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https://www.readbyqxmd.com/read/28657744/discovery-of-n-substituted-2-phenylcyclopropylmethylamines-as-functionally-selective-serotonin-2c-5-ht2c-receptor-agonists-for-potential-use-as-antipsychotic-medications
#1
Guiping Zhang, Jianjun Cheng, John D McCorvy, Paul J Lorello, Barbara J Caldarone, Bryan L Roth, Alan P Kozikowski
A series of N-substituted 2-phenylcyclopropylmethylamines were designed and synthesized, with the aim of finding 5-HT2C-selective agonists with preference for Gq signaling. A number of these compounds exhibit 5-HT2C selectivity with preference for Gq-mediated signaling compared with β-arrestin recruitment. Furthermore, the N-methyl compound (+)-15a, which displayed an EC50 of 23 nM in the calcium flux assay while showing no β-arrestin recruitment activity, is the most functionally-selective 5-HT2C agonist reported to date...
June 28, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28596834/acute-cocaine-exposure-elicits-rises-in-calcium-in-arousal-related-laterodorsal-tegmental-neurons
#2
Mads Ødum Lambert, Theis Højland Ipsen, Kristi Anne Kohlmeier
Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT...
February 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28243192/the-sodium-channel-%C3%AE-4-auxiliary-subunit-selectively-controls-long-term-depression-in-core-nucleus-accumbens-medium-spiny-neurons
#3
Xincai Ji, Sucharita Saha, Guangping Gao, Amy W Lasek, Gregg E Homanics, Melissa Guildford, Andrew R Tapper, Gilles E Martin
Voltage-gated sodium channels are essential for generating the initial rapid depolarization of neuronal membrane potential during action potentials (APs) that enable cell-to-cell communication, the propagation of signals throughout the brain, and the induction of synaptic plasticity. Although all brain neurons express one or several variants coding for the core pore-forming sodium channel α subunit, the expression of the β (β1-4) auxiliary subunits varies greatly. Of particular interest is the β4 subunit, encoded by the Scn4b gene, that is highly expressed in dorsal and ventral (i...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28112453/food-restriction-induces-synaptic-incorporation-of-calcium-permeable-ampa-receptors-in-nucleus-accumbens
#4
Jiangyong Ouyang, Ioana Carcea, Jennifer K Schiavo, Kymry T Jones, Ariana Rabinowitsch, Rhonda Kolaric, Soledad Cabeza de Vaca, Robert C Froemke, Kenneth D Carr
Chronic food restriction potentiates behavioral and cellular responses to drugs of abuse and D-1 dopamine receptor agonists administered systemically or locally in the nucleus accumbens (NAc). However, the alterations in NAc synaptic transmission underlying these effects are incompletely understood. AMPA receptor trafficking is a major mechanism for regulating synaptic strength, and previous studies have shown that both sucrose and d-amphetamine rapidly alter the abundance of AMPA receptor subunits in the NAc postsynaptic density (PSD) in a manner that differs between food-restricted and ad libitum fed rats...
March 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/27958713/inositol-phosphate-accumulation-in-vivo-provides-a-measure-of-muscarinic-m1-receptor-activation
#5
Michael Popiolek, David P Nguyen, Veronica Reinhart, Jeremy R Edgerton, John Harms, Susan M Lotarski, Stefanus J Steyn, Jennifer E Davoren, Sarah Grimwood
The rationale for using M1 selective muscarinic acetylcholine receptor activators for the treatment of cognitive impairment associated with psychiatric and neurodegenerative disease is well-established in the literature. Here, we investigate measurement of inositol phosphate accumulation, an end point immediately downstream of the M1 muscarinic acetylcholine receptor signaling cascade, as an in vivo biochemical readout for M1 muscarinic acetylcholine receptor activation. Five brain penetrant M1-subtype selective activators from three structurally distinct chemical series were pharmacologically profiled for functional activity in vitro using recombinant cell calcium mobilization and inositol phosphate assays, and a native tissue hippocampal slice electrophysiology assay, to show that all five compounds presented a positive allosteric modulator agonist profile, within a narrow range of potencies...
December 27, 2016: Biochemistry
https://www.readbyqxmd.com/read/27908658/cocaine-and-amphetamine-regulated-transcript-peptide-and-calcium-binding-proteins-immunoreactivity-in-the-superficial-layers-of-the-superior-colliculus-in-the-guinea-pig-implications-for-visual-sensory-processing
#6
Janusz Najdzion
The purpose of this study was to investigate the distribution and colocalization of cocaine- and amphetamine-regulated transcript peptide (CART) and three calcium-binding proteins (calbindin, calretinin and parvalbumin) in the superficial layers of the superior colliculus (SCs) in the guinea pig. The CART immunoreactivity was observed exclusively in the solitary fibers and neuropil, which formed various CART-ir tiers, that corresponded partially or entirely to anatomically defined layers of the SCs. The CART-ir structures exhibited a characteristic morphology with bundles of densely intermingled neuronal fibers and terminals...
January 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/27663745/exposure-to-amphetamines-leads-to-development-of-amphetamine%C3%A2-type-stimulants%C3%A2-associated-cardiomyopathy-atsac
#7
REVIEW
Mahsa Jafari Giv
With rapidly rising prevalence of exposure to Amphetamine Type Stimulants (ATS), novel insights into cardiotoxic effects of this substance are being presented in the literature and remarkably ATS Associated Cardiomyopathy (ATSAC) is emerging as a novel cardiovascular condition with its distinctive pathogenesis, risk factors, clinical features and prognosis. A comprehensive systematic review was performed to explore and analyze the current evidence on the association between ATS exposure and development of cardiomyopathy, biological mechanisms involved in pathogenesis of ATSAC, risk factors, clinical features and course of patients with ATSAC...
January 2017: Cardiovascular Toxicology
https://www.readbyqxmd.com/read/27623093/pkc%C3%AE-knockout-mice-are-protected-from-para-methoxymethamphetamine-induced-mitochondrial-stress-and-associated-neurotoxicity-in-the-striatum-of-mice
#8
Eun-Joo Shin, Duy-Khanh Dang, Hai-Quyen Tran, Yunsung Nam, Ji Hoon Jeong, Young Hun Lee, Kyung Tae Park, Yong Sup Lee, Choon-Gon Jang, Jau-Shyong Hong, Toshitaka Nabeshima, Hyoung-Chun Kim
Para-methoxymethamphetamine (PMMA) is a para-ring-substituted amphetamine derivative sold worldwide as an illegal psychotropic drug. Although PMMA use has been reported to lead to severe intoxication and even death, little is known about the mechanism(s) by which PMMA exerts its neurotoxic effects. Here we found that PMMA treatment resulted in phosphorylation of protein kinase Cδ (PKCδ) and subsequent mitochondrial translocation of cleaved PKCδ. PMMA-induced oxidative stress was more pronounced in mitochondria than in the cytosol...
September 10, 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27578016/neurochemistry-of-the-anterior-thalamic-nuclei
#9
Witold Żakowski
This paper reviews the distribution of several bioactive substances and their possible physiological roles in the anterior thalamic nuclei of various species, with a special emphasis on the rat. The anterior thalamus is a part of extended hippocampal system and its significance for learning and memory processes is well known. Although our knowledge about a specific role of this brain structure has increased in recent years considerably, this is the first attempt to summarize neurochemical diversity of the anterior thalamus...
August 30, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27260673/inhibition-by-ketamine-and-amphetamine-analogs-of-the-neurogenic-nitrergic-vasodilations-in-porcine-basilar-arteries
#10
Mei-Fang Chen, Su-Yu Lai, Po-Cheng Kung, Yo-Cheng Lin, Hui-I Yang, Po-Yi Chen, Ingrid Y Liu, Ahai Chang Lua, Tony Jer-Fu Lee
The abuse of ketamine and amphetamine analogs is associated with incidence of hypertension and strokes involving activation of sympathetic activities. Large cerebral arteries at the base of the brain from several species receive dense sympathetic innervation which upon activation causes parasympathetic-nitrergic vasodilation with increased regional blood flow via axo-axonal interaction mechanism, serving as a protective mechanism to meet O2 demand in an acutely stressful situation. The present study was designed to examine effects of ketamine and amphetamine analogs on axo-axonal interaction-mediated neurogenic nitrergic vasodilation in porcine basilar arteries using techniques of blood-vessel myography, patch clamp and two-electrode voltage clamp, and calcium imaging...
August 15, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27149913/neurotoxicity-screening-of-illicit-drugs-using-novel-methods-for-analysis-of-microelectrode-array-mea-recordings
#11
L Hondebrink, A H A Verboven, W S Drega, S Schmeink, M W G D M de Groot, R G D M van Kleef, F M J Wijnolts, A de Groot, J Meulenbelt, R H S Westerink
Annual prevalence of the use of common illicit drugs and new psychoactive substances (NPS) is high, despite the often limited knowledge on the health risks of these substances. Recently, cortical cultures grown on multi-well microelectrode arrays (mwMEAs) have been used for neurotoxicity screening of chemicals, pharmaceuticals, and toxins with a high sensitivity and specificity. However, the use of mwMEAs to investigate the effects of illicit drugs on neuronal activity is largely unexplored. We therefore first characterised the cortical cultures using immunocytochemistry and show the presence of astrocytes, glutamatergic and GABAergic neurons...
July 2016: Neurotoxicology
https://www.readbyqxmd.com/read/26617160/cocaine-and-amphetamine-regulated-transcript-and-calcium-binding-proteins-immunoreactivity-in-the-subicular-complex-of-the-guinea-pig
#12
Barbara Wasilewska, Janusz Najdzion, Maciej Równiak, Krystyna Bogus-Nowakowska, Beata Hermanowicz, Małgorzata Kolenkiewicz, Witold Żakowski, Anna Robak
In this study we present the distribution and colocalization pattern of cocaine- and amphetamine-regulated transcript (CART) and three calcium-binding proteins: calbindin (CB), calretinin (CR) and parvalbumin (PV) in the subicular complex (SC) of the guinea pig. The subiculum (S) and presubiculum (PrS) showed higher CART-immunoreactivity (-IR) than the parasubiculum (PaS) as far as the perikarya and neuropil were concerned. CART- IR cells were mainly observed in the pyramidal layer and occasionally in the molecular layer of the S...
March 2016: Annals of Anatomy, Anatomischer Anzeiger: Official Organ of the Anatomische Gesellschaft
https://www.readbyqxmd.com/read/26300320/multiple-functions-of-neuronal-plasma-membrane-neurotransmitter-transporters
#13
REVIEW
Luca Raiteri, Maurizio Raiteri
Removal from receptors of neurotransmitters just released into synapses is one of the major steps in neurotransmission. Transporters situated on the plasma membrane of nerve endings and glial cells perform the process of neurotransmitter (re)uptake. Because the density of transporters in the membranes can fluctuate, transporters can determine the transmitter concentrations at receptors, thus modulating indirectly the excitability of neighboring neurons. Evidence is accumulating that neurotransmitter transporters can exhibit multiple functions...
November 2015: Progress in Neurobiology
https://www.readbyqxmd.com/read/26162812/amphetamine-activates-calcium-channels-through-dopamine-transporter-mediated-depolarization
#14
Krasnodara N Cameron, Ernesto Solis, Iwona Ruchala, Louis J De Felice, Jose M Eltit
Amphetamine (AMPH) and its more potent enantiomer S(+)AMPH are psychostimulants used therapeutically to treat attention deficit hyperactivity disorder and have significant abuse liability. AMPH is a dopamine transporter (DAT) substrate that inhibits dopamine (DA) uptake and is implicated in DA release. Furthermore, AMPH activates ionic currents through DAT that modify cell excitability presumably by modulating voltage-gated channel activity. Indeed, several studies suggest that monoamine transporter-induced depolarization opens voltage-gated Ca(2+) channels (CaV), which would constitute an additional AMPH mechanism of action...
November 2015: Cell Calcium
https://www.readbyqxmd.com/read/26157160/suppressed-bone-remodeling-in-black-bears-conserves-energy-and-bone-mass-during-hibernation
#15
Meghan McGee-Lawrence, Patricia Buckendahl, Caren Carpenter, Kim Henriksen, Michael Vaughan, Seth Donahue
Decreased physical activity in mammals increases bone turnover and uncouples bone formation from bone resorption, leading to hypercalcemia, hypercalcuria, bone loss and increased fracture risk. Black bears, however, are physically inactive for up to 6 months annually during hibernation without losing cortical or trabecular bone mass. Bears have been shown to preserve trabecular bone volume and architectural parameters and cortical bone strength, porosity and geometrical properties during hibernation. The mechanisms that prevent disuse osteoporosis in bears are unclear as previous studies using histological and serum markers of bone remodeling show conflicting results...
July 2015: Journal of Experimental Biology
https://www.readbyqxmd.com/read/25843748/multivariate-analysis-of-subjective-responses-to-d-amphetamine-in-healthy-volunteers-finds-novel-genetic-pathway-associations
#16
Haley L Yarosh, Shashwath A Meda, Harriet de Wit, Amy B Hart, Godfrey D Pearlson
RATIONALE: Researchers studying behavioral and physiologic effects of d-amphetamine have explored individual response differences to the drug. Concurrently, genome-wide analyses have identified several single-nucleotide polymorphisms (SNPs) associated with these traits. Univariate methods can identify SNPs associated with behavioral and physiological traits, but multivariate analyses allow identification of clusters of related biologically relevant SNPs and behavioral components. OBJECTIVES: The aim of the study was to identify clusters of related biologically relevant SNPs and behavioral components in the responses of healthy individuals to d-amphetamine using multivariate analysis...
August 2015: Psychopharmacology
https://www.readbyqxmd.com/read/25724076/treatment-of-toxicity-from-amphetamines-related-derivatives-and-analogues-a-systematic-clinical-review
#17
REVIEW
John R Richards, Timothy E Albertson, Robert W Derlet, Richard A Lange, Kent R Olson, B Zane Horowitz
BACKGROUND: Overdose of amphetamine, related derivatives, and analogues (ARDA) continues to be a serious worldwide health problem. Patients frequently present to the hospital and require treatment for agitation, psychosis, and hyperadrenegic symptoms leading to pathologic sequelae and mortality. OBJECTIVE: To review the pharmacologic treatment of agitation, psychosis, and the hyperadrenergic state resulting from ARDA toxicity. METHODS: MEDLINE, PsycINFO, and the Cochrane Library were searched from inception to September 2014...
May 1, 2015: Drug and Alcohol Dependence
https://www.readbyqxmd.com/read/25540101/peripheral-oxytocin-activates-vagal-afferent-neurons-to-suppress-feeding-in-normal-and-leptin-resistant-mice-a-route-for-ameliorating-hyperphagia-and-obesity
#18
Yusaku Iwasaki, Yuko Maejima, Shigetomo Suyama, Masashi Yoshida, Takeshi Arai, Kenichi Katsurada, Parmila Kumari, Hajime Nakabayashi, Masafumi Kakei, Toshihiko Yada
Oxytocin (Oxt), a neuropeptide produced in the hypothalamus, is implicated in regulation of feeding. Recent studies have shown that peripheral administration of Oxt suppresses feeding and, when infused subchronically, ameliorates hyperphagic obesity. However, the route through which peripheral Oxt informs the brain is obscure. This study aimed to explore whether vagal afferents mediate the sensing and anorexigenic effect of peripherally injected Oxt in mice. Intraperitoneal Oxt injection suppressed food intake and increased c-Fos expression in nucleus tractus solitarius to which vagal afferents project...
March 1, 2015: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
https://www.readbyqxmd.com/read/25284318/excitatory-synaptic-function-and-plasticity-is-persistently-altered-in-ventral-tegmental-area-dopamine-neurons-after-prenatal-ethanol-exposure
#19
Kathryn Hausknecht, Samir Haj-Dahmane, Ying-Ling Shen, Paul Vezina, Cynthia Dlugos, Roh-Yu Shen
Prenatal ethanol exposure (PE) is one of the developmental factors leading to increased addiction propensity (risk). However, the neuronal mechanisms underlying this effect remain unknown. We examined whether increased excitatory synaptic transmission in ventral tegmental area (VTA) dopamine (DA) neurons, which is associated with drug addiction, was impacted by PE. Pregnant rats were exposed to ethanol (0 or 6 g/kg/day) via intragastric intubation from gestational day 8-20. Amphetamine self-administration, whole-cell recordings, and electron microscopy were performed in male offspring between 2 and 12-week-old...
March 2015: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/25246351/repeated-amphetamine-treatment-alters-spinal-magnetic-resonance-signals-and-pain-sensitivity-in-mice
#20
Bing-Hsuan Lei, Jyh-Horng Chen, Hsiang-Shu Yin
Manganese-enhanced magnetic resonance imaging (MEMRI) has been extensively used in studying the structural and functional features of the central nervous system (CNS). Divalent manganese ion (Mn(2+)) not only enhances MRI contrast, but also enters cells via voltage-gated calcium channels or ionotropic glutamate receptors, which represents an index of neural activities. In the current mouse model, following the repeated amphetamine (Amph) treatment, a reduction of reactivity to thermal pain stimulus was noticed...
November 7, 2014: Neuroscience Letters
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