OSA. Six-eight month old (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) AD mutant mice and wild-type (WT) littermates were subjected to IH (21% O2 40 s to 5% O2 20 s; 6 h/day) or normoxia for 8 weeks. After euthanasia, the stiffness (E) of 200-μm brain cortex slices was measured by atomic force microscopy. Two-way ANOVA indicated significant cortical softening and weight increase in AD mice compared to WT littermates, but no significant effects of IH on cortical stiffness and weight were detected. In addition, reduced myelin was apparent in AD (vs. WT), but no significant differences emerged in the cortex extracellular matrix components laminin and glycosaminoglycans when comparing baseline AD and WT mice. AD mutant mice exhibit reduced brain tissue stiffness following both normoxia and IH mimicking sleep apnea, and such differences are commensurate with increased edema and demyelination in AD.

Positive N-Methyl-D-Aspartate Receptor Modulation by Rapastinel Promotes Rapid and Sustained Antidepressant-Like Effects.

BackgroundModulation of glutamatergic synaptic transmission by N-methyl-D-aspartate receptors can produce rapid and sustained antidepressant effects. Rapastinel (GLYX-13), initially described as a N-methyl-D-aspartate receptor partial glycine site agonist, exhibits rapid antidepressant effect in rodents without the accompanying dissociative effects of N-methyl-D-aspartate receptor antagonists.MethodsThe relationship between rapastinel’s in vitro N-methyl-D-aspartate receptor pharmacology and antidepressant efficacy was determined by brain microdialysis and subsequent pharmacological characterization of therapeutic rapastinel concentrations in N-methyl-D-aspartate receptor-specific radioligand displacement, calcium mobilization, and medial prefrontal cortex electrophysiology assays.ResultsBrain rapastinel concentrations of 30 to 100 nM were associated with its antidepressant-like efficacy and enhancement of N-methyl-D-aspartate receptor-dependent neuronal intracellular calcium mobilization. Modulation of N-methyl-D-aspartate receptors by rapastinel was independent of D-serine concentrations, and glycine site antagonists did not block rapastinel’s effect. In rat medial prefrontal cortex slices, 100 nM rapastinel increased N-methyl-D-aspartate receptor-mediated excitatory postsynaptic currents and enhanced the magnitude of long-term potentiation without any effect on miniature EPSCs or paired-pulse facilitation responses, indicating postsynaptic action of rapastinel. A critical amino acid within the NR2 subunit was identified as necessary for rapastinel’s modulatory effect.ConclusionRapastinel brain concentrations associated with antidepressant-like activity directly enhance medial prefrontal cortex N-methyl-D-aspartate receptor activity and N-methyl-D-aspartate receptor-mediated synaptic plasticity in vitro. At therapeutic concentrations, rapastinel directly enhances N-methyl-D-aspartate receptor activity through a novel site independent of the glycine coagonist site. While both rapastinel and ketamine physically target N-methyl-D-aspartate receptors, the 2 molecules have opposing actions on N-methyl-D-aspartate receptors. Modest positive modulation of N-methyl-D-aspartate receptors by rapastinel represents a novel pharmacological approach to promote well-tolerated, rapid, and sustained improvements in mood disorders.

K2P channels and NMDA receptor as new targets of fast onset antidepressants

Major depressive disorder (MDD) is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations highlighted an urgent and clear need for more efficacious and faster-acting therapeutic agents to treat patients with MDD, especially those who are refractory to the traditional antidepressants. In the present study, we assessed a novel compound, YY-21, from timosaponin B-III derived from sarsasapogenin of Anemarrhenae Rhizoma. We found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 minutes as determined by excitatory postsynaptic current (EPSC) and field excitatory postsynaptic potential (fEPSP) in medial prefrontal cortex (mPFC) slices, respectively. YY-21 demonstrated anxiolytic-like effects following acute administration in animals and reversed the depressive-like and anxiety phenotypes induced by chronic unpredictable mild stress (CMS) with a relatively fast therapeutic onset.Our mechanism research reveals that NMDA receptors and K2P(TREK1) channels emerged as new drug targets for faster acting antidepressants.

Modification of glutamatergic mechanisms in the model of posttraumatic stress disorder

To study the involvement of NMDA-dependent mechanisms in the development of posttraumatic stress disorder (PTSD) by investigation of the effects induced by NMDA application in olfactory cortex slices of active and passive rats exposed to inescapable water-immersion stress. Wistar rats were selected in behavioral experiments according to their active or passive behavior. Rats were subjected to unavoidable water-immersion stress, and then after 10 days the surviving brain slices (olfactory cortex) were prepared. NMDA-dependent responses were recorded and analyzed after 50 μM NMDA applications on the slices. Different changes in NMDA-stimulated amplitudes were detected in brain slices of rats depending on their passive or active behavior during the formation of PTSD. NMDA responses in the brains of rats with active behavioral strategy were more resistant to stress. Their activity was inhibited, but not blocked. In rats with passive behavior strategies, NMDA-dependent mechanisms were more vulnerable that was manifested as prominent depression of their activity.

Specific Effects of Antipsychotic Chlorpromazine on Glutamatergic Ionotropic Mechanisms. Novel Targets for Treatment Schizophrenia

Chlorpromazine hydrochloride (CPZ) refers to antipsychotic drugs. CPZ is drug of first choice for the treatment of schizophrenia. However, its impact on the main excitatory neurotransmitter system, glutamatergic, is unclear. This issue is the aim of our study. Experiments carried out on brain slices of the olfactory cortex of rats. We used electrophysiological techniques extracellular recordings in brain slice to investigate CPZ effects on the activity of the glutamatergic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPAR) and N-methyl-D-aspartic acid type glutamate receptors (NMDAR).