Glutamate receptors in the central nervous system

A lot of clinical processes following excessive stimulation of glutamate receptors seem to participate in pathophysiology of numerous acute and chronic neurological disorders. The whole of these reactions has been named as "glutamate cascade", because of the central role of glutamate in initiation and intensification of these processes. In this article, classification of different types of glutamate receptors and several hypotheses concerning mechanisms of glutamate neurotoxic activity are presented. A wide variety of neurological diseases, which etiologies are more or less connected with glutamate toxicity are discussed. At last, the future perspectives for treatment by drugs which action is thought to be mediated through glutamate receptors are presented.     

Vasopressin and oxytocin receptors in the central nervous system

This review concentrates on the pharmacological properties and the regional distribution of the arginine vasopressin (AVP) and oxytocin (OT) receptors that are present in the central nervous system. Of particular interest are the kinetics and the pharmacological profiles of these receptors that resemble those present at the periphery. However, their transduction mechanisms need to be further investigated. This should be rendered easier by molecular biology technology. The current knowledge of the anatomical distribution of AVP and OT receptors in the brain is reviewed. Also of great interest for double labeling studies will be the receptor antibodies, now being developed. The existence of additional receptors (AVP4-9) is examined, and aspects of the regulation of the receptors' expression in relation to the age, the species, and the hormonal status or following injury are also discussed.     

Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system

Three subtypes of the alpha 2-adrenoceptor have been characterized. The drugs currently available which most specifically activate (e.g. dexmedetomidine) or antagonize alpha 2-receptors (e.g. atipamezole, idazoxan) do not show significant differences in their affinities for the subtypes. The drugs which do show some subtype selectivity (oxymetazoline for alpha 2A; prazosin for alpha 2B and alpha 2C) are not useful for in vivo pharmacology due to their relative nonspecificity in binding to other receptors (e.g. alpha 1-adrenoceptors). By examining the distribution of the mRNA coding for the three subtypes, it has been possible to map those regions in the brain which possess cells which synthetize the distinct subtypes. The mRNA coding for alpha 2A receptors is found throughout the brain, especially in locus coeruleus, a region which contains the cell bodies for the ascending and descending noradrenergic neurones. The mRNA for alpha 2B receptors was only found in thalamus. The alpha 2C mRNA had a wider distribution, in basal ganglia its expression was particularly intense. One must hope that the fact that the receptor subtypes are not uniformly distributed throughout the brain means that new subtype selective drugs will not suffer from the same broad diversity of actions of the present alpha 2-agonists and antagonists.     

Pharmacological modulation of glucocorticoid and mineralocorticoid receptors in the rat central nervous system

Hypnosis is not a therapy, but can provide the clinician with a set of techniques which may be used to augment or facilitate a particular course of treatment. The importance of the patient's history and clinical findings in the diagnosis of intolerance to dentures and the selection of patients for hypnosis is discussed. Principles of treatment using relaxation, anxiety control, conditioning/desensitisation and confidence boosting techniques are described. Some examples of typical case histories are used to illustrate the application of a variety of techniques that have been found to be successful.     

Current excitation threshold in sensory neurons of leech central nervous system

1. The sensory neurons in the leech central nervous system differ in their accommodation to linearly rising currents. Advantage was taken of these differences to study the ionic mechanism of accommodation in single pairs of N (noxious), P (pressure), and T (touch) cells. 2. Nonlinearities in membrane-potential changes and current-voltage relationships with square-wave and ramp currents are more pronounced in P and T cells than in N cells. The accommodation coefficients increase in conditions that reflect this delayed rectification. When rectification is absent, the accommodation coefficients depart from unity only slightly or not at all. 3. Accommodation coefficients remain unchanged when half of the chloride in the bathing medium is replaced by sulfate. Accommodation coefficients become greater when the extracellular potassium concentration is reduced from 4 to 0 mM, and decrease when the concentration is raised to 8 mM. The membrane potential changes by only a few millivolts. 4. As extracellular potassium concentration is increased, the action potential is lengthened and the maximal rate of fall of the action potential is reduced. With concentrations greater than 4 mM these relationships are linear, but depart from linearity at lower concentrations. The amplitude of the undershoot decreases linearly as the extracellular potassium concentration increases from 4 to 16 mM, and increases non-linearly at concentrations below 4 mM. 5. The rapid accommodation of leech neurons is based primarily on an increased potassium conductance. The possibility is considered that concentration changes like those produced experimentally may occur naturally, affecting integrative processes in the central nervous system.     

Excitation of central nervous system neurons by nonuniform electric fields

The goal of this study was to determine which neural elements are excited by microstimulation of the central nervous system. A cable model of a neuron including an axon, initial segment, axon hillock, soma, and simplified dendritic tree was used to study excitation with an extracellular point source electrode. The model reproduced a wide range of experimentally documented extracellular excitation patterns. The site of action potential initiation (API) was a function of the electrode position, stimulus duration, and stimulus polarity. The axon or initial segment was always the site of API at threshold. When the electrode was positioned near the cell body, the site of excitation was dependent on the stimulus amplitude. With the electrode in close proximity to the neuron, short-duration cathodic pulses produced lower thresholds with the electrode positioned over the axon than over the cell body, and long-duration stimuli produced opposite relative thresholds. This result was robust to alterations in either the maximum conductances or the intracellular resistivities of the model. The site of maximum depolarization was not always an accurate predictor of the site of API, and the temporal evolution of the changes in membrane potential played a strong role in determining the site of excitation.     

Met-enkephalin Arg-Phe-immunoreactive neurons in the central nervous system of the pond snail Lymnaea stagnalis

The distribution of an opioid peptide related to YGGFMRF was determined in the CNS and other organs of the pond snail, Lymnaea stagnalis, by RIA and immunocytochemistry. RIA revealed the highest levels in the CNS (1 pmol/organ) and penis (400 fmol/organ). There were also significant levels in the haemolymph, most of which was not associated with haemocytes (580 fmol/ml). Both serial section and whole-mount immunocytochemistry of the CNS revealed immunoreactive cells in every ganglion with the majority in the cerebral and pedal ganglia. In the pedal ganglia some of the immunoreactive cells were close to the cells of the A-cluster, which are known to respond to opioids, and could innervate them. In the cerebral ganglia the immunoreactive cells included a group of neurosecretory cells, the caudo dorsal cells (CDCs) and the terminals of these cells in the cerebral commissure were also stained. The CDCs secrete peptides into the haemolymph and so could be the source of the YGGFMRF immunoreactivity. Immunoreactivity (including the CDCs) was observed in locations that correspond to those reported for other fragments of proenkephalin, such as Met- and Leu-enkephalin, suggesting that they may share a common precursor, a Lymnaea proenkephalin. A map of the 358 YGGFMRF-immunoreactive cells in the CNS is presented, many of which have not been previously identified.     

1,25-Dihydroxyvitamin D3 receptors in the central nervous system of the rat embryo

The major aim was to identify predictors of the large age differences that exist in eyeblink classical conditioning. Eyeblink conditioning was assessed in 190 participants over the age range of 20-89 years, with 150 trained in the paired condition and 40 trained in the explicitly unpaired control condition. Timed-interval tapping was used to assess cerebellar function. Blink reaction time and explicit learning and memory were also assessed. Stepwise multiple regression indicated that the effect of age accounted for the largest proportion of the variance, but the cerebellar measure also predicted eyeblink conditioning at a significant level. Reaction time and explicit memory measures did not account for a significant amount of the variance in eyeblink conditioning. Age-related effects in the cerebellum apparently affect timing and learning in normal adults.     

Distribution of NADPH diaphorase-positive neurons in the enteric nervous system of the rabbit intestine

Although insulin has been shown to raise plasma concentrations of endothelin (ET) and up regulate vascular smooth muscle ETA receptor expression, the interaction of vanadate, an insulinomimetic agent, with the vascular ET system has not been investigated. We compared the effects of oral vanadate treatment (0.5 mg/ml; p.o.) and insulin infusion (12 mU.kg-1.min-1 s.c.) for two weeks on plasma ET concentrations and vascular responses to endothelin-1 (ET-1) and the alpha-1 adrenoceptor agonist, methoxamine, in aortic ring preparations from streptozotocin (STZ) diabetic and non-diabetic adult male Sprague-Dawley rats. Plasma ET concentrations were lower (p < 0.01) in STZ diabetic rats compared with normal control rats. Insulin and vanadate treatment restored plasma ET to normal (p < 0.01) in STZ rats and increased ET concentrations in the control (p < 0.05) group. Higher maximal tension responses to both ET-1 (p < 0.01) and methoxamine (p < 0.05) were present in STZ rats in both endothelium intact and denuded aortic preparations compared with the control group. Both insulin and vanadate treatment returned these responses to normal. It is concluded that low plasma concentrations of insulin and high plasma glucose in STZ diabetic rats are accompanied by lower concentrations of plasma ET. Insulin and vanadate treatment restores diminished plasma ET to control concentrations and attenuates exaggerated agonist(s)-evoked vascular smooth muscle responses in STZ-induced diabetic rats. In addition to well known beneficial metabolic effects, insulin and vanadate may beneficially affect cardiovascular regulation in the STZ diabetic rat by correcting abnormal ET activity.     

Cyclooxygenases and the central nervous system

Prostaglandins (PGs) were first described in the brain by Samuelsson over 30 years ago (Samuelsson, 1964). Since then a large number of studies have shown that PGs are formed in regions of the brain and spinal cord in response to a variety of stimuli. The recent identification of two forms of cyclooxygenase (COX; Kujubu et al., 1991; Xie et al., 1991; Smith and DeWitt, 1996), both of which are expressed in the brain, along with superior tools for mapping COX distribution, has spurred a resurgence of interest in the role of PGs in the central nervous system (CNS). In this review we will describe new data in this area, focusing on the distribution and potential role of the COX isoforms in brain function and disease.     

Aging and the central nervous system

This review of the literature on aging and the central nervous system attempts to cover the basic perameters investigated at both human and infrahuman levels for the better part of the last century. The results have indicated that there is a rather considerable lack of consistency in the data both within the frame of reference of a single species, and with regard to intraspecies comparisons. We have suggested that possible reasons for the contradictory findings would rest upon variability in techniques employed but, perhaps more importantly, on the failure of investigators in this area to standardize terminology. It is suggested that such a standardization might well be one of the more useful things to be accomplished in order to facilitate the interpretation of future work. The literature review first dealt with gross, i.e., macroscopic changes in brain morphology that could correlate with age, and then covered changes at the microscopic level. Finally, a brief review of the literature with regard to the biochemistry of aging was carried out. Implications of the data were noted where appropriate.     

Cytokines and their receptors in the central nervous system: physiology, pharmacology, and pathology

Rapid advances in molecular technology have led to the identification of many genes responsible for inherited disease in ophthalmology. These discoveries also portend an understanding of the pathogenesis of more common ophthalmic disorders which have a genetic component, such as open-angle glaucoma and age-related macular degeneration. This review comprises a summary of these advances in molecular genetics, particularly the contribution of the Human Genome Project; a tabulation of the genes recently proven to be mutated in hereditary ocular conditions; and a discussion of the implications for the practising ophthalmologist.     

Remyelination of the central nervous system

The three typical stages in the clinical course of multiple sclerosis (relapse, persistent disability and progression) can be explained on the basis of inflammation, demyelination and failure of repair leading to axon degeneration and astrocytosis. Strategies are being evaluated for limiting the inflammatory process using immunological treatments and these may have unexpected dividends in promoting endogenous remyelination. Increasing knowledge on glial lineages and axon-glial interactions needed for stable myelination also offer the prospect for enhancing remyelination through growth factor therapy and cell implantation.     

Tumors of the central nervous system

Neoplasia of the central nervous system (CNS) can be divided into two main categories: nonpituitary CNS neoplasia and pituitary adenomas. Nonpituitary CNS neoplasias are generally compressive in nature, although some are also invasive. The majority of reported CNS tumors are secondary with only a few originating from nervous tissue. Pituitary adenomas predominantly occur in the pars intermedia of the older horse. Clinical signs, diagnostic testing, and possible treatments are discussed.     

The angiotensinogen gene is expressed in both astrocytes and neurons in murine central nervous system

Two transgenic mouse models were used to examine the cellular localization of angiotensinogen (AGT) in the brain. The first model was previously described in detail and consists of a human AGT genomic transgene containing all exons and introns of the gene and 1. 2 kb of the 5' flanking DNA. The second model contains a fusion between 1.2 kb of HAGT 5' flanking DNA and the beta-gal reporter gene which exhibits a similar pattern of tissue-specific expression to the HAGT transgene. Expression of both transgenes qualitatively mirrors the expression of endogenous AGT. Double staining of transgenic mouse brain sections with X-gal and GFAP revealed that a majority of beta-gal activity was localized to astrocytes in almost all brain areas. However, both beta-gal activity as identified by X-gal, and HAGT mRNA as detected by in situ hybridization, were also found in neurons in restricted areas of the brain, including the mesencephalic trigeminal nucleus (meV), subfornical organ (SFO) and the external lateral parabrachial nucleus (elPB). The expression of these transgenes provides the first convincing evidence for AGT gene expression in neurons in the brain. We further report by angiotensin II (Ang-II) immunostaining in rat brains after selective lesioning, that Ang-II is likely involved in a neuronal pathway from the PB to the amygdala (Ce). Finally, we performed double-labeling, first by retrograde labeling of HRP injected into the Ce, and then by X-gal on PB neurons in beta-gal transgenic mice, and identified doubly labeled neurons. Based on these results, we propose that AGT is generated in neurons in the elPB, transported to the Ce and converted into Ang-II locally to exert is biological functions.