Growth arrest DNA damage-inducible protein 45 β (GADD45B) has been reported to be a regulatory factor for active DNA demethylation and is implicated in the modulation of synaptic plasticity and chronic stress-related psychopathological processes. However, its precise role and mechanism of action in stress susceptibility remain elusive. In this study, we found a significant reduction in GADD45B expression specifically in the ventral, but not the dorsal hippocampal CA1 (dCA1) of stress-susceptible mice. Furthermore, we demonstrated that GADD45B negatively regulates susceptibility to social stress and NMDA receptor-dependent long-term potentiation (LTP) in the ventral hippocampal CA1 (vCA1). Importantly, through pharmacological inhibition using the NMDA receptor antagonist MK801, we provided further evidence supporting the hypothesis that GADD45B potentially modulates susceptibility to social stress by influencing NMDA receptor-mediated LTP. Collectively, these results suggested that modulation of NMDA receptor-mediated synaptic plasticity is a pivotal mechanism underlying the regulation of susceptibility to social stress by GADD45B.
Animals ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; CA1 Region, Hippocampal/drug effects* ; Male ; Stress, Psychological/physiopathology* ; Mice ; Neuronal Plasticity/drug effects* ; Long-Term Potentiation/drug effects* ; Mice, Inbred C57BL ; Antigens, Differentiation/metabolism* ; Dizocilpine Maleate/pharmacology* ; Excitatory Amino Acid Antagonists/pharmacology* ; GADD45 Proteins

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.
Animals ; Brain ; drug effects ; metabolism ; pathology ; Cognitive Dysfunction ; drug therapy ; metabolism ; pathology ; Disease Models, Animal ; Dizocilpine Maleate ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Hydrocarbons, Brominated ; Inflammasomes ; drug effects ; metabolism ; Male ; Maze Learning ; drug effects ; physiology ; Microglia ; drug effects ; metabolism ; pathology ; NLR Family, Pyrin Domain-Containing 3 Protein ; metabolism ; Neurons ; drug effects ; metabolism ; pathology ; Nootropic Agents ; pharmacology ; Random Allocation ; Rats, Wistar ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; metabolism ; Spatial Memory ; drug effects ; physiology ; Specific Pathogen-Free Organisms

Gamma band oscillation (GBO) and sensory gating (SG) are associated with many cognitive functions. Ketamine induces deficits of GBO and SG in the prefrontal cortex (PFC). However, the time-courses of the effects of different doses of ketamine on GBO power and SG are poorly understood. Studies have indicated that GBO power and SG have a common substrate for their generation and abnormalities. In this study, we found that (1) ketamine administration increased GBO power in the PFC in rats differently in the low- and high-dose groups; (2) auditory SG was significantly lower than baseline in the 30 mg/kg and 60 mg/kg groups, but not in the 15 mg/kg and 120 mg/kg groups; and (3) changes in SG and basal GBO power were significantly correlated in awake rats. These results indicate a relationship between mechanisms underlying auditory SG and GBO power.
Acoustic Stimulation ; Analysis of Variance ; Animals ; Dose-Response Relationship, Drug ; Electroencephalography ; Excitatory Amino Acid Antagonists ; pharmacology ; Gamma Rhythm ; drug effects ; Ketamine ; pharmacology ; Male ; Prefrontal Cortex ; drug effects ; Rats ; Rats, Sprague-Dawley ; Sensory Gating ; drug effects ; Sleep Stages ; drug effects ; Statistics as Topic ; Time Factors ; Wakefulness ; drug effects

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Animals ; Benzoxazines ; pharmacology ; therapeutic use ; Chemokine CCL2 ; antagonists & inhibitors ; genetics ; metabolism ; pharmacology ; Excitatory Amino Acid Agents ; pharmacology ; Excitatory Amino Acid Agonists ; pharmacology ; Female ; Freund's Adjuvant ; toxicity ; Hyperalgesia ; chemically induced ; metabolism ; prevention & control ; Long-Term Potentiation ; drug effects ; physiology ; Luminescent Proteins ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelitis ; chemically induced ; drug therapy ; metabolism ; Neurons ; drug effects ; Pain Management ; Somatostatin ; genetics ; metabolism ; Spinal Cord ; cytology ; Spiro Compounds ; pharmacology ; therapeutic use ; Vesicular Glutamate Transport Protein 2 ; genetics ; metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins ; genetics ; metabolism

Orthostatic hypotension (OH) is associated with symptoms including headache, dizziness, and syncope. The incidence of OH increases with age. Attenuation of the vestibulosympathetic reflex (VSR) is also associated with an increased incidence of OH. In order to understand the pathophysiology of OH, we investigated the physiological characteristics of the VSR in the disorder. We applied sodium nitroprusside (SNP) to conscious rats with sinoaortic denervation in order to induce hypotension. Expression of pERK in the intermediolateral cell column (IMC) of the T4~7 thoracic spinal regions, blood epinephrine levels, and blood pressure were evaluated following the administration of glutamate and/or SNP. SNP-induced hypotension led to increased pERK expression in the medial vestibular nucleus (MVN), rostral ventrolateral medullary nucleus (RVLM) and the IMC, as well as increased blood epinephrine levels. We co-administered either a glutamate receptor agonist or a glutamate receptor antagonist to the MVN or the RVLM. The administration of the glutamate receptor agonists, AMPA or NMDA, to the MVN or RVLM led to elevated blood pressure, increased pERK expression in the IMC, and increased blood epinephrine levels. Administration of the glutamate receptor antagonists, CNQX or MK801, to the MVN or RVLM attenuated the increased pERK expression and blood epinephrine levels caused by SNP-induced hypotension. These results suggest that two components of the pathway which maintains blood pressure are involved in the VSR induced by SNP. These are the neurogenic control of blood pressure via the RVLM and the humoral control of blood pressure via epinephrine release from the adrenal medulla.
6-Cyano-7-nitroquinoxaline-2,3-dione ; Adrenal Medulla ; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid ; Animals ; Blood Pressure ; Denervation ; Dizocilpine Maleate ; Dizziness ; Epinephrine ; Excitatory Amino Acid Antagonists ; Glutamic Acid ; Headache ; Hypotension* ; Hypotension, Orthostatic ; Incidence ; N-Methylaspartate ; Nitroprusside ; Rats* ; Receptors, Glutamate ; Reflex* ; Spinal Cord Lateral Horn ; Syncope ; Vestibular Nuclei

OBJECTIVEThe present study was undertaken to design antisense oligodeoxynucleotides (AS-ODNs) of glial glutamate transporter-la (GLT-1a) and to evaluate the effectiveness of the designed AS-ODNs on the expression of GLT-1a.

METHODSFive sequences of GLT-1a AS-ODNs were designed according to the C terminus specific sequences of GLT-1a mRNA using antisense design software of IDT Com- pany. Western blot analysis was used to evaluate the inhibition effects of the five GLT-1a AS-ODNs on the expression of GLT-la.

RESULTSThe sequence of GLT-1a AS-ODNs with sequence of 5'-GGTTCTTCCTCAACACTGCA-3' could specifically inhibit the expression of GLT-1a in the hippocampal CA1 subfield of rats, while it had no effect on the expression of GLT-1b. This sequence showed similar inhibition on the expression of GLT-la in sham and ceftriaxone (Cef)-treated rats. It could also significantly inhibit the cerebral ischemic preconditioning (CIP)-induced up-regulation in the expression of GLT-1a. The magnitude of the inhibition in sham, Cef- or CIP-treated rats was similar by more than 60%.

CONCLUSIONFrom the designed five sequences of GLT-1a AS-ODNs, we obtained an effective sequence which can specifically inhibit the expression of GLT-1a.

Animals ; CA1 Region, Hippocampal ; metabolism ; Excitatory Amino Acid Transporter 2 ; antagonists & inhibitors ; metabolism ; Ischemic Preconditioning ; Oligonucleotides, Antisense ; genetics ; RNA, Messenger ; Rats ; Up-Regulation

Significant evidence supports the role of the vestibular system in the regulation of blood pressure during postural movements. In the present study, the role of the vestibulo-spino-adrenal (VSA) axis in the modulation of blood pressure via the vestibulosympathetic reflex was clarified by immunohistochemical and enzyme immunoassay methods in conscious rats with sinoaortic denervation. Expression of c-Fos protein in the intermediolateral cell column of the middle thoracic spinal regions and blood epinephrine levels were investigated, following microinjection of glutamate receptor agonists or antagonists into the medial vestibular nucleus (MVN) and/or sodium nitroprusside (SNP)-induced hypotension. Both microinjection of glutamate receptor agonists (NMDA and AMPA) into the MVN or rostral ventrolateral medullary nucleus (RVLM) and SNP-induced hypotension led to increased number of c-Fos positive neurons in the intermediolateral cell column of the middle thoracic spinal regions and increased blood epinephrine levels. Pretreatment with microinjection of glutamate receptor antagonists (MK-801 and CNQX) into the MVN or RVLM prevented the increased number of c-Fos positive neurons resulting from SNP-induced hypotension, and reversed the increased blood epinephrine levels. These results indicate that the VSA axis may be a key component of the pathway used by the vestibulosympathetic reflex to maintain blood pressure during postural movements.
Animals ; Axis, Cervical Vertebra* ; Blood Pressure* ; Denervation ; Epinephrine ; Excitatory Amino Acid Antagonists ; Glutamic Acid ; Hypotension ; Immunoenzyme Techniques ; Microinjections ; Neurons ; Nitroprusside ; Rats* ; Receptors, Glutamate ; Reflex* ; Vestibular Nuclei ; Natural Resources

Orthostatic hypotension is most common in elderly people, and its prevalence increases with age. Attenuation of the vestibulo-sympathetic reflex (VSR) is commonly associated with orthostatic hypotension. In this study, we investigated the role of glutamate on the vestibulo-solitary projection of the VSR pathway to clarify the pathophysiology of orthostatic hypotension. Blood pressure and expression of both pERK and c-Fos protein were evaluated in the nucleus tractus solitarius (NTS) after microinjection of glutamate into the medial vestibular nucleus (MVN) in conscious rats with sodium nitroprusside (SNP)-induced hypotension that received baroreceptor unloading via sinoaortic denervation (SAD). SNP-induced hypotension increased the expression of both pERK and c-Fos protein in the NTS, which was abolished by pretreatment with glutamate receptor antagonists (MK801 or CNQX) in the MVN. Microinjection of glutamate receptor agonists (NMDA or AMPA) into the MVN increased the expression of both pERK and c-Fos protein in the NTS without causing changes in blood pressure. These results indicate that both NMDA and AMPA receptors play a significant role in the vestibulo-solitary projection of the VSR pathway for maintaining blood pressure, and that glutamatergic transmission in this projection might play a key role in the pathophysiology of orthostatic hypotension.
Aged ; Animals ; Blood Pressure ; Denervation ; Excitatory Amino Acid Antagonists ; Glutamic Acid* ; Humans ; Hypotension* ; Hypotension, Orthostatic ; Microinjections ; N-Methylaspartate ; Nitroprusside ; Pressoreceptors ; Prevalence ; Rats* ; Receptors, AMPA ; Receptors, Glutamate ; Reflex ; Sodium* ; Solitary Nucleus ; Vestibular Nuclei

OBJECTIVETo investigate the effect of µ-opioid receptors (µ-ORs) in the central nucleus of the amygdala (CeA) on feeding and drinking behaviors in rats and evaluate the role of glutamate signaling in opioid-mediated ingestive behaviors.

METHODSStainless steel cannulas were implanted in the unilateral CeA for microinjection of different doses of the selective µ-OR agonist DAMGO in satiated or water-deprived male SD rats. The subsequent food intake or water intake of the rats was measured at 60, 120, and 240 min after the injection. The rats receiving microinjections of naloxone (NTX, a nonselective opioid antagonist) or D-AP-5 (a selective N-methyl-D-aspartic acid-type glutamate receptor antagonist) prior to DAMGO microinjection were tested for food intake at 60, 120, and 240 min after the injections.

RESULTSInjections of DAMGO (1-4 nmol in 0.5 µl) into the CeA significantly increased food intake in satiated rats, but did not affect water intake in rats with water deprivation. NTX (26.5 nmol in 0.5 µl) injected into the CeA antagonized DAMGO-induced feeding but D-AP-5 (6.3-25.4 nmol in 0.5 µl) injections did not produce such an effect.

CONCLUSIONµ-ORs in the CeA regulate food intake rather than water intake in rats, and the orexigenic role of µ-ORs is not dependent on the activation of the NMDA receptors in the CeA.

2-Amino-5-phosphonovalerate ; pharmacology ; Animals ; Central Amygdaloid Nucleus ; physiology ; Drinking ; physiology ; Eating ; physiology ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- ; pharmacology ; Excitatory Amino Acid Antagonists ; pharmacology ; Male ; Naloxone ; pharmacology ; Narcotic Antagonists ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu ; physiology

This study explored the effect of the excitatory amino acid receptor antagonists on the impairment of learning-memory and the hyperphosphorylation of Tau protein induced by electroconvulsive shock (ECT) in depressed rats, in order to provide experimental evidence for the study on neuropsychological mechanisms improving learning and memory impairment and the clinical intervention treatment. The analysis of variance of factorial design set up two intervention factors which were the electroconvulsive shock (two level: no disposition; a course of ECT) and the excitatory amino acid receptor antagonists (three level: iv saline; iv NMDA receptor antagonist MK-801; iv AMPA receptor antagonist DNQX). Forty-eight adult Wistar-Kyoto (WKY) rats (an animal model for depressive behavior) were randomly divided into six experimental groups (n = 8 in each group): saline (iv 2 mL saline through the tail veins of WKY rats ); MK-801 (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats) ; DNQX (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats ); saline + ECT (iv 2 mL saline through the tail veins of WKY rats and giving a course of ECT); MK-801 + ECT (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats and giving a course of ECT); DNQX + ECT (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats and giving a course of ECT). The Morris water maze test started within 1 day after the finish of the course of ECT to evaluate learning and memory. The hippocampus was removed from rats within 1 day after the finish of Morris water maze test. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. The contents of Tau protein which included Tau5 (total Tau protein), p-PHF1(Ser396/404), p-AT8(Ser199/202) and p-12E8(Ser262) in the hippocampus of rats were detected by immunohistochemistry staining (SP) and Western blot. The results showed that ECT and the glutamate ionic receptor blockers (NMDA receptor antagonist MK-801 and AMPA receptor antagonist DNQX) induced the impairment of learning and memory in depressed rats with extended evasive latency time and shortened space exploration time. And the two factors presented a subtractive effect. ECT significantly up-regulated the content of glutamate in the hippocampus of depressed rats which were not affected by the glutamate ionic receptor blockers. ECT and the glutamate ionic receptor blockers did not affect the total Tau protein in the hippocampus of rats. ECT up-regulated the hyperphosphorylation of Tau protein in the hippocampus of depressed rats, while the glutamate ionic receptor blockers down-regulated it, and combination of the two factors presented a subtractive effect. Our results indicate that ECT up-regulates the content of glutamate in the hippocampus of depressed rats, which up-regulates the hyperphosphorylation of Tau protein resulting in the impairment of learning and memory in depressed rats.
Animals ; Disease Models, Animal ; Dizocilpine Maleate ; pharmacology ; Electroshock ; adverse effects ; Excitatory Amino Acid Antagonists ; pharmacology ; Glutamic Acid ; metabolism ; Hippocampus ; metabolism ; Learning ; Memory ; Memory Disorders ; Phosphorylation ; Quinoxalines ; pharmacology ; Rats ; Rats, Inbred WKY ; Rats, Sprague-Dawley ; Receptors, AMPA ; antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; tau Proteins ; metabolism