Metabotropic glutamate receptors as novel targets for anxiety and stress disorders

Anxiety and stress disorders are the most commonly occurring of all mental illnesses, and current treatments are less than satisfactory. So, the discovery of novel approaches to treat anxiety disorders remains an important area of neuroscience research. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, and G-protein-coupled metabotropic glutamate (mGlu) receptors function to regulate excitability via pre- and postsynaptic mechanisms. Various mGlu receptor subtypes, including group I (mGlu(1) and mGlu(5)), group II (mGlu(2) and mGlu(3)), and group III (mGlu(4), mGlu(7) and mGlu(8)) receptors, specifically modulate excitability within crucial brain structures involved in anxiety states. In addition, agonists for group II (mGlu(2/3)) receptors and antagonists for group I (in particular mGlu(5)) receptors have shown activity in animal and/or human conditions of fear, anxiety or stress. These studies indicate that metabotropic glutamate receptors are interesting new targets to treat anxiety disorders in humans.     

The group II metabotropic glutamate receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) and clozapine reverse phencyclidine-induced behaviors in monoamine-depleted rats

Recent studies have indicated that the selective group II metabotropic glutamate (mGlu) receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) shares common biochemical and pharmacological effects with the atypical antipsychotic clozapine. The present study aimed to further investigate these similarities (or differences) in monoamine-depleted animals by using the phencyclidine (PCP) model. Animals were pretreated 24 h before PCP administration with (i.p.) vehicle, alpha-methyl-DL-p-tyrosine methyl ester (alpha-MPT; 400 mg/kg), or DL-p-chlorophenyl-alanine methyl ester (PCPA; 300 mg/kg) injections. alpha-MPT and PCPA pretreatment significantly and selectively reduced catecholamine (dopamine and norepinepherine) or 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxyindoleacetic acid levels, respectively, in whole brain tissue. Both LY379268 and clozapine (s.c.) blocked PCP-evoked ambulatory activity and fine movements in control, alpha-MPT-, and PCPA-treated animals. In contrast, the typical antipsychotic haloperidol (s.c.) attenuated PCP behaviors in control and PCPA-pretreated animals, but was without effect in subjects pretreated with alpha-MPT. The alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/kainate-selective antagonist (3S,4aR,6R,8aR)-6-[2-(1(2)OH-tetrazole-6-yl)ethyl]decahydroisoquinoline-3-carboxylic acid (LY293558) attenuated locomotor activity in alpha-MPT-treated animals only, whereas the 5-HT(2A/2C)-selective antagonist ketanserin was effective at reducing ambulations and fine movements in control and alpha-MPT-treated animals. Taken together, these data indicate an important role for glutamatergic and serotonergic mechanisms for PCP-evoked behaviors in catecholamine-depleted animals and suggest that like clozapine, LY379268 is more effective than typical antipsychotics in these models. This study further supports the potential use of group II mGlu agonists as novel therapeutic agents in the treatment of schizophrenia.     

(S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord

(S)-3,4-Dicarboxyphenylglycine (DCPG) has been tested on cloned human mGlu1-8 receptors individually expressed in AV12-664 cells co-expressing a rat glutamate/aspartate transporter and shown to be a potent and selective mGlu8a receptor agonist (EC(50) value 31+/-2 nM, n=3) with weaker effects on the other cloned mGlu receptors (EC(50) or IC(50) values >3.5 microM on mGlu1-7).Electrophysiological characterisation on the neonatal rat spinal cord preparation revealed that (S)-3,4-DCPG depressed the fast component of the dorsal root-evoked ventral root potential (fDR-VRP) giving a biphasic concentration-response curve showing EC(50) values of 1.3+/-0.2 microM (n=17) and 391+/-81 microM (n=17) for the higher and lower affinity components, respectively. The receptor mediating the high-affinity component was antagonised by 200 microM (S)-alpha-methyl-2-amino-4-phosphonobutyrate (MAP4, K(D) value 5.4+/-1.5 microM (n=3)), a group III metabotropic glutamate (mGlu) receptor antagonist. The alpha-methyl substituted analogue of (S)-3,4-DCPG, (RS)-3,4-MDCPG (100 microM), antagonised the effects of (S)-3,4-DCPG (K(D) value 5.0+/-0.4 microM, n=3) in a similar manner to MAP4. (S)-3,4-DCPG-induced depressions of the fDR-VRP in the low-affinity range of the concentration-response curve were potentiated by 200 microM (S)-alpha-ethylglutamate (EGLU), a group II mGlu receptor antagonist, and were relatively unaffected by MAP4 (200 microM). However, depressions of the fDR-VRP mediated by the AMPA selective antagonist (R)-3,4-DCPG were not potentiated by EGLU, suggesting that the low-affinity component of the concentration-response curve for (S)-3,4-DCPG is not due to antagonism of postsynaptic AMPA receptors. It is suggested that the receptor responsible for mediating the high-affinity component is mGlu8. The receptor responsible for mediating the low-affinity effect of (S)-3,4-DCPG has yet to be identified but it is unlikely to be one of the known mGlu receptors present on primary afferent terminals or an ionotropic glutamate receptor of the AMPA or NMDA subtype.     

Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

The potent metabotropic glutamate (mGlu) receptor agonist, LY379268, selectively activates mGlu2/3 receptors with EC50 values in the low nanomolar range. We have previously shown in rats that LY379268 reverses phencyclidine (PCP)-induced motor activations (increases in ambulations and fine movements, and decreases in the animals time at rest). Here, we have investigated: (1) the dose-response and time course for this action of LY379268 following oral (p.o.) administration and (2) the therapeutic index in this model following acute versus subchronic (4 days) p.o. dosing. LY379268 (3 mg/kg p.o.) evoked a maximal effect on PCP (5 mg/kg s.c.)-elicited behaviors 4 h post-dosing. At this time point, p.o. LY379268 inhibited the effects on PCP-elicited activities with a similar potency (ED50 values ca 1 mg/kg) to that previously obtained following s.c. administration. Doses up to 3 mg/kg p.o. LY379268 were without effect on the rotorod performance of rats when measured at 1, 2, 4, 8, and 24 h post-administration. In agreement with the peak time-effect on PCP-evoked motor behaviors, 10 mg/kg p.o. LY379268 only significantly impaired rotorod performance at the 4-h time point. Interestingly, acute motor impairment produced by higher doses of LY379268 (10, 30, or 100 mg/kg p.o.) was absent following 4-day repeated administration of LY379268. In contrast, the potency of LY379268 for the inhibition of PCP-evoked motor activities was not affected following multiple dosing over a similar period. These results demonstrate that although the reduction of PCP motor activities by LY379268 is maintained after subchronic dosing, tolerance to the motor impairment evoked by the compound occurs, thus greatly widening the therapeutic index of LY379268.     

B7-1和IL-12基因转染对肝癌细胞免疫原性的影响

目的 观察Ｂ７－１和ＩＬ－１２基因表达对人肝癌细胞免疫原性原影响。方法 分别将Ｂ７－１和ＩＬ－１２基因以逆转录病毒介导转染ＨｅｐＧ２细胞。阳性克隆细胞与健康人外周血淋巴细胞（ＰＢＬ）混合培养后,用流式细胞仪检测ＰＢＬ表面Ⅰ类人白细胞抗原（ＨＬＡ－Ⅰ）分子表达,以ＭＴＴ法检测ＰＢＬ的特异性杀伤活性Ｋ５６２细胞的活性。结果 混合ＨｅｐＧ２／Ｂ７－１ＨｅｐＧ２／ＩＬ－１２细胞组ＰＢＬ表面的ＨＬＡ－Ⅰ分子     

Handgrip strength in English schoolchildren

Aims: The aims of this study were to evaluate patterns of handgrip (HG) strength in relation to gender and age in English schoolchildren and to compare this with existing data and produce reference data for this population. Methods: The HG of 7147 English schoolchildren (3773 boys and 3374 girls) aged 10–15.9 years was measured using a portable Takei handgrip dynamometer (Takei Scientific Instruments Co. Ltd, Tokyo, Japan). Centile data were produced using the Generalized Additive Models for Location, Scale and Shape. Z‐scores were generated using existing data for European children. Age and gender interactions were analysed using analysis of covariance. Results: In boys and girls, significant increases in HG were found between every age‐group (p < 0.001). Boys were significantly stronger than girls at every age (p < 0.001) and the boys’ age‐related increase was significantly greater than the girls’ (p < 0.001). Conclusion: This study provides reference data for handgrip strength in English schoolchildren. Handgrip strength in English children is broadly similar to existing European data, after adjusting for mass and stature. These data could be used for clinical or athletic screening of low and high strength in this population.     

Endothelium enhances tachyphylaxis to angiotensins II and III in rat aorta

Development of tachyphylaxis to angiotensin-induced contraction was compared in rings of rat aorta with and without functional endothelium. Rat aorta with functional endothelium rapidly developed marked tachyphylaxis to contraction induced by angiotensin II or angiotensin III. Destruction of endothelium significantly depressed, but did not prevent, development of tachyphylaxis to contractile responses induced by repeated exposure to angiotensin II or angiotensin III. The findings suggest that two mechanisms are involved in the development of tachyphylaxis to angiotensin in rat aorta, an endothelium-dependent mechanism and an endothelium-independent mechanism.     

Mammographic findings after breast cancer treatment with local excision and definitive irradiation

Following local excision and definitive irradiation of 163 breast cancers in 160 women, alterations in mammographic patterns were observed for up to 7 years. Skin thickening was observed in 96% of mammograms obtained within 1 year of completing therapy and was most pronounced in women treated with iridium implant, chemotherapy, or axillary dissection. In 76% of mammograms, alterations in the parenchymal pattern, including coarsening of stroma and increased breast density, were seen at 1 year. Neither skin nor parenchymal changes progressed after 1 year. Within 3 years of treatment the parenchymal density, which usually regressed, did not change in all patients. At 3 years skin thickness and the parenchymal pattern had returned to normal in less than 50% of the breasts of these women. Scars developed in approximately one-quarter of women. They were present on the initial post-treatment mammogram and remained unchanged on serial studies. Coarse, benign calcifications also developed in the breasts of about one-quarter of women. Microcalcifications developed in 11 breasts; biopsy specimens of six were benign. Benign microcalcifications may be related to therapy.     

Liver metastases: detection by phase-contrast MR imaging

Forty patients with biopsy-proved metastatic liver cancers were studied by magnetic resonance (MR) imaging using one or more conventional (in-phase) pulse sequences and a corresponding phase-contrast (opposed-phase) pulse sequence. Pulse-sequence performance was quantitated by measuring signal-difference-to-noise (SD/N) ratios between cancerous tissue and liver. The SD/N performance of T2-weighted spin-echo (SE) pulse sequences improved when used with the phase-contrast technique. SE 2,000/30 opposed-phase images showed improved (P less than .001) SD/N in 72% of patients over in-phase images. The SD/N of T1-weighted SE or inversion recovery pulse sequences deteriorated when used with the phase-contrast technique. Changes in measured SD/N correlated well with image appearance and actual lesion detectability in individual cases. Phase-contrast imaging should be employed routinely when T2-weighted SE pulse sequences are relied on to detect liver cancer.