Somatostatin,a Presynaptic Modulator of Glutamatergic Signal in the Central Nervous System

Somatostatin is widely diffused in the central nervous system, where it participates to control the efficiency of synaptic transmission. This peptide mainly colocalizes with GABA, in inhibitory, GABA-containing interneurons from which it is actively released in a Ca²⁺ dependent manner upon application of depolarizing stimuli. Once released in the synaptic cleft, somatostatin acts locally, or it diffuses in the extracellular space through “volume diffusion”, a mechanism(s) of distribution which mainly operates in the cerebrospinal fluid and that assures the progression of neuronal signalling from signal-secreting sender structures towards receptor-expressing targeted neurons located extrasynaptically, in a non-synaptic, inter-neuronal form of communication. Somatostatin controls the efficiency of central glutamate transmission by either modulating presynaptically the glutamate exocytosis or by metamodulating the activity of glutamate receptors colocalized and functionally coupled with somatostatin receptors in selected subpopulations of nerve terminals. Deciphering the role of somatostatin in the mechanisms of “volume diffusion” and in the “receptor-receptor interaction” unveils new perspectives in the central role of this fine tuner of synaptic strength, paving the road to new therapeutic approaches for the cure of central disorders.     

Alterations of regional cerebral blood flow after NMDA receptor antagonist administration in patients with alcohol‐related dementia

Although N‐methyl‐d ‐aspartate (NMDA) receptor antagonists may have beneficial influences on cognition in patients with alcohol‐related dementia (ARD), their effects on regional cerebral blood flow (rCBF) remain unknown. This study evaluated changes in rCBF in ARD patients after administration of NMDA receptor antagonist for 12 weeks using technetium‐99m ethyl cysteinate dimer (Tc‐99m ECD) single‐photon emission computed tomography (SPECT). Twenty‐eight ARD patients were administered memantine for 12 weeks and underwent clinical evaluations and brain SPECT scans at baseline and follow‐up. Whole‐brain changes in perfusion were examined on a voxel‐by‐voxel basis. At follow‐up, the patients showed reduced rCBF in the left medial frontal gyrus, left cingulate gyrus, left claustrum, right brainstem, left superior temporal gyrus, bilateral fusiform gyrus, and left cerebellum. On the other hand, increased rCBF was found in the bilateral uncus, left parahippocampal gyrus, bilateral superior frontal gyrus, right inferior parietal lobule, left cuneus, and left superior temporal gyrus. Perfusion increases in various brain areas including the superior frontal, parahippocampal, and inferior parietal areas, which may play important roles in the pathophysiology of ARD, suggest potential benefits of NMDA receptor antagonists on brain functions in patients with ARD.     

Mating activates NMDA receptors in the medial preoptic area of male rats.

Studies have emphasized the role of the medial preoptic area (MPOA) as an important site for the regulation of male sexual behavior. Indeed, ablations of the MPOA impair sexual behavior, whereas stimulation of the MPOA enhances behavior. Furthermore, neural activity in the MPOA increases with mating. The current study tested the hypothesis that activation of N-methyl-D-aspartate (NMDA) receptors occurs in MPOA neurons and is essential for the expression of male sexual behavior in rats. Results indicate that nearly all MPOA neurons that expressed Fos following mating also contained the NR1 subunit of NMDA receptors. Furthermore, mating increased phosphorylation, thus activation, of NR1 in the MPOA. Additionally, blocking NMDA receptors significantly decreased mating-induced Fos expression and mating-induced phosphorylation of NMDA receptors and impaired male sexual behavior. These results provide evidence that mating activates NMDA receptors in the MPOA and that this activation is important for the expression of male sexual behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

外周NMDA受体在疼痛发生及药物干预中的作用

NMDA(N-甲酰-D 天门冬氨酸)受体是一种离子型谷氨酸受体, 广泛存在于外周躯体或内脏的痛觉传导通路上。外周NMDA 受体的活化或表达的改变与疼痛发生发展密切相关, 外周局部使用NMDA 受体拮抗剂可有效缓解或预防疼痛, 并能增加阿片类药物的镇痛效果, 此种用药方式可减少药物作用于中枢神经系统所导致的副作用, 是今后疼痛治疗研究的重要方向。     

Neural bistability and amplification mediated by NMDA receptors: Analysis of stationary equations

The macroscopic current/voltage relationship of NMDA receptor ion channels is nonmonotonic under physiological conditions, which can give rise to bistable and amplifying/facilitatory behavior in neurons and neural structures, supporting significant computational primitives. Conditions under which bistable regimes of operation prevail, and also general amplifying properties associated with active NMDA receptors, are examined in a single compartment enclosed by a cell membrane, and subsequently in cable-like dendrites under varying boundary conditions. Methodology consists of numerical and mathematical analyses of stationary versions of equations governing the electrical behavior of these systems. Bistability mediated by NMDA receptors requires interaction with other conductances in the membrane or cytoplasm, with particular importance attached to membrane potassium conductance, especially that of inward-rectifying potassium channels. A corollary conclusion is that coactivation of GABA_B synaptic receptors or SK channels is a computationally powerful and sometimes necessary adjunct condition for NMDA receptor-mediated bistability. Neural multistability due to dendritic bistability is considered, including the case of closely coupled dendrites. The characteristics of coactivation-dependent facilitation, and amplifying states in which NMDA receptor activation boosts the efficacy of other classes of synapses, are also described. Coactive inward-rectifying potassium channels are found to significantly affect the characteristics of such amplification.     

Blockade of NMDA receptors 2A subunit in the dorsal striatum impairs the learning of a complex motor skill.

Accumulating evidence proposes that the striatum, known to control voluntary movement, may also play a role in learning and memory. Striatum learning is thought to require long-lasting reorganization of striatal circuits and changes in the strength of synaptic connections during the memorization of a complex motor task. Whether the ionotropic glutamate receptor N-methyl-D-aspartate (NMDAR) contributes to the molecular mechanisms of these memory processes is still unclear. The aim of the present study was to investigate the role of striatal NMDAR and its subunit composition during the learning of the accelerating rotarod task in mice. To this end, we injected directly into the dorsal striatum of mice, via chronically implanted cannula, the NMDAR channel blocker MK-801 as well as the NR2A and NR2B subunit-selective antagonists NVP-AAM077 and Ro 25-6981, respectively, before rotarod training. There was no effect in the motor performances of mice treated with 1.0 μg/side of MK-801, 0.1 μg/side of NVP-AAM077, or 5 and 10 μg/side of Ro 25-6981. In contrast, injections of 2.5 and 5 μg/side of MK-801 or 0.5 and 1 μg/side of NVP-AAM077 impaired motor learning at Day 3 and 8. Interestingly, treatments with MK-801 and NVP-AAM077 did not alter the general motor capacities of mice as revealed by the stepping, wire suspension, and pole tests. Our study demonstrates that the NMDAR of the dorsal striatum contributes to motor learning, especially during the slow acquisition phase, and that NR2A subunits play a critical role in this process. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

The effects of NMDA lesions centered on the postrhinal cortex on spatial memory tasks in the rat.

Rats with bilateral N-methyl-D-aspartate lesions centered on the postrhinal cortex (POR) and sham lesions were tested in a series of spatial memory tasks. The POR-lesioned rats were significantly impaired compared with sham rats in the reference memory version of both the water maze and radial arm maze tasks and in the standard radial arm maze working memory task. The POR-lesioned rats displayed a delay-independent impairment in the working memory versions of the water maze and in a delayed nonmatching-to-place (DNMP) version of the radial arm maze task. The POR-lesioned rats were also impaired in a DNMP procedure conducted in the T-maze. These findings indicate that the POR has a delay-independent role in the processing of spatial information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA receptor antagonists impair memory for nonspatial, socially transmitted food preference.

Rats avoid unfamiliar foods and learn to prefer those that they smell on the breath of conspecifics. Hippocampal lesions produce rapid forgetting of this socially acquired memory. The authors report that NMDA receptor antagonists impair this memory. Rats given CPP were trained in the social transmission of food preference task. Normal rats showed robust memory 72 hr later. CPP-injected rats performed normally 24 hr, but randomly 72 hr, after training. Spatial context was irrelevant: Rats trained and tested in different rooms performed the same as rats trained and tested in 1 room. MK801 and intrahippocampal injections of APV produced amnestic effects similar to CPP. Thus, NMDA receptor activation is crucial for the persistence of socially acquired, hippocampus-dependent, nonspatial memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Towards Quantum-Chemical Modeling of the Activity of Anesthetic Compounds

The modeling of the activity of anesthetics is a real challenge because of their unique electronic and structural characteristics. Microscopic approaches relevant to the typical features of these systems have been developed based on the advancements in the theory of intermolecular interactions. By stressing the quantum chemical point of view, here, we review the advances in the field highlighting differences and similarities among the chemicals within this group. The binding of the anesthetics to their partners has been analyzed by Symmetry-Adapted Perturbation Theory to provide insight into the nature of the interaction and the modeling of the adducts/complexes allows us to rationalize their anesthetic properties. A new approach in the frame of microtubule concept and the importance of lipid rafts and channels in membranes is also discussed.