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Blaine A Jacobs, Miryam M Pando, Elaine M Jennings, Raehannah J Jamshidi, Joshua C Zamora, Teresa S Chavera, William P Clarke, Kelly A Berg
Receptor heteromers often display distinct pharmacological and functional properties compared to the individual receptor constituents. In this study, we compared the properties of the DOP-KOP heteromer agonist, 6'-guanidinonaltrindole (6'-GNTI), with agonists for DOP ([D-Pen2,5]-enkephalin [DPDPE]) and KOP (U50488) in peripheral sensory neurons in culture and in vivo. In primary cultures, all three agonists inhibited PGE2 -stimulated cAMP accumulation as well as activated extracellular signal-regulated kinase 1/2 (ERK) with similar efficacy...
February 15, 2019: Neuropharmacology
Shota Murayama, Kiyofumi Yamamoto, Satoshi Fujita, Hiroki Takei, Tadashi Inui, Bunnai Ogiso, Masayuki Kobayashi
Leptin is produced in the adipocytes and plays a pivotal role in regulation of energy balance by controlling appetite and metabolism. Leptin receptors are widely distributed in the brain, especially in the hypothalamus, hippocampus, and neocortex. The insular cortex (IC) processes gustatory and visceral information, which functionally correlate to feeding behavior. However, it is still an open issue whether and how leptin modulates IC neural activities. Our paired whole-cell patch-clamp recordings using IC slice preparations demonstrated that unitary inhibitory postsynaptic currents (uIPSCs) but not uEPSCs were potentiated by leptin in the connections between pyramidal (PNs) and fast-spiking neurons (FSNs)...
February 14, 2019: Neuropharmacology
Daniel Vallöf, Jesper Vestlund, Elisabet Jerlhag
The ability of glucagon-like peptide-1 (GLP-1) to reduce food intake involves activation of GLP-1 receptors (GLP-1R) in the nucleus of the solitary tract (NTS). It has also been demonstrated that systemic administration of GLP-1R agonists attenuates alcohol-mediated behaviors via, to date, unknown mechanisms. Therefore, we evaluated the effects of NTS-GLP-1R activation by exendin-4 (Ex4) on alcohol-induced locomotor stimulation, accumbal dopamine release and memory of alcohol reward in the conditioned place preference (CPP) model in mice...
February 14, 2019: Neuropharmacology
Priyanka D Pinky, Jenna Bloemer, Warren D Smith, Timothy Moore, Hao Hong, Vishnu Suppiramaniam, Miranda N Reed
Marijuana is one of the most commonly used illicit drugs worldwide. In addition, use of synthetic cannabinoids is increasing, especially among adolescents and young adults. Although human studies have shown that the use of marijuana during pregnancy leads to adverse behavioral effects, such as deficiencies in attention and executive function in affected offspring, the rate of marijuana use among pregnant women is steadily increasing. Various aspects of human behavior including emotion, learning, and memory are dependent on complex interactions between multiple neurotransmitter systems that are especially vulnerable to alterations during the developmental period...
February 13, 2019: Neuropharmacology
Thibault P Bittar, Betina B Nair, Joon S Kim, Dhananjie Chandrasekera, Aidan Sherrington, Karl J Iremonger
Corticosteroid stress hormones drive a multitude of adaptations in the brain. Hypothalamic corticotropin-releasing hormone (CRH) neurons control the circulating levels of corticosteroid stress hormones in the body and are themselves highly sensitive to corticosteroids. CRH neurons have been shown to undergo various adaptions in response to acute stress hormone elevations. However, their structural and physiological changes under chronically elevated corticosterone are less clear. To address this, we determined the structural and functional changes in CRH neurons in the paraventricular nucleus of the hypothalamus following 14 days of corticosterone treatment...
February 13, 2019: Neuropharmacology
Nikita Mikhailov, Jarkko Leskinen, Ilkka Fagerlund, Ekaterina Poguzhelskaya, Raisa Giniatullina, Oleg Gafurov, Tarja Malm, Tero Karjalainen, Olli Gröhn, Rashid Giniatullin
BACKGROUND: Recent discovery of mechanosensitive Piezo receptors in trigeminal ganglia suggested the novel molecular candidate for generation of migraine pain. However, the contribution of Piezo channels in migraine pathology was not tested yet. Therefore, in this study, we explored a potential involvement of Piezo channels in peripheral trigeminal nociception implicated in generation of migraine pain. METHODS: We used immunohistochemistry, calcium imaging, calcitonin gene related peptide (CGRP) release assay and electrophysiology in mouse and rat isolated trigeminal neurons and rat hemiskulls to study action of various stimulants of Piezo receptors on migraine-related peripheral nociception...
February 13, 2019: Neuropharmacology
Diana V Atigari, Rajendra Uprety, Gavril W Pasternak, Susruta Majumdar, Bronwyn M Kivell
Kappa opioid receptor (KOPr) agonists have preclinical anti-cocaine and antinociceptive effects. However, adverse effects including dysphoria, aversion, sedation, anxiety and depression limit their clinical development. MP1104, an analogue of 3-iodobenzoyl naltrexamine, is a potent dual agonist at KOPr and delta opioid receptor (DOPr), with full agonist efficacy at both these receptors. In this study, we evaluate the ability of MP1104 to modulate cocaine-induced behaviors and side-effects preclinically. In male Sprague-Dawley rats trained to self-administer cocaine, MP1104 (0...
February 12, 2019: Neuropharmacology
Jianxiong Jiang, Ying Yu, Erika Kinjo, Yifeng Du, Hoang Nguyen, Ray Dingledine
Glutamate receptor-mediated excitotoxicity is a common pathogenic process in many neurological conditions including epilepsy. Prolonged seizures induce elevations in extracellular glutamate that contribute to excitotoxic damage, which in turn can trigger chronic neuroinflammatory reactions, leading to secondary damage to the brain. Blocking key inflammatory pathways could prevent such secondary brain injury following the initial excitotoxic insults. Prostaglandin E2 (PGE2 ) has emerged as an important mediator of neuroinflammation-associated injury, in large part via activating its EP2 receptor subtype...
February 11, 2019: Neuropharmacology
Amy Chia-Ching Kao, Ka Wai Chan, Daniel C Anthony, Belinda R Lennox, Philip Wj Burnet
The intestinal microbiome is emerging as a novel therapeutic target owing to the wide range of potential health benefits that could result by manipulating the microbiota composition through relatively simple interventions. Ingestion of the prebiotic Bimuno™ galacto-oligosaccharide (B-GOS® ) is one such intervention that has been shown to attenuate olanzapine-induced weight gain and improve cognitive flexibility in rats, potentially through mechanisms involving acetate, the major short-chain fatty acid (SCFA) that is produced by B-GOS® fermentation...
February 11, 2019: Neuropharmacology
Midori Usui, Keisuke Kaneko, Yoshiyuki Oi, Masayuki Kobayashi
Orexin has multiple physiological functions including wakefulness, appetite, nicotine intake, and nociception. The cerebral cortex receives abundant orexinergic projections and expresses both orexinergic receptor 1 (OX1 R) and 2 (OX2 R). However, little is known about orexinergic regulation of GABA-mediated inhibitory synaptic transmission. In the cerebral cortex, there are multiple GABAergic neural subtypes, each of which has its own morphological and physiological characteristics. Therefore, identification of presynaptic GABAergic neural subtypes is critical to understand orexinergic effects on GABAergic connections...
February 11, 2019: Neuropharmacology
Kathy Sengmany, Shane D Hellyer, Sabine Albold, Taide Wang, P Jeffrey Conn, Lauren T May, Arthur Christopoulos, Katie Leach, Karen J Gregory
Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5 ) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu5 allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation. To establish whether negative allosteric modulators (NAMs) engender similar bias, we rigorously characterized the pharmacology of eight diverse mGlu5 NAMs...
February 11, 2019: Neuropharmacology
Jaanus Harro, Kariina Laas, Diva Eensoo, Triin Kurrikoff, Katre Sakala, Mariliis Vaht, Jüri Parik, Jarek Mäestu, Toomas Veidebaum
Orexins, alternatively called hypocretins, are neuropeptides with crucial role in maintaining wakefulness. The orexin system is thought to mediate a coordinated defense response but thus far investigated from the flight, but never fight, response perspective. An HCRTR1 gene variant (rs2271933 G > A) leading to amino acid substitution (Ile408Val) has been associated with migraine and mood disorders. We genotyped, and assessed aggressive behaviour in both birth cohorts (n = 655 and 583) of the Estonian Children Personality Behaviour and Health Study (ECPBHS)...
February 10, 2019: Neuropharmacology
Jordan M Buck, Kelsey N Sanders, Charles R Wageman, Valerie S Knopik, Jerry A Stitzel, Heidi C O'Neill
Maternal smoking during pregnancy, a form of developmental nicotine exposure (DNE), is associated with increased nicotine use and neurodevelopmental disorders such as ADHD in children. Here, we characterize the behavioral, rhythmometric, neuropharmacological, and epigenetic consequences of DNE in the F1 (first) and F2 (second) generation adolescent offspring of mice exposed to nicotine prior to and throughout breeding. We assessed the effects of passive oral methylphenidate (MPH) administration and voluntary nicotine consumption on home cage activity rhythms and activity and risk-taking behaviors in the open field...
February 8, 2019: Neuropharmacology
Roberto Frau, Silvia Fanni, Valeria Serra, Nicola Simola, Sean Godar, Francesco Traccis, Paola Devoto, Marco Bortolato, Miriam Melis
Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAONeo ) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC)...
February 6, 2019: Neuropharmacology
Rafael Franco, María Villa, Paula Morales, Irene Reyes-Resina, Ana Gutiérrez-Rodríguez, Jasmina Jiménez, Nadine Jagerovic, José Martínez-Orgado, Gemma Navarro
Preclinical work shows cannabidiol as a promising drug to manage neonatal hypoxic-ischemic brain damage (NHIBD). The molecular mechanism is not well defined but the beneficial effects of this phytocannabinoid are blocked by antagonists of both cannabinoid CB2 (CB2 R) and serotonin 5-HT1A (5-HT1AR) receptors that, in addition, may form heteromers in a heterologous expression system. Using bioluminescence energy transfer, we have shown a direct interaction of the two receptors that leads to a particular signaling in a heterologous system...
February 6, 2019: Neuropharmacology
Eugene A Kiyatkin
Opioid drugs are important tools to alleviate pain of different origins, but they have strong addictive potential and their abuse at higher doses often results in serious health complications. Respiratory depression that leads to brain hypoxia is perhaps the most dangerous symptom of acute intoxication with opioids, and it could result in lethality. The development of substrate-specific sensors coupled with amperometry made it possible to directly evaluate physiological and drug-induced fluctuations in brain oxygen levels in awake, freely-moving rats...
February 5, 2019: Neuropharmacology
D Matthew Walentiny, Léa T Moisa, Patrick M Beardsley
BACKGROUND: Fentanyl and its structurally related compounds have emerged as the most significant contributors to opioid overdose fatalities in recent years. While there is abundant information about the pharmacological effects of fentanyl, far less is known of its more recently abused analogs. The objective of this study was to determine whether fentanyl and several fentanyl-related substances would engender oxycodone-like responding in a mouse model of oxycodone discrimination. Oxycodone and fentanyl were selected as test compounds due to their high selectivity for mu opioid receptors...
February 5, 2019: Neuropharmacology
Shunsuke Tanahashi, Satoshi Yamamura, Masanori Nakagawa, Eishi Motomura, Motohiro Okada
No abstract text is available yet for this article.
February 4, 2019: Neuropharmacology
Luis A Martinez, Meghan E Lees, David N Ruskin, Susan A Masino
Ketogenic diets (KDs) are high fat, low carbohydrate formulations traditionally used to treat epilepsy; more recently, KDs have shown promise for a wide range of other neurological disorders. Drug addiction studies suggest that repeated exposure to drugs of abuse, including cocaine, results in a suite of neurobiological changes that includes neuroinflammation, decreased glucose metabolism, and disordered neurotransmission. Given that KDs positively regulate these factors, we addressed whether administration of a KD has potential as a novel therapy for drug addiction...
February 4, 2019: Neuropharmacology
Matthias Höllerhage, Natascha Fussi, Thomas W Rösler, Wolfgang Wurst, Christian Behrends, Günter U Höglinger
Pathological aggregates of alpha-synuclein are the common hallmarks of synucleinopathies, including Parkinson's disease. There is currently no disease-modifying therapy approved for neurodegenerative synucleinopathies. The induction of macroautophagy by small compounds may be a strategy to reduce the cellular alpha-synuclein burden and to confer neuroprotection. Therefore, in the present study, we investigated a broad spectrum of druggable molecular signaling pathways reported to induce macroautophagy in human cells and compared their protective efficacy against alpha-synuclein-induced toxicity in cultured human postmitotic dopaminergic neurons...
February 4, 2019: Neuropharmacology
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