Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations.

https://science.sciencemag.org/content/sci/262/5134/679.full.pdf

Thalamocortical oscillations in the sleeping and aroused brain

Authors Jan L. Brozek, MD, PhD – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada Jean Bousquet, MD, PhD – Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France, INSERM, CESP U1018, Respiratory and Environmental Epidemiology Team, France, and WHO Collaborating Center for Rhinitis and Asthma Carlos E. Baena-Cagnani, MD – Faculty of Medicine, Catholic University of Cordoba, Cordoba, Argentina Sergio Bonini, MD – Institute of Neurobiology and Molecular Medicine – CNR, Rome, Italy and Department of Medicine, Second University of Naples, Naples, Italy G. Walter Canonica, MD – Allergy & Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy Thomas B. Casale, MD – Division of Allergy and Immunology, Department of Medicine, Creighton University, Omaha, Nebraska, USA Roy Gerth van Wijk, MD, PhD – Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands Ken Ohta, MD, PhD – Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Torsten Zuberbier, MD – Department of Dermatology and Allergy, Charite Universitatsmedizin Berlin, Berlin, Germany Holger J. Schunemann, MD, PhD, MSc – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada

/pdf/allergic-rhinitis-and-its-impact-on-asthma-20b4c7y0pr.pdf

Allergic Rhinitis and Its Impact on Asthma

A review of central 5-HT receptors and their function

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.

/pdf/prolactin-structure-function-and-regulation-of-secretion-3w4x6fqbg3.pdf

Prolactin: Structure, Function, and Regulation of Secretion

Serotonin (5-hydroxytryptamine, 5-HT) is probably unique among the monoamines in that its effects are subserved by as many as 13 distinct heptahelical, G-protein-coupled receptors (GPCRs) and one (presumably a family of) ligand-gated ion channel(s). These receptors are divided into seven distinct classes (5-HT(1) to 5-HT(7)) largely on the basis of their structural and operational characteristics. Whilst this degree of physical diversity clearly underscores the physiological importance of serotonin, evidence for an even greater degree of operational diversity continues to emerge. The challenge for modern 5-HT research has therefore been to define more precisely the properties of the systems that make this incredible diversity possible. Much progress in this regard has been made during the last decade with the realisation that serotonin is possibly the least conservative monoamine transmitter and the cloning of its many receptors. Coupled with the actions of an extremely avid and efficient reuptake system, this array of receptor subtypes provides almost limitless signalling capabilities to the extent that one might even question the need for other transmitter systems. However, the complexity of the system appears endless, since posttranslational modifications, such as alternate splicing and RNA editing, increase the number of proteins, oligomerisation and heteromerisation increase the number of complexes, and multiple G-protein suggest receptor trafficking, allowing phenotypic switching and crosstalk within and possibly between receptor families. Whether all these possibilities are used in vivo under physiological or pathological conditions remains to be firmly established, but in essence, such variety will keep the 5-HT community busy for quite some time. Those who may have predicted that molecular biology would largely simplify the life of pharmacologists have missed the point for 5-HT research in particular and, most probably, for many other transmitters. This chapter is an attempt to summarise very briefly 5-HT receptor diversity. The reward for unravelling this complex array of serotonin receptor--effector systems may be substantial, the ultimate prize being the development of important new drugs in a range of disease areas.

Molecular, pharmacological and functional diversity of 5-HT receptors

Although histaminergic neurones have not yet been histochemically visualized, there is little doubt that histamine (HA) has a neurotransmitter role in the invertebrate and mammalian central nervous system. For example, a combination of biochemical, electrophysiological and lesion studies in rats have shown that histamine is synthesized in and released from a discrete set of neurones ascending through the lateral hypothalamic area and widely projecting in the telencephalon. Histamine acts on target cells in mammalian brain via stimulation of two classes of receptor (H1 and H2) previously characterized in peripheral organs and probably uses Ca2+ and cyclic AMP, respectively, as second messengers. It is well established that several neurotransmitters affect neuronal activity in the central nervous system through stimulation not only of postsynaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specificity and by which they may control their own release. Such 'autoreceptors' have been demonstrated (or postulated) in the case of noradrenaline, dopamine, serotonin, acetylcholine and gamma-aminobutyric acid (GABA) neurones but have never been demonstrated for histamine. We show here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.

Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor.

Article de synthese sur le metabolisme de l'histamine, sur la localisation des voies neuronales et des recepteurs histaminergiques. Role de l'histamine dans le controle neuroendocrine, dans la regulation cardiovasculaire, dans la circulation cerebrale, dans la thermoregulation, dans le controle de certains comportements, dans la nociception, dans la vigilance, le sommeil et l'eveil chez les mammiferes

Histaminergic transmission in the mammalian brain

The classification of histamine receptors has to date been based on rigorous classical pharmacological analysis, and as yet, the classification of the three histamine receptors that have been defined by this process, (i.e., the H1-, H2-, and H 3-receptors) have not been added to because of more

https://pharmrev.aspetjournals.org/content/pharmrev/49/3/253.full.pdf

International Union of Pharmacology. XIII. Classification of Histamine Receptors

New drugs selective for histamine H3-receptors can be used to establish that these receptors are involved in the feedback control of histamine synthesis and release, and to demonstrate their distribution in the brain and peripheral tissues These drugs provide new tools for affecting physiological and possibly pathological conditions in which histamine is involved

Highly potent and selective ligands for histamine H3-receptors.

There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct fropm angiotensin coverting enzyme (ACE), might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this enzyme further, we have designed a potent and specific enkephalinase inhibitor. We report here that this compound, thiorphan [(DL-3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601] protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors.

J C Schwartz

Papers

Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor.

Histaminergic transmission in the mammalian brain

International Union of Pharmacology. XIII. Classification of Histamine Receptors

Highly potent and selective ligands for histamine H3-receptors.

The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice