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S Charntikov, A M Falco, K Fink, L P Dwoskin, R A Bevins
Nicotine is the primary addictive component of tobacco products and its complex stimulus effects are readily discriminated by human and non-human animals. Previous research with rodents directly investigating the nature of the nicotine stimulus has been limited to males. The current study began to address this significant gap in the literature by training female and male rats to discriminate 0.4 mg/kg nicotine from saline in the discriminated goal-tracking task. In this task, access to sucrose was intermittently available on nicotine session...
October 17, 2016: Neuropharmacology
Emmanuel Bourinet, Gerald W Zamponi
Venoms from various predatory species, such as fish hunting mollusks scorpions, snakes and arachnids contain a large spectrum of toxins that include blockers of voltage-gated calcium channels. These peptide blockers act by two principal manners - physical occlusion of the pore and prevention of activation gating. Many of the calcium channel-blocking peptides have evolved to tightly occupy their binding pocket on the principal pore forming subunit of the channel, often rendering block poorly reversible. Moreover, several of the best characterized blocking peptides have developed a high degree of channel subtype selectivity...
October 15, 2016: Neuropharmacology
Nan Zhang, Shengchang Yang, Chang Wang, Jianghua Zhang, Lifang Huo, Yiru Cheng, Chuan Wang, Zhanfeng Jia, Leiming Ren, Lin Kang, Wei Zhang
Alzheimer's disease (AD) and type II diabetes mellitus (DM2) are the most common aging-related diseases and are characterized by β-amyloid and amylin accumulation, respectively. Multiple studies have indicated a strong correlation between these two diseases. Amylin oligomerization in the brain appears to be a novel risk factor for developing AD. Although amylin aggregation has been demonstrated to induce cytotoxicity in neurons through altering Ca(2+) homeostasis, the underlying mechanisms have not been fully explored...
October 12, 2016: Neuropharmacology
Wei Sun, Fei Yang, Yan Wang, Han Fu, Yan Yang, Chun-Li Li, Xiao-Liang Wang, Qing Lin, Jun Chen
Under physiological state, small- and medium-sized dorsal root ganglia (DRG) neurons are believed to mediate nociceptive behavioral responses to painful stimuli. However, recently it has been found that a number of large-sized neurons are also involved in nociceptive transmission under neuropathic conditions. Nonetheless, the underlying mechanisms that large-sized DRG neurons mediate nociception are poorly understood. In the present study, the role of large-sized neurons in bee venom (BV)-induced mechanical allodynia and the underlying mechanisms were investigated...
October 12, 2016: Neuropharmacology
Xiaotian T Fang, Jonas Eriksson, Gunnar Antoni, Ulrika Yngve, Linda Cato, Lars Lannfelt, Dag Sehlin, Stina Syvänen
Alzheimer's disease (AD) is characterized by aggregation of amyloid beta (Aβ) into insoluble plaques. Intermediates, Aβ oligomers (Aβo), appear to be the mechanistic cause of disease. The de facto PET AD ligand, [(11)C]PIB, binds and visualizes Aβ plaque load, which does not correlate well with disease severity. Therefore, finding a dynamic target that changes with pathology progression in AD is of great interest. Aβo alter synaptic plasticity, inhibit long-term potentiation, and facilitate long-term depression; key mechanisms involved in memory and learning...
October 12, 2016: Neuropharmacology
Santhanalakshmi Sundaramurthy, Balasubramaniam Annamalai, Devadoss J Samuvel, Toni S Shippenberg, Lankupalle D Jayanthi, Sammanda Ramamoorthy
Kappa opioid receptor (KOR) agonists produce dysphoria and psychotomimesis. While KOR agonists produce pro-depressant-like effects, KOR antagonists produce anti-depressant-like effects in rodent models. The cellular mechanisms and downstream effector(s) by which KOR ligands produce these effects are not clear. KOR agonists modulate serotonin (5-HT) transmission in the brain regions implicated in mood and motivation regulation. Presynaptic serotonin transporter (SERT) activity is critical in the modulation of synaptic 5-HT and, subsequently, in mood disorders...
October 12, 2016: Neuropharmacology
Amit Modgil, Manasa L Parakala, Mike A Ackley, James J Doherty, Stephen J Moss, Paul A Davies
The neuroactive steroid (NAS) tetrahydrodeoxycorticosterone (THDOC) increases protein kinase C (PKC) mediated phosphorylation of extrasynaptic GABAA receptor (GABAAR) subunits leading to increased surface expression of α4/β3 subunit-containing extrasynaptic GABAARs, leading to a sustained increase in GABAAR tonic current density. Whether other naturally occurring and synthetic NASs share both an allosteric and metabotropic action on GABAARs is unknown. Here, we examine the allosteric and metabotropic properties of allopregnanolone (ALLO), and synthetic NASs SGE-516 and ganaxolone...
October 12, 2016: Neuropharmacology
Michela De Bellis, Roberta Carbonara, Julien Roussel, Alessandro Farinato, Ada Massari, Sabata Pierno, Marilena Muraglia, Filomena Corbo, Carlo Franchini, Maria Rosaria Carratù, Annamaria De Luca, Diana Conte Camerino, Jean-François Desaphy
Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers...
October 12, 2016: Neuropharmacology
Ermelinda Lomazzo, Florian König, Leila Abassi, Ruth Jelinek, Beat Lutz
Persistent stress triggers a variety of mechanisms, which may ultimately lead to the occurrence of anxiety- and depression-related disorders. Epigenetic modifications represent a mechanism by which chronic stress mediates long-term effects. Here, we analyzed brain tissue from mice exposed to chronic unpredictable stress (CUS), which induced impaired emotional and nociceptive behaviors. As endocannabinoid (eCB) and neuropeptide-Y (Npy) systems modulate emotional processes, we hypothesized that CUS may affect these systems through epigenetic mechanisms...
October 10, 2016: Neuropharmacology
Simonnet A, Zamberletti E, Cador M, Rubino T, Caillé S
The role of the endocannabinoid system in nicotine addiction is being increasingly acknowledged. Acute inhibition of anandamide (AEA) degradation efficiently reduces nicotine withdrawal-induced affective symptoms in rats and fatty acid amide hydrolase (FAAH), the degradation enzyme of AEA, has been proposed as a possible treatment against nicotine addiction. However, it is unclear whether chronic inhibition of AEA during nicotine abstinence will have beneficial or deleterious affective side-effects. Using a rat model of nicotine addiction, we found that, during abstinence, rats injected daily with a FAAH inhibitor (URB597) developed a depressive-like phenotype...
October 10, 2016: Neuropharmacology
Morgane Milienne-Petiot, James P Kesby, Mary Graves, Jordy van Enkhuizen, Svetlana Semenova, Arpi Minassian, Athina Markou, Mark A Geyer, Jared W Young
BACKGROUND: Bipolar disorder (BD) mania patients exhibit poor cognition and reward-seeking/hypermotivation, negatively impacting a patient's quality of life. Current treatments (e.g., lithium), do not treat such deficits. Treatment development has been limited due to a poor understanding of the neural mechanisms underlying these behaviors. Here, we investigated putative mechanisms underlying cognition and reward-seeking/motivational changes relevant to BD mania patients using two validated mouse models and neurochemical analyses...
October 9, 2016: Neuropharmacology
Fair M Vassoler, David J Oliver, Cristina Wyse, Ashley Blau, Michael Shtutman, Jill R Turner, Elizabeth M Byrnes
The United States is in the midst of an opiate epidemic, with abuse of prescription and illegal opioids increasing steadily over the past decade. While it is clear that there is a genetic component to opioid addiction, there is a significant portion of heritability that cannot be explained by genetics alone. The current study was designed to test the hypothesis that maternal exposure to opioids prior to pregnancy alters abuse liability in subsequent generations. Female adolescent Sprague Dawley rats were administered morphine at increasing doses (5-25 mg/kg, s...
October 8, 2016: Neuropharmacology
David M Housley, Gary D Housley, Michael J Liddell, Ernest A Jennings
This review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes...
October 8, 2016: Neuropharmacology
J T Gass, J T McGonigal, L J Chandler
Alcoholism is a chronic relapsing disorder characterized by periods of heavy alcohol consumption and unsuccessful attempts at abstinence. Relapse is one of the most problematic aspects in the treatment of alcoholism and is triggered by ethanol-associated cues. Extinction-based cue exposure therapies have proven ineffective in the treatment of alcoholism. However, positive allosteric modulation of mGlu5 with CDPPB enhances the extinction learning of alcohol-seeking behavior. The current study investigated the impact of chronic alcohol exposure on the extinction of ethanol-seeking behavior...
October 7, 2016: Neuropharmacology
M J Skelly, O J Ariwodola, J L Weiner
Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region...
October 5, 2016: Neuropharmacology
Agnieszka Potasiewicz, Małgorzata Hołuj, Tomasz Kos, Piotr Popik, Hugo R Arias, Agnieszka Nikiforuk
The cognitive impairments and negative symptoms experienced by schizophrenia patients still await effective treatment. Alpha7 nicotinic acetylcholine receptors (α7 nAChRs) have gain considerable attention in this regard. It has been recently proposed that positive allosteric modulators (PAMs) of α7 nAChRs may represent an alternative strategy to that based on orthosteric agonists. The aim of the present study is to evaluate the efficacy of PAM-2 (3-furan-2-yl-N-p-tolyl-acrylamide) against cognitive deficits and negative-like symptoms in a rat model of schizophrenia based on administration of ketamine, a NMDAR antagonist...
October 4, 2016: Neuropharmacology
Luiz Luciano Falconi-Sobrinho, Tayllon Dos Anjos-Garcia, Daoud Hibrahim Elias Filho, Norberto Cysne Coimbra
The medial prefrontal cortex can influence unconditioned fear-induced defensive mechanisms organised by diencephalic neurons that are under tonic GABAergic inhibition. The posterior hypothalamus (PH) is involved with anxiety- and panic attack-like responses. To understand this cortical mediation, our study characterised anterior cingulate cortex (ACC)-PH pathways and investigated the effect of ACC local inactivation with lidocaine. We also investigated the involvement of PH ionotropic glutamate receptors in the defensive behaviours and fear-induced antinociception by microinjecting NBQX (an AMPA/kainate receptor antagonist) and LY235959 (a NMDA receptor antagonist) into the PH...
October 3, 2016: Neuropharmacology
Prashanth Komirishetty, Aparna Areti, Ranadeep Gogoi, Ramakrishna Sistla, Ashutosh Kumar
Neuropathic pain, a debilitating pain condition and the underlying pathogenic mechanisms are complex and interwoven amongst each other and still there is scant information available regarding therapies which promise to treat the condition. Evidence indicate that oxidative/nitrosative stress induced poly (ADP-ribose) polymerase (PARP) overactivation initiate neuroinflammation and bioenergetic crisis culminating into neurodegenerative changes following nerve injury. Hence, we investigated the therapeutic effect of combining an antioxidant, quercetin and a PARP inhibitor, 4-amino 1, 8-naphthalimide (4-ANI) on the hallmark deficits induced by chronic constriction injury (CCI) of sciatic nerve in rats...
October 3, 2016: Neuropharmacology
Daniela Elgueta, María S Aymerich, Francisco Contreras, Andro Montoya, Marta Celorrio, Estefanía Rojo-Bustamante, Eduardo Riquelme, Hugo González, Mónica Vásquez, Rafael Franco, Rodrigo Pacheco
Neuroinflammation involves the activation of glial cells, which is associated to the progression of neurodegeneration in Parkinson's disease. Recently, we and other researchers demonstrated that dopamine receptor D3 (D3R)-deficient mice are completely refractory to neuroinflammation and consequent neurodegeneration associated to the acute intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we examined the therapeutic potential and underlying mechanism of a D3R-selective antagonist, PG01037, in mice intoxicated with a chronic regime of administration of MPTP and probenecid (MPTPp)...
September 28, 2016: Neuropharmacology
Wanhong Zuo, Liwei Wang, Lixin Chen, Krešimir Krnjević, Rao Fu, Xia Feng, Wen He, Seungwoo Kang, Avi Shah, Alex Bekker, Jiang-Hong Ye
Ethanol's aversive property may limit it's use, but the underlying mechanisms are no well-understood. Emerging evidence suggests a critical role for the lateral habenula (LHb) in the aversive response to various drugs, including ethanol. We previously showed that ethanol enhances glutamatergic transmission and stimulates LHb neurons. GABAergic transmission, a major target of ethanol in many brain regions, also tightly regulates LHb activity. This study assessed the action of ethanol on LHb GABAergic transmission in rat brain slices...
September 25, 2016: Neuropharmacology
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