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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
F Woodward Hopf, Regina A Mangieri
Ionotropic glutamate receptors (AMPA, NMDA, and kainate receptors) play a central role in excitatory glutamatergic signaling throughout the brain. As a result, functional changes, especially long-lasting forms of plasticity, have the potential to profoundly alter neuronal function and the expression of adaptive and pathological behaviors. Thus, alcohol-related adaptations in ionotropic glutamate receptors are of great interest, since they could promote excessive alcohol consumption, even after long-term abstinence...
April 20, 2018: Handbook of Experimental Pharmacology
Jessica P Anand, Deanna Montgomery
The opioid receptor system plays a major role in the regulation of mood, reward, and pain. The opioid receptors therefore make attractive targets for the treatment of many different conditions, including pain, depression, and addiction. However, stimulation or blockade of any one opioid receptor type often leads to on-target adverse effects that limit the clinical utility of a selective opioid agonist or antagonist. Literature precedent suggests that the opioid receptors do not act in isolation and that interactions among the opioid receptors and between the opioid receptors and other proteins may produce clinically useful targets...
April 20, 2018: Handbook of Experimental Pharmacology
Cody A Siciliano, Anushree N Karkhanis, Katherine M Holleran, James R Melchior, Sara R Jones
Alcohol use disorders are a leading public health concern, engendering enormous costs in terms of both economic loss and human suffering. These disorders are characterized by compulsive and excessive alcohol use, as well as negative affect and alcohol craving during abstinence. Extensive research has implicated the dopamine system in both the acute pharmacological effects of alcohol and the symptomology of alcohol use disorders that develop after extended alcohol use. Preclinical research has shed light on many mechanisms by which chronic alcohol exposure dysregulates the dopamine system...
April 20, 2018: Handbook of Experimental Pharmacology
Martin E Lidell
Adapting to the cold extrauterine environment after birth is a great challenge for the newborn. Due to their high surface area-to-volume ratio, infants tend to lose more heat to the environment as compared to adults. In addition, human newborns lack sufficiently developed skeletal muscle mass to maintain body temperature through shivering thermogenesis, an important source of heat in cold-exposed adults. Evolution has provided humans and other placental mammals with brown adipose tissue (BAT), a tissue that converts chemically stored energy, in the form of fatty acids and glucose, into heat through non-shivering thermogenesis...
April 20, 2018: Handbook of Experimental Pharmacology
Deborah Goody, Alexander Pfeifer
In the last decade, exosomes have gained interest as a new type of intercellular communication between cells and tissues. Exosomes are circulating, cell-derived lipid vesicles smaller than 200 nm that contain proteins and nucleic acids, including microRNAs (miRNAs), and are able to modify cellular targets. Exosomal miRNAs function as signalling molecules that regulate the transcription of their target genes and can cause phenotypic transformation of recipient cells. Recent studies have shown that brown fat secretes exosomes as a form of communication with other metabolic organs such as the liver...
April 10, 2018: Handbook of Experimental Pharmacology
Catherine M Cahill, Edmund Ong
Opioid receptors are the sites of action for morphine and most other clinically used opioid drugs. Abundant evidence now demonstrates that different opioid receptor types can physically associate to form heteromers. Owing to their constituent monomers' involvement in analgesia, mu/delta opioid receptor (M/DOR) heteromers have been a particular focus of attention. Understandings of the physiological relevance and indisputable proof of M/DOR formation in vivo are still evolving. This aspect of the field has been slow to progress in large part by the limitations of most available experimental models; recently however, promising progress is being made...
April 10, 2018: Handbook of Experimental Pharmacology
Laia Reverte-Salisa, Abhishek Sanyal, Alexander Pfeifer
Cold-induced activation of brown adipose tissue (BAT) is mediated by norepinephrine and adenosine that are released during sympathetic nerve activation. Both signaling molecules induce an increase in intracellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) in murine and human BAT. In brown adipocytes, cAMP plays a central role, because it activates lipolysis, glucose uptake, and thermogenesis. Another well-studied intracellular second messenger is 3',5'-cyclic guanosine monophosphate (cGMP), which closely resembles cAMP...
April 10, 2018: Handbook of Experimental Pharmacology
Xi Yao, Barbara Salingova, Christian Dani
Alternative strategies are urgently required to fight obesity and associated metabolic disorders including diabetes and cardiovascular diseases. Brown and brown-like adipocytes (BAs) store fat, but in contrast to white adipocytes, activated BAs are equipped to dissipate energy stored. Therefore, BAs represent promising cell targets to counteract obesity. However, the scarcity of BAs in adults is a major limitation for a BA-based therapy of obesity, and the notion to increase the BA mass by transplanting BA progenitors (BAPs) in obese patients recently emerged...
April 10, 2018: Handbook of Experimental Pharmacology
Linda D Simmler, Matthias E Liechti
New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile...
April 10, 2018: Handbook of Experimental Pharmacology
Jonathan P Wisor
Over the period of decades in the mid to late twentieth century, arousal-promoting functions were attributed to neuromodulators including serotonin, hypocretin, histamine, and noradrenaline. For some time, a relatively minor role in regulating sleep and wake states was ascribed to dopamine and the dopamine-producing cells of the ventral tegmental area, despite the fact that dopaminergic signaling is a major target, if not the primary target, for wake-promoting agents. In recent years, due to observations from human genetic studies, pharmacogenetic studies in animal models, and the increasingly sophisticated methods used to manipulate the nervous systems of experimental animals, it has become clear that dopaminergic signaling is central to the regulation of arousal...
April 4, 2018: Handbook of Experimental Pharmacology
Antonia M Savarese, Amy W Lasek
Alcohol use disorder (AUD) is a chronic relapsing brain disease that currently afflicts over 15 million adults in the United States. Despite its prevalence, there are only three FDA-approved medications for AUD treatment, all of which show limited efficacy. Because of their ability to alter expression of a large number of genes, often with great cell-type and brain-region specificity, transcription factors and epigenetic modifiers serve as promising new targets for the development of AUD treatments aimed at the neural circuitry that underlies chronic alcohol abuse...
March 29, 2018: Handbook of Experimental Pharmacology
Clinton E Canal
Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits...
March 13, 2018: Handbook of Experimental Pharmacology
Jian Payandeh, David H Hackos
The voltage-gated sodium (Nav) channel Nav1.7 has been the focus of intense investigation in recent years. Human genetics studies of individuals with gain-of-function and loss-of-function mutations in the Nav1.7 channel have implicated Nav1.7 as playing a critical role in pain. Therefore, selective inhibition of Nav1.7 represents a potentially new analgesic strategy that is expected to be devoid of the significant liabilities associated with available treatment options. Although the identification and development of selective Nav channel modulators have historically been challenging, a number of recent publications has demonstrated progression of increasingly subtype-selective small molecules and peptides toward potential use in preclinical or clinical studies...
March 13, 2018: Handbook of Experimental Pharmacology
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