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Handbook of Experimental Pharmacology

Samuel D Banister, Mark Connor
Synthetic cannabinoid receptor agonists (SCRAs) have proliferated as new psychoactive substances (NPS) over the past decade. Relative to other classes of NPS, SCRAs are structurally heterogeneous; however, most SCRAs act as potent, high-efficacy agonists of cannabinoid type 1 and type 2 receptors (CB1 and CB2 , respectively). Characterization of the pharmacology and toxicology of these substances is hindered by the dynamic nature of the SCRA marketplace. Beyond basic pharmacological profiling at CB1 and CB2 receptors, very little is known about the acute or chronic effects of SCRAs...
July 7, 2018: Handbook of Experimental Pharmacology
Francesco De Logu, Romina Nassini, Lorenzo Landini, Pierangelo Geppetti
The benefit reported in a variety of clinical trials by a series of small molecule antagonists for the calcitonin gene-related peptide (CGRP) receptor, or four monoclonal antibodies against the neuropeptide or its receptor, has underscored the release of CGRP from terminals of primary sensory neurons, including trigeminal neurons, as one of the major mechanisms of migraine headaches. A large variety of excitatory ion channels and receptors have been reported to elicit CGRP release, thus proposing these agonists as migraine-provoking agents...
July 7, 2018: Handbook of Experimental Pharmacology
James Law, David E Morris, Helen Budge, Michael E Symonds
Historically, brown adipose tissue has been elusive and not easy to detect, hence its relative obscurity in human physiology until its rediscovery in 2009. At that point, it was proven that the symmetrical artefacts frequently detected on positron emission tomography-computed tomography (PET-CT), which resolved if the environment was kept warm, were brown adipose tissue deposits. PET-CT has remained the stalwart of human brown adipose tissue research and is still considered the gold standard. However, PET-CT exposes the participant to ionising radiation, limiting studies to large, but retrospective, review of clinical imaging or a small-scale, but prospective, design...
July 7, 2018: Handbook of Experimental Pharmacology
Therese Juhlin Larsen, Naja Zenius Jespersen, Camilla Scheele
Obesity involves a contrasting expansion of the energy-storing white fat and loss of functionally competent brown fat, an energy-consuming thermogenic adipose. Leveraging our understanding of white and brown adipocyte recruitment and investigating factors that regulate these processes might reveal novel targets for counteracting obesity. In vitro differentiation of primary preadipocytes mimics many of the morphological and transcriptional events occurring during adipogenesis in vivo. Moreover, preadipocytes isolated from a specific depot maintain features of their originating niche...
July 7, 2018: Handbook of Experimental Pharmacology
Christoph Ort, Lubertus Bijlsma, Sara Castiglioni, Adrian Covaci, Pim de Voogt, Erik Emke, Félix Hernández, Malcolm Reid, Alexander L N van Nuijs, Kevin V Thomas, Barbara Kasprzyk-Hordern
Wastewater-based epidemiology (WBE) complements existing epidemiology-based estimation techniques and provides objective, evidence-based estimates of illicit drug use. After consumption, biomarkers - drugs and their metabolites - excreted to toilets and flushed into urban sewer networks can be measured in raw wastewater samples. The quantified loads can serve as an estimate for the collective consumption of all people contributing to the wastewater sample. This transdisciplinary approach, further explained in this chapter, has developed, matured and is now established for monitoring substances such as cocaine and amphetamine-type stimulants...
June 13, 2018: Handbook of Experimental Pharmacology
Justice N A Tettey, Conor Crean, Susan C Ifeagwu, Martin Raithelhuber
The phenomenon of new psychoactive substances (NPS), which came to the attention of the wider international community at the beginning of the 2010s, has been unprecedented in terms of the sheer number of substances, their rate of emergence, chemical diversity, and range of pharmacological effects. In particular, the chemical diversity has been a challenge to promoting a better understanding of the NPS market - a fundamental requirement for effective policy decisions and interventions. This manuscript highlights the significant chemical diversity of NPS and describes an alternative, complementary, and pragmatic classification based on pharmacological effects, which aligns NPS to traditional controlled drugs and enhances understanding of the phenomenon...
June 13, 2018: Handbook of Experimental Pharmacology
Simon L Hill, Paul I Dargan
This chapter begins by considering why it is important to understand the clinical patterns of acute toxicity associated with new psychoactive substances (NPS), the challenges associated with gathering these data, the sources of information available and the limitations of each. It describes the data triangulation approach that can be used to combine individual, each inherently limited, data sources to help build the picture of the pattern of acute non-fatal toxicity associated with NPS. The chapter illustrates the data triangulation approach by the use of clinical examples and aims to consider mechanism of action data in conjunction with clinical features to provide an overarching understanding of the clinical presentation...
June 13, 2018: Handbook of Experimental Pharmacology
Håkan Ashina, Henrik Winther Schytz, Messoud Ashina
Over the past three decades, calcitonin gene-related peptide (CGRP) has emerged as a key molecule. Provocation experiments have demonstrated that intravenous CGRP infusion induces migraine-like attacks in migraine with and without aura patients. In addition, these studies have revealed a heterogeneous CGRP response, i.e., some migraine patients develop migraine-like attacks after CGRP infusion, while others do not. The role of CGRP in human migraine models has pointed to three potential sites of CGRP-induced migraine: (1) vasodilation via cyclic adenosine monophosphate (cAMP) and possibly cyclic guanosine monophosphate (cGMP); (2) activation of trigeminal sensory afferents, and (3) modulation of deep brain structures...
June 13, 2018: Handbook of Experimental Pharmacology
Angelos Karlas, Josefine Reber, Evangelos Liapis, Korbinian Paul-Yuan, Vasilis Ntziachristos
MSOT has revolutionized biomedical imaging because it allows anatomical, functional, and molecular imaging of deep tissues in vivo in an entirely noninvasive, label-free, and real-time manner. This imaging modality works by pulsing light onto tissue, triggering the production of acoustic waves, which can be collected and reconstructed to provide high-resolution images of features as deep as several centimeters below the body surface. Advances in hardware and software continue to bring MSOT closer to clinical translation...
June 13, 2018: Handbook of Experimental Pharmacology
Ambre M Bertholet, Yuriy Kirichok
Uncoupling protein 1 (UCP1) is an integral protein of the inner mitochondrial membrane (IMM) that is expressed specifically in brown and beige fat depots. UCP1 is responsible for the production of heat to control core body temperature, the regulation of fat metabolism, and the energy balance. As an uncoupling protein, UCP1 transports H+ across the IMM in presence of long-chain fatty acids (FA), which makes brown fat mitochondria produce heat at the expense of ATP. However, the exact mechanism of UCP1 action has remained difficult to elucidate, because direct methods for studying currents generated by UCP1 were unavailable...
May 25, 2018: Handbook of Experimental Pharmacology
John Simms, Sarah Routledge, Romez Uddin, David Poyner
The canonical CGRP receptor is a complex between calcitonin receptor-like receptor (CLR), a family B G-protein-coupled receptor (GPCR) and receptor activity-modifying protein 1 (RAMP1). A third protein, receptor component protein (RCP) is needed for coupling to Gs. CGRP can interact with other RAMP-receptor complexes, particularly the AMY1 receptor formed between the calcitonin receptor (CTR) and RAMP1. Crystal structures are available for the binding of CGRP27-37 [D31 ,P34 ,F35 ] to the extracellular domain (ECD) of CLR and RAMP1; these show that extreme C-terminal amide of CGRP interacts with W84 of RAMP1 but the rest of the analogue interacts with CLR...
May 25, 2018: Handbook of Experimental Pharmacology
Debbie L Hay
Calcitonin gene-related peptide (CGRP) has many reported pharmacological actions. Can a single receptor explain all of these? This chapter outlines the molecular nature of reported CGRP binding proteins and their pharmacology. Consideration of whether CGRP has only one or has more receptors is important because of the key role that this peptide plays in migraine. It is widely thought that the calcitonin receptor-like receptor together with receptor activity-modifying protein 1 (RAMP1) is the only relevant receptor for CGRP...
May 25, 2018: Handbook of Experimental Pharmacology
Emma K O'Callaghan, Edward W Green, Paul Franken, Valérie Mongrain
Although sleep seems an obvious and simple behaviour, it is extremely complex involving numerous interactions both at the neuronal and the molecular levels. While we have gained detailed insight into the molecules and neuronal networks responsible for the circadian organization of sleep and wakefulness, the molecular underpinnings of the homeostatic aspect of sleep regulation are still unknown and the focus of a considerable research effort. In the last 20 years, the development of techniques allowing the simultaneous measurement of hundreds to thousands of molecular targets (i...
May 10, 2018: Handbook of Experimental Pharmacology
Michael J Gaudry, Kevin L Campbell, Martin Jastroch
Brown adipose tissue (BAT), the specialized heat-producing organ found in many placental mammals including humans, may be accessible for clinical drug intervention to help combat metabolic diseases. Understanding the biology of BAT and its thermogenic uncoupling protein 1 (UCP1) will benefit from an assessment of its evolution, answering where UCP1 originated and how it has been modified and integrated into cellular energy metabolism. Here, we review topical insights regarding the molecular evolution of UCP1-also reconstructing the proximate and ultimate factors selecting for brown fat thermogenesis in placental mammals...
May 10, 2018: Handbook of Experimental Pharmacology
David J Rossi, Ben D Richardson
In the brain, fast inhibitory neurotransmission is mediated primarily by the ionotropic subtype of the gamma-aminobutyric acid (GABA) receptor subtype A (GABAA R). It is well established that the brain's GABAA R system mediates many aspects of neurobehavioral responses to alcohol (ethanol; EtOH). Accordingly, in both preclinical studies and some clinical scenarios, pharmacologically targeting the GABAA R system can alter neurobehavioral responses to acute and chronic EtOH consumption. However, many of the well-established interactions of EtOH and the GABAA R system have been identified at concentrations of EtOH ([EtOH]) that would only occur during abusive consumption of EtOH (≥40 mM), and there are still inadequate treatment options for prevention of or recovery from alcohol use disorder (AUD, including abuse and dependence)...
May 8, 2018: Handbook of Experimental Pharmacology
Emmani B M Nascimento, Wouter D van Marken Lichtenbelt
The role of brown adipose tissue (BAT) in non-shivering thermogenesis is well established in animals. BAT is activated following cold exposure, resulting in non-shivering thermogenesis, to ensure a constant body temperature. In mitochondria of brown adipocytes, glucose and fatty acids are used as substrate for uncoupling resulting in heat production. Activated BAT functions as a sink for glucose and fatty acids and this hallmark has designated BAT a target in the fight against metabolic diseases like type 2 diabetes mellitus and obesity...
May 4, 2018: Handbook of Experimental Pharmacology
Elena M Vazey, Carolina R den Hartog, David E Moorman
Alcohol use disorder (AUD) results from disruption of a number of neural systems underlying motivation, emotion, and cognition. Patients with AUD exhibit not only elevated motivation for alcohol but heightened stress and anxiety, and disruptions in cognitive domains such as decision-making. One system at the intersection of these functions is the central norepinephrine (NE) system. This catecholaminergic neuromodulator, produced by several brainstem nuclei, plays profound roles in a wide range of behaviors and functions, including arousal, attention, and other aspects of cognition, motivation, emotional regulation, and control over basic physiological processes...
April 24, 2018: Handbook of Experimental Pharmacology
Antoine Adamantidis, Anita Lüthi
Optogenetic tools have revolutionized insights into the fundamentals of brain function. This is particularly true for our current understanding of sleep-wake regulation and sleep rhythms. This is illustrated here through a comprehensive and step-by-step review over the major brain areas involved in transitions between sleep and wake states and in sleep rhythmogenesis.
April 24, 2018: Handbook of Experimental Pharmacology
Verginia C Cuzon Carlson
No abstract text is available yet for this article.
April 21, 2018: Handbook of Experimental Pharmacology
Francesc Villarroya, Aleix Gavaldà-Navarro, Marion Peyrou, Joan Villarroya, Marta Giralt
Brown adipokines are regulatory factors secreted by brown and beige adipocytes that exhibit endocrine, paracrine, and autocrine actions. Peptidic and non-peptidic molecules, including miRNAs and lipids, are constituents of brown adipokines. Brown adipose tissue remodeling to meet thermogenic needs is dependent on the secretory properties of brown/beige adipocytes. The association between brown fat activity and a healthy metabolic profile, in relation to energy balance and glucose and lipid homeostasis, is influenced by the endocrine actions of brown adipokines...
April 20, 2018: Handbook of Experimental Pharmacology
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