Showing papers in "International Review of Neurobiology in 1983"

Characterization of alpha 1- and alpha 2-adrenergic receptors.

Abstract: Publisher Summary Alpha-1 (α1) receptors by and large appear to occur in a single-affinity state with respect to both agonists and antagonists. By comparison, α2 receptors may exist in multiple-affinity states reflecting the ability of the α2 binding-site protein to form a complex with additional membrane proteins that themselves are receptors for the physiological substrates guanosine 5'-triphosphate (GTP), Na+, Mg2+, and possibly Ca2+-calmodulin. Binding studies have also strongly indicated that α2 receptors in most, if not all, tissues are probably coupled in an inhibitory manner to adenylate cyclase, as has been demonstrated in platelets, adipocytes, and NG 108-15 cells. Nothing is known about the mechanisms of regulation of α1 receptors, although both up- and down-regulations of α1 receptor have been demonstrated. In this regard, the ability to label and study α1 receptors on cells in culture would be particularly useful. With regard to α2 receptors, the number of affinity states that exist and their role in terms of the kinetics of α2-receptor coupling to adenylate cyclase are still not clear.

Biochemical and Electrophysiological Characteristics of Mammalian Gaba Receptors

Abstract: Publisher Summary The identification of γ-aminobutyric acid (GABA) in the vertebrate central nervous system was made by Roberts and Frankel, Udenfriend, and Awapara. In the succeeding 30 years, data have accumulated to suggest that this amino acid may serve as one of the more important neurotransmitters in mammalian brain and spinal cord. While early work concentrated on characterizing the manner in which this substance is synthesized, catabolized, stored, released, and accumulated in brain tissue, in more recent years there has been a shift in emphasis to identifying and defining the synaptic receptor sites for GABA. There was skepticism about a neurotransmitter role for GABA prior to the discovery of agents capable of antagonizing, relatively specifically, the electrophysiological effects of this substance. During the past decade, the tempo of research on GABA transmission has increased dramatically. Evidence has been found to link alterations in GABA function with the symptoms of a variety of neuropsychiatric disorders. Discoveries have been made implicating GABA and its receptors in the mechanism of action of a variety of clinically effective agents, such as anxiolytics, hypnotics, muscle relaxants, and anticonvulsants. Knowledge in this area has advanced to a stage where it is now possible to design drugs that will rather selectively modify the GABA system. Many of these agents are currently undergoing clinical trials. This chapter discusses the results of recent biochemical and electrophysiological studies directed toward characterizing GABA receptors. Because of the rapid developments in this field, the chapter focuses on highlighting and discussing topics that represent some of the more exciting advances in this area.

Pharmacology of Barbiturates: Electrophysiological and Neurochemical Studies

Abstract: Publisher Summary Barbituric acid was first synthesized by Baeyer in 1864, and this date marks the birth of an era that has witnessed the production of over 2,500 derivatives. The first barbiturate introduced into clinical medicine was barbital—a long-acting sedative-hypnotic agent. Phenobarbital was marketed in 1912 for use in the treatment of certain forms of epilepsy. The use of ultra-short-acting barbiturates as intravenous anesthetics began in the early 1930s, and thiopental, in particular, gained rapid popularity following its introduction in 1935. While many of the sedative-hypnotic barbiturates have been superseded following the discovery of the benzodiazepines, barbiturates still maintain an important role in therapeutics, especially in their use as anesthetics and antiepileptics. The molecular structure of many of the barbiturates and the effects of barbiturates on neuronal systems in vertebrate species are discussed in this chapter.

On the Sacred Disease: The Neurochemistry of Epilepsy

Abstract: Publisher Summary Scientists have been in search of Hippocrates' natural cause of epilepsy, the sacred disease, for centuries. Experimental work in the neurophysiology of epilepsy was initiated late in the nineteenth and early in the twentieth century. The suggestion that inhibitory mechanisms play a major role in the pathogenesis of seizures was put forth by Adrian in 1936. In 1954, Florey provided the first evidence for a neurochemical mechanism for this inhibition with the demonstration of an inhibitory (I) factor in brain extract that proved to be inhibitory to crayfish stretch receptors. Florey's I factor was subsequently identified as γ-aminobutyric acid (GABA)—a compound now generally acknowledged to be a major inhibitory neurotransmitter in the brain. Since the classic paper of Symonds on excitation and inhibition in epilepsy, the various research strategies in this group of diseases have focused more and more on basic excitatory and inhibitory mechanisms in seizures on a cellular as well as a whole-brain level. To understand the complex neurochemistry of seizure states, it is first necessary to define precisely the meaning of the terms “seizure” and “epilepsy” and review the neurophysiology of these aberrant neuronal systems. This chapter discusses various animal models of seizures and reviews the neurochemistry of epilepsy in the context of neurotransmitters and neuroactive agents in animal models, anticonvulsant drug interaction, and the clinical seizure state.

Recent developments in the structure and function of the acetylcholine receptor.

Abstract: Publisher Summary This chapter discusses recent advances in some areas of research on the nicotinic acetylcholine receptor (AChR) Emphasis is put on the structure and dynamics of the AChR in the membrane, the correlation of structure with the ion-gating properties as assessed by electrical or flux measurements, and the influence of nonreceptor proteins on AChR properties Crude or purified, membrane-bound or detergent-solubilized AChR can be reduced to a minimal molecular form upon cleavage of disulfide bonds by reducing agents In the absence of reducing agents, higher oligomeric species can be directly visualized in the native membrane The AChR from Torpedo species is at present the most extensively characterized case The Torpedo AChR channel is voltage-insensitive, and it responds to cholinergic agonists in a manner similar to that of the neuromuscular junction

Synaptic Mechanisms and Circuitry Involved in Motoneuron Control During Sleep

Abstract: Spontaneous amplitude fluctuations of the brainstem monosynaptic trigeminal jaw-closing reflex were examined in the freely moving chronic cat during wakefulness, quiet sleep, and active sleep. The largest amplitude responses occurred during active wakefulness; they decreased in size during quiet sleep. The lowest amplitude responses occurred during active sleep. A chronic cat preparation was developed in order to record intracellularly from identified trigeminal motoneurons for prolonged period of time throughout the states of sleep and wakefulness. The membrane potential of trigeminal motoneurons exhibited fluctuations that were correlated with changes in the animal's behavioral state. The fundamental pattern consisted of (a) slight hyperpolarization during quiet sleep, compared to arousal or alert wakefulness, (b) little if any hyperpolarization during quiet sleep compared to quiet wakefulness, and (c) dramatic hyperpolarization when active sleep was compared to quiet sleep. Sustained spike activity of trigeminal motoneurons, when present during wakefulness, decreased in frequency or tended to occur in bursts when the animal was in quiet sleep. During active sleep, activity ceased except for a few isolated spikes or short-duration bursts of action potentials. Based on an analysis of antidromically induced spike potentials and monosynaptically induced postsynaptic potentials, it was concluded that postsynaptic inhibition of trigeminal motoneurons during active sleep acts to suppress somatic reflex activity and produce muscular atonia. A companion study of the membrane potential of lumbar motoneurons in the chronic, unanesthetized, undrugged, normally respiring cat was performed during sleep and wakefulness. The antidromic field potential, antidromic and orthodromic spike, EPSP, membrane input resistance, and rheobasic current of lumbar motoneurons were studied during sleep and wakefulness. No change in motoneuron excitability occurred when quiet wakefulness was compared to quiet sleep. Postsynaptic inhibition resulted in decrease in excitability during active sleep. Further phasic decreases in excitability, also due to postsynaptic inhibition, occurred during active sleep in conjunction with clusters of rapid eye movements. The mesencephalon, pons, and medulla were explored in a conditioning-test paradigm in an attempt to find a site where electrical stimulation induced a pattern of somatomotor reflex and motoneuron membrane potential modulation comparable to that which occurs spontaneously during sleep and wakefulness. In unanesthetized, freely moving cats during wakefulness and quiet sleep, electrical stimulation within and in the vicinity of the nucleus pontis oralis produced facilitation of the masseteric reflex, whereas during active sleep the identical stimulus resulted in potent suppression of the reflex.(ABSTRACT TRUNCATED AT 400 WORDS)

Ontogenesis of the axolemma and axoglial relationships in myelinated fibers: electrophysiological and freeze-fracture correlates of membrane plasticity.

Abstract: Publisher Summary Although it is well known that myelinated nerve fibers are differentiated, at the light microscopic level, into regions covered by myelin (internodes) and regions devoid of myelin (the nodes of Ranvier), it has only been in the past few years that details of axon membrane differentiation itself have been studied. It is now becoming apparent that the axon membrane (axolemma) exhibits an elegant differentiation in terms of its macromolecular architecture and that the nodal and internodal regions of this membrane can be shown to be different by morphological, electrophysiological, and pharmacological techniques. This differentiation of the mature axolemma into nodal and internodal domains with distinct properties has recently been reviewed. The chapter discusses studies from laboratories dealing with the electrophysiological and freeze-fracture aspects of axon-membrane reorganization during the ontogenesis of the trunk of the mammalian myelinated fiber. It describes the development of the axon membrane of the myelinated fiber. The axolemma exhibits a high degree of plasticity during development, with significant changes in axon-membrane structure being related to association with glial cells.

Immunodetection of endorphins and enkephalins: a search for reliability.

Abstract: Publisher Summary The isolation and identification of the endogeneous opioid peptides called “enkephalins” and the discovery of the biologically and chemically related endorphins have generated one of the fastest growing fields in current neurobiological research. Investigations of the role played by these opiate-like substances in nervous function have posed to scientists methodological problems of identification and quantitation that demand more than the traditional neurochemical expertise. This is because of the greater chemical complexity of peptides compared to classical neurotransmitters and because peptide levels in nervous tissues are very low. The twin demands of high specificity and high sensitivity can be met by methods based on stereomolecular recognition—that is, the molecule-to-molecule interaction that occurs in antigen–antibody recognition. Thus, immunological detection has become a major tool in understanding the actions of biologically active peptides because it discriminates molecules on the basis of chemical structure rather than biological actions. Immunodetection has provided the possibility of using the same specific instrument for studying these peptides from both histological and biochemical aspects. This chapter discusses the usefulness and the limitations of immunological methods as reflected in the study of the opioid peptides in the laboratory and provides guidance for developing new methodologies and for evaluating the existing literature on endorphins and enkephalins. Special emphasis is given to testing the sensitivity and specificity of antisera in the experimental conditions used in radioimmunoassay (RIA) and immunocytochemistry (ICC); the differences and similarities between RIA and ICC are also discussed in the chapter.

Antiacetylcholine Receptor Antibodies and Myasthenia Gravis

Abstract: Publisher Summary Myasthenia gravis is a human muscle disease characterized by weakness and abnormal fatigability of voluntary muscles with recovery of motor power on resting and positive response to treatment with anticholinesterase drugs. The basic defect is in a reduction of available nicotinic acetylcholine receptors (nAcChRs) at neuromuscular junctions brought about by an antibody-mediated autoimmune reaction. The elucidation of this defect has followed detailed studies of the molecular organization of nicotinic cholinergic synapses, which were made possible by the development and the application of a set of tools—the neurotoxins from elapid snake venoms—used to identify specifically nAcChR. Both humoral and cellular immunity to nAcChR are implicated in the pathogenesis of myasthenia gravis. There is little evidence of their relative role in the defect of the neuromuscular transmission, although humoral immunity, in the form of anti-nAcChR antibodies alone or in conjunction with complement factors, would be sufficient to cause a reduction of available receptors at neuromuscular junctions. This chapter discusses the mode of action of anti-nAcChR antibodies in this disease.