This study was designed to investigate the cardiovascular effects of sulfur dioxide (SO₂) in the caudal ventrolateral medulla (CVLM) of anesthetized rats and its mechanism. Different doses of SO₂ (2, 20, 200 pmol) or artificial cerebrospinal fluid (aCSF) were injected into the CVLM unilaterally or bilaterally, and the effects of SO₂ on blood pressure and heart rate of rats were observed. In order to explore the possible mechanisms of SO₂ in the CVLM, different signal pathway blockers were injected into the CVLM before the treatment with SO₂ (20 pmol). The results showed that unilateral or bilateral microinjection of SO₂ reduced blood pressure and heart rate in a dose-dependent manner (P < 0.01). Moreover, compared with unilateral injection of SO₂ (2 pmol), bilateral injection of 2 pmol SO₂ produced a greater reduction in blood pressure. Local pre-injection of the glutamate receptor blocker kynurenic acid (Kyn, 5 nmol) or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 pmol) into the CVLM attenuated the inhibitory effects of SO₂ on both blood pressure and heart rate. However, local pre-injection of nitric oxide synthase (NOS) inhibitor N^G-Nitro-L-arginine methyl ester (L-NAME, 10 nmol) only attenuated the inhibitory effect of SO₂ on heart rate but not blood pressure. In conclusion, SO₂ in rat CVLM has cardiovascular inhibitory effects, and its mechanism is related to the glutamate receptor and NOS/cGMP signal pathways.
Animals ; Rats ; Heart Rate ; Sulfur Dioxide ; Blood Pressure ; Cyclic GMP ; Receptors, Glutamate

OBJECTIVE: To observe the clinical significance of translocator proteins (TSPO) gene in the treatment of FLT3-ITD/DNMT3A R882 double-mutated acute myeloid leukemia (AML). METHODS: Seventy-six patients with AML hospitalized in the Department of Hematology of the Affiliated People's Hospital of Ningbo University from June 2018 to June 2020 were selected, including 34 patients with FLT3-ITD mutation, 27 patients with DNMT3A R882 mutation, 15 patients with FLT3-ITD/DNMT3A R882 double mutation, as well as 19 patients with immune thrombocytopenia (ITP) hospitalized during the same period as control group. RNA was routinely extracted from 3 ml bone marrow retained during bone puncture, and TSPO gene expression was detected by transcriptome sequencing (using 2-deltadeltaCt calculation). RESULTS: The expression of TSPO gene in FLT3-ITD group and DNMT3A R882 group at first diagnosis was 2.02±1.04 and 1.85±0.76, respectively, which were both higher than 1.00±0.06 in control group, but the differences were not statistically significant (P=0.671, P=0.821). The expression of TSPO gene in the FLT3-ITD/DNMT3A R882 group was 3.98±1.07, wich was significantly higher than that in the FLT3-ITD group and DNMT3A R882 group, the differences were statistically significant (P=0.032, P=0.021). The expression of TSPO gene in patients who achieved complete response after chemotherapy in the FLT3-ITD/DNMT3A R882 group was 1.19±0.87, which was significantly lower than that at first diagnosis, and the difference was statistically significant (P=0.011). CONCLUSION TSPO gene may be used as an indicator of efficacy in FLT3-ITD /DNMT3A R882 double-mutated AML.
Humans ; DNA (Cytosine-5-)-Methyltransferases/genetics* ; DNA Methyltransferase 3A ; Mutation ; Leukemia, Myeloid, Acute/drug therapy* ; Nucleophosmin ; Prognosis ; fms-Like Tyrosine Kinase 3/genetics* ; Receptors, GABA/therapeutic use*

Receptors, Purinergic ; Signal Transduction/physiology*

Insomnia is a common sleep disorder without effective therapy and can affect a person's life. The mechanism of the disease is not completely understood. Hence, there is a need to understand the targets related to insomnia, in order to develop innovative therapies and new compounds. Recently, increasing interest has been focused on complementary and alternative medicines for treating or preventing insomnia. Research into their molecular components has revealed that their sedative and sleep-promoting properties rely on the interactions with various neurotransmitter systems in the brain. In this review, the role of 5-hydroxytryptamine (5-HT) in insomnia development is summarized, while a systematic analysis of studies is conducted to assess the mechanisms of herbal medicines on different 5-HT receptors subtypes, in order to provide reference for subsequent research.
Humans ; Sleep Initiation and Maintenance Disorders/drug therapy* ; Medicine, Chinese Traditional ; Drugs, Chinese Herbal/therapeutic use* ; Plants, Medicinal ; Receptors, Serotonin ; Serotonin

OBJECTIVE: To investigate the expression and localization of metabotropic glutamate receptors 7 and 8 (mGluR7/8) in rat superior cervical ganglion (SCG) and their changes in response to chronic intermittent hypoxia (CIH). METHODS: We detected the expressions of mGluR7 and mGluR8 in the SCG of 8-week-old male SD rats using immunohistochemistry and characterized their distribution with immunofluorescence staining. The expression of mGluR7 and mGluR8 in the cytoplasm and nucleus was detected using Western blotting. A 6-week CIH rat model was established by exposure to intermittent hypoxia (6% oxygen for 30 s followed by normoxia for 4 min) for 8 h daily, and the changes in systolic blood pressure, diastolic blood pressure and mean arterial pressure were measured. The effect of CIH on expression levels of mGluR7 and mGluR8 in the SCG was analyzed using Western blotting. RESULTS: Positive expressions of mGluR7 and mGluR8 were detected in rat SCG. mGluR7 was distributed in the neurons and small fluorescent (SIF) cells with positive staining in both the cytoplasm and nuclei, but not expressed in satellite glial cells (SGCs), nerve fibers or blood vessels; mGluR8 was localized in the cytoplasm of neurons and SIF cells, but not expressed in SGCs, nerve fibers, or blood vessels. Western blotting of the nuclear and cytoplasmic fractions of rat SCG further confirmed that mGluR7 was expressed in both the cytoplasm and the nucleus, while mGluR8 exists only in the cytoplasm. Exposure to CIH significantly increased systolic blood pressure, diastolic blood pressure and mean arterial pressure of the rats (all P < 0.001) and augmented the protein expressions of mGluR7 and mGluR8 in the SCG (P < 0.05). CONCLUSION mGluR7 and mGluR8 are present in rat SCG but with different localization patterns. CIH increases blood pressure of rats and enhanced protein expressions of mGluR7 and mGluR8 in rat SCG.
Male ; Animals ; Rats ; Rats, Sprague-Dawley ; Superior Cervical Ganglion ; Receptors, Metabotropic Glutamate ; Hypoxia

Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D₃ receptor (D₃R) have effects on addiction in different animal models. We have previously reported that YQA14, a D₃R antagonist, exhibits very high affinity and selectivity for D₃Rs over D₂Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D₃R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

OBJECTIVE: To observe the effects of electroacupuncture (EA) pretreatment on cardiac function, sympathetic nerve activity, indexes of myocardial injury and GABA_A receptor in fastigial nucleus in rats with myocardial ischemia reperfusion injury (MIRI), and to explore the neuroregulatory mechanism of EA pretreatment in improving MIRI. METHODS: A total of 60 male SD rats were randomly divided into a sham operation group, a model group, an EA group, an agonist group and an agonist+EA group, 12 rats in each group. The MIRI model was established by ligation of the left anterior descending coronary artery. EA was applied at bilateral "Shenmen" (HT 7) and "Tongli" (HT 5) in the EA group and the agonist+EA group, with continuous wave, in frequency of 2 Hz and intensity of 1 mA, 30 min each time, once a day for 7 consecutive days. After intervention, the MIRI model was established. In the agonist group, the muscone (agonist of GABA_A receptor, 1 g/L) was injected in fastigial nucleus for 7 consecutive days before modeling, 150 μL each time, once a day. In the agonist+EA group, the muscone was injected in fastigial nucleus 30 min before EA intervention. The data of electrocardiogram was collected by PowerLab standard Ⅱ lead, and ST segment displacement and heart rate variability (HRV) were analyzed; the serum levels of norepinephrine (NE), creatine kinase isoenzyme MB (CK-MB) and cardiac troponin I (cTnI) were detected by ELISA; the myocardial infarction area was measured by TTC staining; the morphology of myocardial tissue was observed by HE staining; the positive expression and mRNA expression of GABA_A receptor in fastigial nucleus were detected by immunohistochemistry and real-time PCR. RESULTS: Compared with the sham operation group, in the model group, ST segment displacement and ratio of low frequency to high frequency (LF/HF) of HRV were increased (P<0.01), HRV frequency domain analysis showed enhanced sympathetic nerve excitability, the serum levels of NE, CK-MB and cTnI were increased (P<0.01), the percentage of myocardial infarction area was increased (P<0.01), myocardial fiber was broken and interstitial edema was serious, the positive expression and mRNA expression of GABA_A receptor in fastigial nucleus were increased (P<0.01). Compared with the model group, in the EA group, ST segment displacement and LF/HF ratio were decreased (P<0.01), HRV frequency domain analysis showed reduced sympathetic nerve excitability, the serum levels of NE, CK-MB and cTnI were decreased (P<0.01), the percentage of myocardial infarction area was decreased (P<0.01), myocardial fiber breakage and interstitial edema were lightened, the positive expression and mRNA expression of GABA_A receptor in fastigial nucleus were decreased (P<0.01). Compared with the EA group, in the agonist group and the agonist+EA group, ST segment displacement and LF/HF ratio were increased (P<0.01), HRV frequency domain analysis showed enhanced sympathetic nerve excitability, the serum levels of NE, CK-MB and cTnI were increased (P<0.01), the percentage of myocardial infarction area was increased (P<0.01), myocardial fiber breakage and interstitial edema were aggravated, the positive expression and mRNA expression of GABA_A receptor in fastigial nucleus were increased (P<0.01). CONCLUSION EA pretreatment can improve the myocardial injury in MIRI rats, and its mechanism may be related to the inhibition of GABA_A receptor expression in fastigial nucleus, thereby down-regulating the excitability of sympathetic nerve.
Male ; Animals ; Rats ; Rats, Sprague-Dawley ; Cerebellar Nuclei ; Electroacupuncture ; Myocardial Reperfusion Injury/therapy* ; Receptors, GABA-A/genetics* ; RNA, Messenger

The aim of the present study was to explore the role of group II and III metabotropic glutamate receptors (mGluRs) in carotid body plasticity induced by chronic intermittent hypoxia (CIH) in rats. Sprague Dawley (SD) rats were treated with CIH in Oxycycler A84 hypoxic chamber for 4 weeks, and the tail artery blood pressure was measured at the end of model preparation. RT-qPCR was performed to examine the mRNA expression levels of mGluR2/3/8 in rat carotid body. Carotid sinus nerve activity was detected by ex vivo carotid sinus nerve discharge recording technique, and acute intermittent hypoxia (AIH) was administered to induce carotid body sensory long-term facilitation (sLTF), in order to observe the role of group II and group III mGluRs in carotid body plasticity induced by CIH. The results showed that: 1) After 4 weeks of CIH exposure, the blood pressure of rats increased significantly; 2) CIH down-regulated the mRNA levels of mGluR2/3, and up-regulated the mRNA level of mGluR8 in the carotid body; 3) AIH induced sLTF in carotid body of CIH group. In the CIH group, activation of group II mGluRs had no effect on sLTF of carotid body, while activation of group III mGluRs completely inhibited sLTF. These results suggest that CIH increases blood pressure in rats, and group III mGluRs play an inhibitory role in CIH-induced carotid body plasticity in rats.
Rats ; Animals ; Carotid Body/metabolism* ; Rats, Sprague-Dawley ; Hypoxia ; Receptors, Metabotropic Glutamate/metabolism* ; RNA, Messenger/metabolism*

Post-traumatic stress disorder (PTSD) has been reported to be associated with a higher risk of cardiovascular disease. The amygdala may have an important role in regulating cardiovascular function. This study aims to explore the effect of amygdala glutamate receptors (GluRs) on cardiovascular activity in a rat model of PTSD. A compound stress method combining electrical stimulation and single prolonged stress was used to prepare the PTSD model, and the difference of weight gain before and after modeling and the elevated plus maze were used to assess the PTSD model. In addition, the distribution of retrogradely labeled neurons was observed using the FluoroGold (FG) retrograde tracking technique. Western blot was used to analyze the changes of amygdala GluRs content. To further investigate the effects, artificial cerebrospinal fluid (ACSF), non-selective GluR blocker kynurenic acid (KYN) and AMPA receptor blocker CNQX were microinjected into the central nucleus of the amygdala (CeA) in the PTSD rats, respectively. The changes in various indices following the injection were observed using in vivo multi-channel synchronous recording technology. The results indicated that, compared with the control group, the PTSD group exhibited significantly lower weight gain (P < 0.01) and significantly decreased ratio of open arm time (OT%) (P < 0.05). Retrograde labeling of neurons was observed in the CeA after microinjection of 0.5 µL FG in the rostral ventrolateral medulla (RVLM). The content of AMPA receptor in the PTSD group was lower than that in the control group (P < 0.05), while there was no significant differences in RVLM neuron firing frequency and heart rate (P > 0.05) following ACSF injection. However, increases in RVLM neuron firing frequency and heart rate were observed after the injection of KYN or CNQX into the CeA (P < 0.05) in the PTSD group. These findings suggest that AMPA receptors in the amygdala are engaged in the regulation of cardiovascular activity in PTSD rats, possibly by acting on inhibitory pathways.
Rats ; Animals ; Rats, Sprague-Dawley ; Stress Disorders, Post-Traumatic ; Receptors, AMPA ; 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology* ; Receptors, Glutamate/metabolism* ; Amygdala ; Weight Gain ; Medulla Oblongata/physiology* ; Blood Pressure

The purpose of the present study was to explore the role of carotid body metabotropic glutamate receptor 1 (mGluR1) in chronic intermittent hypoxia (CIH)-induced carotid body plasticity. Sprague Dawley (SD) rats were exposed to CIH (6%-21% O₂, 4 min/cycle, 8 h/day) for 4 weeks. The blood pressure of rats was monitored non-invasively by tail-cuff method under consciousness. RT-qPCR was used to examine the mRNA expression level of mGluR1 in rat carotid body. Western blot was used to detect the protein expression level of mGluR1 in rat carotid body. The role of mGluR1 in CIH-induced carotid body sensory long-term facilitation (sLTF) was investigated by ex vivo carotid sinus nerve discharge recording, and the carotid body sLTF was evoked by a 10-episode of repetitive acute intermittent hypoxia (AIH: 1 min of 5% O₂ interspersed with 5 min of 95% O₂). The results showed that: 1) CIH increased the systolic blood pressure (P < 0.001), diastolic blood pressure (P < 0.005) and mean arterial blood pressure (P < 0.001) of rats; 2) CIH decreased the mRNA and protein levels of mGluR1 in the rat carotid body (P < 0.01); 3) 4 weeks of CIH induced carotid body sLTF significantly, exhibiting as an increasing baseline sensory activity during post-AIH, which was inhibited by application of an agonist of group I metabotropic glutamate receptors, (S)-3,5-dihydroxyphenylglycine (DHPG), during sLTF induction (P < 0.005). In summary, these results suggest that activation of mGluR1 inhibits CIH-induced carotid body plasticity in rats.
Rats ; Animals ; Carotid Body/metabolism* ; Rats, Sprague-Dawley ; Hypoxia ; Receptors, Metabotropic Glutamate/metabolism* ; RNA, Messenger/metabolism*