Glutamate Receptor Gene Expression Research Articles

Circulatory levels of dopamine and glutamate and assessment of gene expression of dopamine and glutamate receptors in patients with schizophrenia. A case control study

Circulatory levels of dopamine and glutamate and assessment of gene expression of dopamine and glutamate receptors in patients with schizophrenia. A case control study

Isradipine, an L-type calcium channel blocker, attenuates cocaine effects in mice by reducing central glutamate release

Substance abuse disorder is a chronic condition for which pharmacological treatment options remain limited. L-type calcium channels (LTCC) have been implicated in drug-related plasticity and behavior. Specifically, dopaminergic neurons in the mesocorticolimbic pathway express Cav1.2 and Cav1.3 channels, which may regulate dopaminergic activity associated with reward behavior. Therefore, this study aimed to investigate the hypothesis that pre-administration of the LTCC blocker, isradipine can mitigate the effects of cocaine by modulating central glutamatergic transmission. For that, we administered isradipine at varying concentrations (1, 7.5, and 15 μg/μL) via intracerebroventricular injection in male Swiss mice. This pretreatment was carried out prior to subjecting animals to behavioral assessments to evaluate cocaine-induced locomotor sensitization and conditioned place preference (CPP). The results revealed that isradipine administered at a concentration of 1 μg/μL effectively attenuated both the sensitization and CPP induced by cocaine (15 mg/kg, via i. p.). Moreover, mice treated with 1 μg/μL of isradipine showed decreased presynaptic levels of glutamate and calcium in the cortex and hippocampus as compared to control mice following cocaine exposure. Notably, the gene expression of ionotropic glutamate receptors, AMPA, and NMDA, remained unchanged, as did the expression of Cav1.2 and Cav1.3 channels. Importantly, these findings suggest that LTCC blockage may inhibit behavioral responses to cocaine, most likely by decreasing glutamatergic input in areas related to addiction.

Effect of Suanzaoren Decoction on expression of ionotropic glutamate receptors and synaptic plasticity in hippocampus of anxiety rats

This study investigated the effect of Suanzaoren Decoction on the expression of N-methyl-D-aspartate receptors(NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors(AMPAR) in the hippocampus and synaptic plasticity in rats with conditioned fear-induced anxiety. The effect of Suanzaoren Decoction on rat behaviors were evaluated through open field experiment, elevated plus maze experiment, and light/dark box experiment. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of glutamate(Glu) and γ-aminobutyric acid(GABA) in the rat hippocampus. Real-time fluorescence quantitative PCR(qRT-PCR) and Western blot were employed to assess the gene and protein expression of ionotropic glutamate receptors in the hippocampal region. Transmission electron microscopy was utilized to observe the changes in the ultrastructure of synaptic neurons in the hippocampal region. Long-term potentiation(LTP) detection technique was employed to record the changes in population spike(PS) amplitude in the hippocampal region of mice in each group. The behavioral results showed that compared with the model group, the Suanzaoren Decoction group effectively increased the number of entries into open arms, time spent in open arms, percentage of time spent in open arms out of total movement time, number of entries into open arms out of total entries into both arms(P<0.01), and significantly increased the time spent in the light box and the number of shuttle crossings(P<0.01). There was an increasing trend in the number of grid crossings, entries into the center grid, and time spent in the center grid, indicating a significant anxiolytic effect. ELISA results showed that compared with the model group, the Suanzaoren Decoction group exhibited significantly reduced levels of Glu, Glu/GABA ratio(P<0.01), and significantly increased levels of GABA(P<0.01) in the rat hippocampus. Furthermore, Suanzaoren Decoction significantly decreased the gene and protein expression of NMDAR(GluN2B and GluN2A) and AMPAR(GluA1 and GluA2) compared with the model group. Transmission electron microscopy results demonstrated improvements in synapses, neuronal cells, and organelles in the hippocampal region of the Suanzaoren Decoction group compared with the model group. LTP detection results showed a significant increase in the PS amplitude changes in the hippocampal region of Suanzaoren Decoction group from 5 to 35 min compared with the model group(P<0.05, P<0.01). In conclusion, Suanzaoren Decoction exhibits significant anxiolytic effects, which may be attributed to the reduction in NMDAR and AMPAR expression levels and the improvement of synaptic plasticity.

Genomics and transcriptomic alterations of the glutamate receptors in acute myeloid leukemia.

Glutamine and glutamate have been widely explored as potential therapeutic targets in acute myeloid leukemia (AML). In addition to its bioenergetic role in leukemia cell proliferation, L-glutamate is a neurotransmitter that acts on glutamate receptors. However, the role of glutamate receptors in AML is largely understudied. Here, we comprehensively analyze the genomic and transcriptomic alterations of glutamate receptor genes in AML using publicly available data. We investigated the frequency of mutations in the glutamate receptor genes and whether an association exist between the presence of these mutations and clinical and molecular characteristics or patient's clinical outcome. We also assessed the dysregulation of glutamate receptor gene expression in AML with and without mutations and whether gene dysregulation is associated with clinical outcomes. We found that 29 (14.5%) of 200 patients with AML had a mutation in at least one glutamate receptor gene. The DNMT3A mutations were significantly more frequent in patients with mutations in at least one glutamate receptor gene compared with patients without mutations (13 of 29 [44.8%] vs. 41 of 171 [23.9%], p value: 0.02). Notably, patients with mutations in at least one glutamate receptor gene survived shorter than patients without mutations; however, the results did not reach statistical significance (overall survival: 15.5 vs. 19.0 months; p value: 0.10). Mutations in the glutamate receptor genes were not associated with changes in gene expression and the transcriptomic levels of glutamate receptor genes were not associated with clinical outcome.

Alterations of BDNF, mGluR5, Homer1a, p11 and excitatory/inhibitory balance in corticolimbic brain regions of suicide decedents

BackgroundDeveloping biological based approaches for preventing suicide has become a priority. In recent years, there has been a surge in studies investigating the role of the glutamatergic system in suicide, although it remains unclear. MethodsWe evaluated changes in the gene expression of the metabotropic glutamate receptor 5 (mGluR5) and its scaffolding proteins Homer1a and p11 in the dorsolateral prefrontal cortex (DLPFC), amygdala (AMY), and hippocampus (HIP) of 28 suicide decedents (S) (with no clinical psychiatric history or treatment with anxiolytics or antidepressants) and 26 controls (C) by real-time PCR (qPCR). Indeed, we measured BDNF gene expression and VGluT1 and VGAT immunoreactivities in the HIP by qPCR and immunohistochemistry, respectively. Cases and controls matched for age (C: 48.6 ± 11.6 years; S: 46.9 ± 14.5 years) and postmortem interval (PMI; C: 20.1 ± 13h; S: 16.9 ± 5h). ResultsIn DLPFC, S had lower p11 gene expression levels, but no differences were found in mGluR5 or Homer1a. In the AMY and HIP, mGluR5 and Homer1a were increased, p11 and BDNF were reduced. In the HIP, there were less VGAT-ir and more VGluT1-ir. LimitationsFuture studies are necessary to evaluate protein levels, and determine the cell types and potential compensatory mechanisms in a larger sample including S diagnosed with psychiatric disorders, females and different ethnicities. ConclusionsThis study identified significant alterations in mGluR5, Homer1a, p11, BDNF and excitatory/inhibitory balance in corticolimbic brain areas of S. These results further characterize the biological basis of suicide, contributing to the identification of potential biomarkers for suicide prevention.

Some neurotoxic effects of lead nanoparticles on NMDA glutamate receptor gene expression and behavioral responses in Wistar rats

Introduction. Industrial pollution of the workplace air and the environment with lead oxide nanoparticles (PbO NPs) poses the risk of neurodegenerative diseases in workers of lead and copper smelters and the population living around these enterprises. Various studies showed the involvement of N-methyl-D-aspartate (NMDA) receptor expression in the mechanisms of lead toxicity. Materials and methods. During two months, outbred female rats were exposed to lead nanoparticles (PbO NPs) at a concentration of 0.2 mg/m3 in a “nose-only” inhalation exposure system. The behavioral responses of the rats were assessed using the open field and the elevated plus maze tests. Quantitative expression of the NMDA receptor genes (GRIN1, GRIN2A, GRIN2B) in the rat hippocampus was assessed using a real-time PCR. Statistical data analysis was carried out using the Mann-Whitney U test. Results. The neurotoxic effect of PbO NPs manifested itself in the suppression of GRIN2A gene expression in the hippocampus of experimental rats. The expression of the GRIN1 gene also showed a tendency to decrease in rats under effect of PbO NPs, while the expression of the GRIN2B gene did not change. The results of the open field test did not reveal any differences between the experimental and control groups of rats. The elevated plus maze test revealed a significant decrease in the number of entries into the open arms of the maze in rats from the experimental group. Limitations. This work was performed on female Wistar rats and does not take into account possible inter-gender differences. Conclusion. The results of the experiment demonstrated the neurotoxic effect of PbO NPs including the reduced expression level of the GRIN2A gene of the NMDA receptor and a decrease in the proportion of time spent in the open arms in the elevated plus maze test.

Antiepileptic Effect of Neuroaid® on Strychnine-Induced Convulsions in Mice.

NeuroAid II, a folk Chinese Medicine, is currently used in Asia for the treatment of stroke. An experimental study demonstrated that NeuroAid enables neuronal cells to be more resistant to glutamate toxicity. This research was constructed to evaluate the efficacy of NeuroAid in the prevention of epilepsy (EP). Forty healthy adult male mice were used and divided into four groups (10 mice/group): normal control group; positive control group; NeuroAid-treated group (10 mg/kg); topiramate-treated group (10 mg/kg). The treatment continued for 7 days, and on the last day, EP was induced using strychnine at a dose of 2 mg/kg via intraperitoneal (ip) administration. Seizure severity, latency to the seizure onset, the number of seizures, and the duration of each seizure episode were observed for one hour. The death and protection rates over the next twenty-four hours were recorded. Brain specimens from surviving animals were extracted and examined pathologically for quantification of glutamate receptor (GluR) gene expression in the isolated hippocampus employing real-time PCR analysis. Treatment with NeuroAid resulted in a significant reduction in seizure severity, prolonged the onset of seizures, decreased the number and duration of episodes, reduced brain insult, and decreased mortality rate. Reductions in the gene expression of GluRs in the hippocampus with minor histopathological changes were observed in the NeruoAid- and topiramate-treated groups. It is concluded that NeuroAid has a potential antiepileptic effect (EP) with the ability to prevent convulsion through its effect on the glutamate receptor.

Calcitriol Pretreatment Attenuates Glutamate Neurotoxicity by Regulating NMDAR and CYP46A1 Gene Expression in Rats Subjected to Transient Middle Cerebral Artery Occlusion.

Although the neuroprotective effects of calcitriol have been demonstrated in a variety of neurological diseases, such as stroke, the precise molecular mechanism has yet to be determined. This study aimed to investigate the possible role of calcitriol as a neuroprotective agent via CYP46A1 and glutamate receptors in a middle cerebral artery occlusion (MCAO) animal model. The MCAO technique was performed on adult male Wistar rats to induce focal cerebral ischemia for 1 hour followed by 23 hours of reperfusion. Calcitriol was given for 7 days prior to stroke induction. Sensorimotor functional tests were done 24 hours after ischemia/reperfusion, and infarct volume was estimated by tetrazolium chloride staining of brain sections. Gene expression of NR2A, NR2B, NR3B, and CYP46A1 was evaluated by RT-PCR followed by western blotting for NR3B protein. Our data revealed that calcitriol pretreatment reduced lesion volume and improved ischemic neurobehavioral parameters. Calcitriol therapy altered the expression of glutamate receptor and CYP46A1 genes. A possible molecular mechanism of calcitriol to reduce the severity and complications of ischemia may be through alterations of glutamate receptor and CYP46A1 gene expression.

Changes in Metabotropic Glutamate Receptor Gene Expression in Rat Brain in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy.

Preventing epileptogenesis in people at risk is an unmet medical need. Metabotropic glutamate receptors (mGluRs) are promising targets for such therapy. However, drugs acting on mGluRs are not used in the clinic due to limited knowledge of the involvement of mGluRs in epileptogenesis. This study aimed to analyze the changes in gene expression of mGluR subtypes (1–5, 7, 8) in various rat brain regions in the latent and chronic phases of a lithium–pilocarpine model of epilepsy. For this study, multiplex test systems were selected and optimized to analyze mGluR gene expression using RT-qPCR. Region- and phase-specific changes in expression were revealed. During the latent phase, mGluR5 mRNA levels were increased in the dorsal and ventral hippocampus, and expression of group III genes was decreased in the hippocampus and temporal cortex, which could contribute to epileptogenesis. Most of the changes in expression detected in the latent stage were absent in the chronic stage, but mGluR8 mRNA production remained reduced in the hippocampus. Moreover, we found that gene expression of group II mGluRs was altered only in the chronic phase. The study deepened our understanding of the mechanisms of epileptogenesis and suggested that agonists of group III mGluRs are the most promising targets for preventing epilepsy.

Expression of Glutamate Receptor Genes in the Hippocampus and Frontal Cortex in GC Rat Strain with Genetic Catatonia

Expression of Glutamate Receptor Genes in the Hippocampus and Frontal Cortex in GC Rat Strain with Genetic Catatonia

Экспрессия генов глутаматных рецепторов в гиппокампе и лобной коре у крыс линии ГК с генетической кататонией

The GC rat strain (the abbreviation of the words «genetic» and «catatonia») was obtained in the Institute of Cytology and Genetics of the SB RAS by breeding to enhance the passive-defensive freezing reaction in response to a weak stress stimulus. GC rats have a predisposition to catatonic reactions, as well as a number of behavioral and biochemical features corresponding to the homologous characteristics of patients with schizophrenia and depression. At the basis of the catatonic syndrome, as in schizophrenia, is believed to be the presence of a complex disturbance in functioning brain’s neurotransmitter systems, with special attention having been recently paid to glutamatergic system dysfunction, proposing the glutamate hypothesis of psychopathologies. Glutamate is the main excitatory mediator in the central nervous system and realize physiological effects through ionotropic (AMPA-, NMDA-, kainate) and metabotropic (mGlu) glutamate receptors. There are many studies indicating a change in the expression of glutamate receptor genes and the composition of their subunits in schizophrenia and bipolar disorders, as well as indicating the involvement of NMDA glutamate receptors in the manifestation of catatonic syndrome. In this regard, the aim of the work was to study the expression of the genes of glutamate system in the hippocampus and the frontal cortex of GC rats. Real-time PCR showed low expression of Grm3 gene encoding the metabotropic glutamate autoreceptor in the hippocampus of rats with genetic catatonia. The expression of Grin1, Grin2A, Grin2B, Gria1, Grm2, Slc17a6 in the frontal cortex and the hippocampus, as well as the Grm3 gene in the frontal cortex, did not differ from the control. Thus, the revealed low expression of mRNA of the Grm3 gene in the hippocampus can affect the neurotransmission of glutamate in this structure, and, among other things, contribute to an increase in nervous excitability in GC rats.

Changes in Behavior and the Expression of Ionotropic Glutamate Receptor Genes in the Brains of Adult Rats after Neonatal Administration of Bacterial Lipopolysaccharide

Many studies have shown that early experience, particularly of neonatal infections, has a role in forming high anxiety levels in later life. One of the mechanisms of these changes may consist of impairments to the functional activity of ionotropic glutamate receptors associated with rearrangements in their subunit composition. The aim of the present work was to study measures of anxiety and levels of expression of genes for NMDA receptor (Grin1, Grin2a, Grin2b) and AMPA receptor (Gria1, Gria2) subunits in the medial prefrontal cortex, ventral and dorsal parts of the hippocampus in adult rats which at an early age had received bacterial lipopolysaccharide (LPS) at doses inducing the development of neuroinflammatory processes. Gene expression was studied by real-time reverse transcription PCR (qRT-PCR). Administration of LPS at doses of 25 and 50 μg/kg to male Wistar rats on days 15, 18, and 21 of life induced increases in the expression of genes for proinflammatory cytokines IL-1β and tumor necrosis factor in parts of the hippocampus. Increases in the expression of the Grin2b, Gria1, and Gria2 genes in the ventral parts of the hippocampus were seen three months after LPS administration (after injection of 50 μg/kg LPS), as were increases in expression of the Gria2 gene in the dorsal part of the hippocampus (after injection of 25 μg/kg LPS). These changes were accompanied by impairment to exploratory behavior in the open field test and decreased anxiety levels in the elevated plus maze. These studies showed that administration of bacterial LPS in early postnatal ontogeny leads to time-delayed changes in the expression of genes for NMDA and AMPA receptor subunits in the hippocampus and the associated forms of behavior.

Mom’s diet matters: Maternal prebiotic intake in mice reduces anxiety and alters brain gene expression and the fecal microbiome in offspring

Compelling evidence links enteric microbes to brain function and behavior. Galacto-oligosaccharide prebiotics have been shown to modulate the composition of gut flora and induce metabolic, neurochemical, and behavioral changes in adult rodents. Despite the brain being most susceptible to environmental factors, such as nutrients and toxins, during the earliest stages of development, it is unknown whether maternal prebiotic supplementation during gestation and lactation influences the offspring gut microbiome, brain, or behavior. The aim of this study was to test whether maternal galacto-oligosaccharide intake during pregnancy and lactation alters the brain and behavior in naïve and endotoxin-challenged offspring.CD1 female mice received either normal drinking water or water supplemented with Bimuno® galacto-oligosaccharides (B-GOS) during gestation and suckling. Offspring behavior was tested at weaning age or adulthood, and a cross-foster design was employed in a separate cohort to differentiate between effects of prenatal and postnatal maternal B-GOS intake. Lipopolysaccharide was also administered to pups at postnatal day 9 to determine whether maternal B-GOS influences the neurobiological and behavioral effects of a neonatal pro-inflammatory challenge in adulthood. Fecal microbiome composition and metabolites were analyzed to explore potential relationships between the maternal microbiome, the offspring gut microbiome, and the offspring brain and behavior.Maternal B-GOS supplementation increased exploratory behavior and reduced expression of hippocampal glutamate receptor genes in young, weaning-age offspring. In addition, postnatal, but not prenatal, B-GOS supplementation increased fecal butyrate and propionate levels. Finally, in adult offspring, perinatal B-GOS intake increased cortical glutamate receptor subunits in females, increased social preference, and reduced anxiety. We provide novel and comprehensive evidence for the influence of maternal prebiotic intake on offspring behavior, brain gene expression, and gut microbiome composition in mice.

Glutamate Receptors in Schizophrenia: A Review

The pathophysiology of schizophrenic shows the dysfunction of Glutamate receptors. The inotropic subtypes The NMDA, AMPA and kinate receptors out of various glutamate receptors are most commonly associated. In postmortem brain samples from schizophrenics and controls several levels of gene expression of glutamate receptors were studied. Even though there exist slight inconsistency from various studies certain points. There is an abnormal reduction in the AMPA receptor expression in the schizophrenic hippocampus, including reduced subunit transcript level, protein level and also binding sites. In hippocampus related changes are also seen in the kinate receptor expression. In some cortical regions in schizophrenia NMDAR1 shows abnormal expression. NMDDAR1 is the obligate NMDA receptor subunit. The current review ellustrates the theory of glutamate neurotransmission abnormality in schizophrenia.

Exposure to bacterial lipopolysaccharide in early life affects the expression of ionotropic glutamate receptor genes and is accompanied by disturbances in long-term potentiation and cognitive functions in young rats

Infections in childhood play an essential role in the pathogenesis of cognitive and psycho-emotional disorders. One of the possible mechanisms of these impairments is changes in the functional properties of NMDA and AMPA glutamate receptors in the brain. We suggest that bacterial infections during the early life period, which is critical for excitatory synapse maturation, can affect the subunit composition of NMDA and AMPA receptors. In the present study, we investigated the effect of repetitive lipopolysaccharide (LPS) intraperitoneal (i.p.) administration (25 μg/kg/day on P14, 16, and 18), mimicking an infectious disease, on the expression of subunits of NMDA and AMPA receptors in young rats. We revealed a substantial decrease of GluN2B subunit expression in the hippocampus at P23 using Western blot analysis and real-time polymerase chain reaction assay. Moderate changes were also found in GluN1, GluN2A, and GluA1 mRNA expression. The LPS-treated rats exhibited decreased exploratory and locomotor activity in the open field test and the impairment of spatial learning in the Morris water maze. Behavioral impairments were accompanied by a significant reduction in long-term hippocampal synaptic potentiation. Our data indicate that LPS-treatment in the critical period for excitatory synapse maturation alters ionotropic glutamate receptor gene expression, disturbs synaptic plasticity, and alters behavior.

Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics

The ability of small secretory microvesicles known as exosomes to influence neuronal and glial function via their microRNA (miRNA) cargo has positioned them as a novel and effective method of cell-to-cell communication. However, little is known about the role of exosome-secreted miRNAs in the regulation of glutamate receptor gene expression and their relevance for schizophrenia (SCZ) and bipolar disorder (BD). Using mature miRNA profiling and quantitative real-time PCR (qRT-PCR) in the orbitofrontal cortex (OFC) of SCZ (N = 29; 20 male and 9 female), BD (N = 26; 12 male and 14 female), and unaffected control (N = 25; 21 male and 4 female) subjects, we uncovered that miR-223, an exosome-secreted miRNA that targets glutamate receptors, was increased at the mature miRNA level in the OFC of SCZ and BD patients with positive history of psychosis at the time of death and was inversely associated with deficits in the expression of its targets glutamate ionotropic receptor NMDA-type subunit 2B (GRIN2B) and glutamate ionotropic receptor AMPA-type subunit 2 (GRIA2). Furthermore, changes in miR-223 levels in the OFC were positively and negatively correlated with inflammatory and GABAergic gene expression, respectively. Moreover, miR-223 was found to be enriched in astrocytes and secreted via exosomes, and antipsychotics were shown to control its cellular and exosomal localization in a cell-specific manner. Furthermore, addition of astrocytic exosomes in neuronal cultures resulted in a significant increase in miR-223 expression and a notable reduction in Grin2b and Gria2 mRNA levels, which was strongly inversely associated with miR-223 expression. Lastly, inhibition of astrocytic miR-223 abrogated the exosomal-mediated reduction in neuronal Grin2b expression. Taken together, our results demonstrate that the exosomal secretion of a psychosis-altered and glial-enriched miRNA that controls neuronal gene expression is regulated by antipsychotics.

The Ca2+ signaling, Glu, and GABA responds to Cd stress in duckweed

Cadmium (Cd) affects plants and animal health seriously. Ca2+ signals in plant cells are important for adaptive responses to environmental stresses. Here we showed that 50 μM Cd shock stimulated the Ca2+ signal via modifying the instantaneous Ca2+ flux from influx of 17 pmol·cm-2·s-1 to the efflux of 240 pmol·cm-2·s-1 at 100 μm from rhizoid tip. And the Ca2+ signal transferred to the vein and mesophyll cell. The Ca addition decreased the accumulation of Cd. The gene expression of glutamate receptor–like (GLR) proteins, which is activated by Glu and triggers Ca2+ flux, was increased significantly by 24 h Cd stress. Glu content was increased under Cd stress and exogenous Glu triggered the Ca2+ signal in duckweed, while Ca2+ addition caused no influence to Glu content. GABA, which is synthesized from Glu and acts as an inhibitory neurotransmitter, has been decreased with 24 h Cd treatment. GABA addition increased the abscission rate and Glu addition decreased the abscission rate during Cd stress, suggesting that the Glu/GABA ratio is important for responding to Cd. This research shows the sight of the Glu, Ca2+, GABA signaling networks during Cd stress.

F90. Sex Differences in Predictors of Completed Suicide

The glutamate system is the major excitatory system in the brain and abnormalities of this system occur in major depression (MDD). We have previously reported higher expression of glutamate receptor genes in MDD subjects who died by suicide (MDD-S) relative to MDD non-suicides (MDD-NS).

Dexmedetomidine and propofol sedation requirements in an autistic rat model

BackgroundAutism is a challenging neurodevelopmental disorder. Previous clinical observations have suggested altered sedation requirements for children with autism. Our study aimed to test this observation experimentally in an animal model and to explore its possible mechanisms.MethodsEight adult pregnant female Sprague-Dawley rats were randomly divided into two groups. Four were injected with intraperitoneal sodium valproate on gestational day 12 and four were injected with normal saline. On postnatal day 28, the newborn male rats were subjected to the open-field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). The times to loss of righting reflex (LORR) and to return of righting reflex (RORR) were recorded. On the following day, all rats were re-sedated and underwent electroencephalography (EEG). Thereafter, the rats were euthanized and their hippocampal gamma-aminobutyric acid type A (GABAA) and glutamate N-methyl-D-aspartate (NMDA) receptor gene expressions were assessed.ResultsAutistic rats showed significantly longer LORR times and shorter RORR times than did the controls (median LORR times: 12.0 versus 5.0 min for dexmedetomidine and 22.0 versus 8.0 min for propofol; P < 0.05). EEG showed a low-frequency, high-amplitude wave pattern 2 min after LORR in the control rats. Autistic rats showed a high-frequency, low-amplitude awake pattern. Hippocampal GABAA receptor gene expression was significantly lower and NMDA gene expression was greater in autistic rats.ConclusionsThis study supports the clinical observations of increased anesthetic sedative requirements in children with autism and our biochemical analyses using GABAA and glutamate receptor gene expression highlight possible underlying mechanisms.

Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression

Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated—at least partially—through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine’s rapid antidepressant effects through the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In the present study, we demonstrated that estrogen plus ketamine or estrogen plus active ketamine metabolites displayed additive effects on the induction of the expression of AMPA receptor subunits. In parallel, the expression of estrogen receptor alpha (ERα) was also significantly upregulated. Even more striking, radioligand binding assays demonstrated that [3H]-ketamine can directly bind to ERα (KD: 344.5 ± 13 nM). Furthermore, ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites displayed similar affinity for ERα (IC50: 2.31 ± 0.1, 3.40 ± 0.2, and 3.53 ± 0.2 µM, respectively) as determined by [3H]-ketamine displacement assays. Finally, induction of AMPA receptors by either estrogens or ketamine and its metabolites was lost when ERα was knocked down or silenced pharmacologically. These results suggest a positive feedback loop by which estrogens can augment the effects of ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites on the ERα-induced transcription of CYP2A6 and CYP2B6, estrogen inducible enzymes that catalyze ketamine’s biotransformation to form the two active metabolites. These observations provide novel insight into ketamine’s molecular mechanism(s) of action and have potential implications for the treatment of MDD.