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Thrombosis Research
June 2018
Huntingtin protein: A new option for fixing the Huntington's disease countdown clock
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Marco Caterino, Tiziana Squillaro, Daniela Montesarchio, Antonio Giordano, Concetta Giancola, Mariarosa A.B. Melone Huntington's disease is a dreadful, incurable disorder. It springs from the autosomal dominant mutation in the first exon of the HTT gene, which encodes for the huntingtin protein (HTT) and results in progressive neurodegeneration. Thus far, all the attempted approaches to tackle the mutant HTT-induced toxicity causing this disease have failed. The mutant protein comes with the aberrantly expanded poly-glutamine tract. It is primarily to blame for the build-up of
June 2018
mGlu4 allosteric modulation for treating Parkinson's disease
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Delphine Charvin 2017 is the 200th anniversary of the first published description of Parkinson's disease (PD). Fifty years ago, the clinical benefit of levodopa was first documented, representing the most important advance in the treatment of PD so far. Among the novel targets identified in the last decade, positive allosteric modulators (PAM) of mGlu4 receptors show great promise, with the potential to change the paradigm of the PD treatment approach. mGlu4 PAMs have shown consistent efficacy in various preclinical models of PD, and entered clinical trials for the first time in 2017. This review synthesizes the rationale for mGlu4 PAM development for PD and progress to date, reporting the key achievements from preclinical studies to the first-in-class compound assessment in man.
June 2018
Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Louise Ritchie, Rothwell Tate, Luke H. Chamberlain, Graham Robertson, Michele Zagnoni, Teresa Sposito, Selina Wray, John A. Wright, Clare E. Bryant, Nicholas J. Gay, Trevor J. Bushell Toll like receptor 3 (TLR3) belongs to a family of pattern recognition receptors that recognise molecules found on pathogens referred to as pathogen associated molecular patterns (PAMPs). Its involvement in innate immunity is well known but despite its presence in the central nervous system (CNS), our knowledge of its function is limited. Here, we have investigated whether TLR3 activation modulates synaptic activity in primary hippocampal cultures and induced pluripotent stem cell (iPSC)-derived neurons. Synaptically driven spontaneous action potential (AP) firing was significantly reduced by the TLR3 specific activator, poly I:C, in a concentration-dependent manner following both short (5
June 2018
Targeting the Dvl-1/
June 2018
The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Manoela V. Foga
June 2018
Levo-corydalmine alleviates vincristine-induced neuropathic pain in mice by inhibiting an NF-kappa B-dependent CXCL1/CXCR2 signaling pathway
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Lin Zhou, Yahui Hu, Chengyuan Li, Yunyi Yan, Luyao Ao, Boyang Yu, Weirong Fang, Jihua Liu, Yunman Li Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control inávivo experiments. The results revealed that both l-CDL and oxycodone attenuated vincristine-induced persistent pain hypersensitivity and proinflammatory factors release in mice. CXCL1 and CXCR2 were increased from 6 to 14 days after vincristine administration in the spinal cord. In addition, vincristine injection induced the phosphorylation of NF
June 2018
Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimerĺs disease
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Ana Knezovic, Jelena Osmanovic Barilar, Ana Babic, Robert Bagaric, Vladimir Farkas, Peter Riederer, Melita Salkovic-Petrisic Insulin resistance and metabolic dysfunction in the brain are considered to be the pathophysiological core of sporadic Alzheimer's disease (sAD). In line with that fact, nutrients that could have therapeutic effects at this level have been investigated as possible targets in AD therapy. Galactose, an epimer of glucose, may serve as an alternative source of energy, and given orally may stimulate secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Our preliminary research indicated that oral galactose might prevent development of memory impairment in a rat model of sAD generated by intracerebroventricular administration of streptozotocin (STZ-icv). Here, we explored whether chronic oral galactose treatment could have beneficial effects on cognitive deficits already manifested at the time of initiation of galactose treatment in adult STZ-icv rats (treatment initiated 1 month after STZ-icv injection). The results clearly show that a 2-month exposure to oral galactose (200
June 2018
Deep brain stimulation and fluoxetine exert different long-term changes in the serotonergic system
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Julien Volle, Tatiana Bregman, Brian Scott, Mustansir Diwan, Roger Raymond, Paul J. Fletcher, Jos
June 2018
Striatal GluN2B involved in motor skill learning and stimulus-response learning
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Yanhong Duan, Qi Wang, Qingwen Zeng, Jiayue Wang, Zhenzhen Chen, Meichen Xu, Yale Duan, Zheng Zhao, Qingsheng Xue, Xiaohua Cao Although the striatum has a well-documented role in procedural learning and memory, the underlying mechanisms remain poorly understood. GluN2B subunit is abundantly expressed in striatum, however, the function of striatal GluN2B subunit in striatum-related learning is also unclear. In the present study, using transgenic mice with forebrain-specific overexpression of the GluN2B subunit, we observed that up-regulation of GluN2B subunit expression results in enhanced dorsal striatum-related motor skill learning and stimulus-response (S-R) learning as well as cortico-dorsomedial striatal (cortico-DMS) long-term potentiation (LTP). Consistent with the above results, we also found that GluN2B transgenic mice exhibited a remarkable increase in N-methyl-d-aspartic acid receptor (NMDAR) mediated currents in the dorsomedial striatum. In addition, in order to further verify that striatal GluN2B is involved in the dorsal striatum-related cognitive function, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of GluN2B gene in the dorsomedial striatum. As a consequence of down-regulation of dorsomedial striatal GluN2B subunit expression, defective motor skill learning and S-R learning were observed in the GluN2B-shRNA mice. Furthermore, the impaired cortico-DMS LTP, as well as decreased NMDAR mediated currents in the dorsomedial striatum were also detected. Taken together, our findings demonstrate for the first time that striatal GluN2B subunit plays an important role in the dorsal striatum-related motor skill learning and S-R learning and provide further evidence that the cortico-DMS LTP underlies dorsal striatum-related motor skill learning and S-R learning.
June 2018
Metabotropic glutamate receptor subtype 7 in the dorsal striatum oppositely modulates pain in sham and neuropathic rats
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Ida Marabese, Serena Boccella, Monica Iannotta, Livio Luongo, Vito de Novellis, Francesca Guida, Nicola Serra, Antonio Farina, Sabatino Maione, Enza Palazzo The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N
June 2018
Rhynchophylline suppresses soluble A
June 2018
Altered hippocampal synaptic function in transgenic mice with increased astrocyte expression of CCL2 after withdrawal from chronic alcohol
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Jennifer G. Bray, Kenneth C. Reyes, Amanda J. Roberts, Donna L. Gruol CNS actions of the chemokine CCL2 are thought to play a role in a variety of conditions that can have detrimental consequences to CNS function, including alcohol use disorders. We used transgenic mice that express elevated levels of CCL2 in the CNS (CCL2-tg) and their non-transgenic (non-tg) littermate control mice to investigate long-term consequences of CCL2/alcohol/withdrawal interactions on hippocampal synaptic function, including excitatory synaptic transmission, somatic excitability, and synaptic plasticity. Two alcohol exposure paradigms were tested, a two-bottle choice alcohol (ethanol) drinking protocol (2BC drinking) and a chronic intermittent alcohol (ethanol) (CIE/2BC) protocol. Electrophysiological measurements of hippocampal function were made exávivo, starting
June 2018
Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Joanna Motyl,
June 2018
Retigabine ameliorates acute stress-induced impairment of spatial memory retrieval through regulating USP2 signaling pathways in hippocampal CA1 area
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Cai Li, Ji Zhang, Haiwei Xu, Mujun Chang, Chuntao Lv, Wenhua Xue, Zhizhen Song, Lizhen Zhang, Xiaojian Zhang, Xin Tian Acute stress could trigger maladaptive changes associated with stress-related cognitive and emotional deficits. Dysfunction of ion channel or receptor in the hippocampal area has been linked to the cognitive deficits induced by stress. It is known that Kv7 channel openers, including FDA-approved drug retigabine, show cognitive protective efficacy. However, the underlying molecular mechanisms remain elusive. Here we showed that exposing adult male rats to acute stress significantly impaired the spatial memory, a cognitive process controlled by the hippocampus. Concomitantly, significantly reduced AMPA receptor expression was found in hippocampal CA1 area from acute stressed rats. This effect relied on the down-regulation of deubiquitinating enzyme USP2 and its upstream regulators (PGC-1
June 2018
Antidepressant-like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 (AGTR2) and recruitment of FYN
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Cassiano R.A.F. Diniz, Plinio C. Casarotto, Senem M. Fred, Caroline Biojone, Eero Castr
June 2018
Paradoxical kinesia induced by appetitive 50-kHz ultrasonic vocalizations in rats depends on glutamatergic mechanisms in the inferior colliculus
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Luan Castro Tonelli, Markus W
June 2018
Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Pierpaolo Cerullo, Paola Brancaccio, Serenella Anzilotti, Antonio Vinciguerra, Ornella Cuomo, Ferdinando Fiorino, Beatrice Severino, Paola Di Vaio, Gianfranco Di Renzo, Lucio Annunziato, Giuseppe Pignataro Hypoxic-ischemic encephalopathy (HI) accounts for the majority of developmental, motor and cognitive deficits in children, leading to life-long neurological impairments. Since the plasmamembrane sodium/calcium exchanger (NCX) plays a fundamental role in maintaining ionic homeostasis during adult brain ischemia, in the present work we aimed to demonstrate (1)the involvement of NCX in the pathophysiology of neonatal HI and (2)a possible NCX-based pharmacological intervention. HI was induced in neonatal mice at postnatal day 7(P7) by unilateral cut of the right common carotid artery, followed by 60
June 2018
Acidosis mediates recurrent hypoglycemia-induced increase in ischemic brain injury in treated diabetic rats
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Ashish K. Rehni, Vibha Shukla, Miguel A. Perez-Pinzon, Kunjan R. Dave Objectives Cerebral ischemia is a serious possible manifestation of diabetic vascular disease. Recurrent hypoglycemia (RH) enhances ischemic brain injury in insulin-treated diabetic (ITD) rats. In the present study, we determined the role of ischemic acidosis in enhanced ischemic brain damage in RH-exposed ITD rats. Methods Diabetic rats were treated with insulin and mild/moderate RH was induced for 5 days. Three sets of experiments were performed. The first set evaluated the effects of RH exposure on global cerebral ischemia-induced acidosis in ITD rats. The second set evaluated the effect of an alkalizing agent (Tris-(hydroxymethyl)-aminomethane: THAM) on ischemic acidosis-induced brain injury in RH-exposed ITD rats. The third experiment evaluated the effect of the glucose transporter (GLUT) inhibitor on ischemic acidosis-induced brain injury in RH-exposed ITD rats. Hippocampal pH and lactate were measured during ischemia and early reperfusion for all three experiments. Neuronal survival in Cornu Ammonis 1 (CA1) hippocampus served as a measure of ischemic brain injury. Findings Prior RH exposure increases lactate concentration and decreases pH during ischemia and early reperfusion when compared to controls. THAM and GLUT inhibitor treatments attenuated RH-induced increase in ischemic acidosis. GLUT inhibitor treatment reduced the RH-induced increase in lactate levels. Both THAM and GLUT inhibitor treatments significantly decreased ischemic damage in RH-exposed ITD rats. Conclusions Ischemia causes increased acidosis in RH-exposed ITD rats via a GLUT-sensitive mechanism. Exploring downstream pathways may help understand mechanisms by which prior exposure to RH increases cerebral ischemic damage.
June 2018
Opioid and noradrenergic contributions of tapentadol to the inhibition of locus coeruleus neurons in the streptozotocin rat model of polyneuropathic pain
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Sonia Torres-Sanchez, Gisela Da Silva Borges, Juan A. Mico, Esther Berrocoso Tapentadol is an analgesic that acts as an agonist of Á opioid receptors (MOR) and that inhibits noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats, a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons. Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists, respectively). In STZ rats, the spontaneous activity of LC neurons (0.9
June 2018
Inhibition of mitochondrial permeability transition pore opening contributes to cannabinoid type 1 receptor agonist ACEA-induced neuroprotection
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Lei Ma, Wen Niu, Shuai Yang, Junbin Tian, Hanlin Luan, Ming Cao, Wenbin Xi, Weifeng Tu, Ji Jia, Jianrui Lv Cannabinoid type 1 (CB1) receptor agonist arachidonyl-2-chloroethylamide (ACEA) induces neuroprotection against brain ischemia, and the mechanism, however, is still elusive. In this study, we used bilateral common carotid artery occlusion (BCCAO) in mice and oxygen-glucose deprivation (OGD) in primary cultured neurons to mimic brain ischemic injury, and hypothesized that cannabinoid CB1 receptor agonist ACEA protects ischemic neurons via inhibiting the opening of mitochondrial permeability transition pore (MPTP). Inávivo, we found that BCCAO treatment reduced the neurological functions, increased the number of apoptotic neuronal cells and deteriorated the mitochondrial morphology in the ischemic brain tissue. And inávitro, we observed that OGD injury reduced cell viability, mitochondrial function and anti-oxidant SOD2 expression, increased lactate dehydrogenase (LDH), mitochondrial cytochrome C (Cyto C) and apoptosis-inducing factor (AIF) releases, elevated the cell apoptosis and mitochondrial superoxide level. And the CB1 receptor agonist ACEA significantly abolished the BCCAO and OGD-induced neuronal injury above. However, the MPTP opener atractyloside (Atr) markedly reversed the ACEA-induced neuroprotective effects, inhibited the mitochondrial Cyto C and AIF releases and relieved the mitochondrial swelling, but the MPTP inhibitor cyclosporin A (CsA) did not cause significant effects on the ACEA-induced neuroprotection above. These findings indicated that inhibition of MPTP opening may be involved in the cannabinoid CB1 receptor agonist ACEA-induced neuroprotection.
June 2018
Dynamic changes in hippocampal microglia contribute to depressive-like behavior induced by early social isolation
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Yu Gong, Lijuan Tong, Rongrong Yang, Wenfeng Hu, Xingguo Xu, Wenjing Wang, Peng Wang, Xu Lu, Minhui Gao, Yue Wu, Xing Xu, Yaru Zhang, Zhuo Chen, Chao Huang Depression triggered by early-life stress has begun to attract wide attention due to its severe symptoms and poor treatment outcomes. However, the pathophysiological mechanism for this type of depression remains unclear. Recently, we and others reported that different types of chronic stress induce a significant loss of hippocampal microglia, which is mediated by an initial activation of these microglia. Since early-life stress also promotes microglial activation, we investigated the dynamic changes in hippocampal microglia in mice suffering from depression induced by early social isolation (ESI). Results showed that 8 days of ESI induced depressive-like behaviors in a tail suspension test, forced swim test, sucrose preference test, and open field test, and it also induced a loss and dystrophy of hippocampal microglia. We found that this ESI-induced loss of hippocampal microglia was mediated by both microglial activation and apoptosis. This was demonstrated by the following results: (i) 1 day of ESI induced an obvious activation of hippocampal microglia followed by their apoptosis, and (ii) the blockade of the initial activation of hippocampal microglia by minocycline pretreatment suppressed the ESI-induced apoptosis and loss as well as ESI-induced depressive-like behavior. Lipopolysaccharide (LPS) and macrophage colony-stimulating factor (M-CSF), two activators of microglia, almost completely reversed ESI-induced depressive-like behavior by promoting microglial proliferation in the hippocampus. These results reveal an etiological role of hippocampal microglial loss in ESI-induced depression and demonstrate that the restoration of microglial homeostasis in the hippocampus may serve as a therapeutic strategy for depression induced by early-life stress.
June 2018
Histamine-deficient mice do not respond to the antidepressant-like effects of oleoylethanolamide
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Alessia Costa, Claudia Cristiano, Tommaso Cassano, Cristina Anna Gallelli, Silvana Gaetani, Carla Ghelardini, Patrizio Blandina, Antonio Calignano, M. Beatrice Passani, Gustavo Provensi It has been suggested that the bioactive lipid mediator oleoylethanolamide (OEA), a potent agonist of the peroxisome proliferator-activated receptor-alpha (PPAR-
June 2018
Novel oxindole derivatives prevent oxidative stress-induced cell death in mouse hippocampal HT22
June 2018
Role of dorsal hippocampus
June 2018
Proteomic characterization of hippocampus of chronically socially isolated rats treated with fluoxetine: Depression-like behaviour and fluoxetine mechanism of action
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Ivana Peri
June 2018
The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): S. Morley-Fletcher, A.R. Zuena, J. Mairesse, E. Gatta, G. Van Camp, H. Bouwalerh, B. Riozzi, G. Battaglia, A. Pittaluga, G. Olivero, E. Mocaer, S. Bretin, F. Nicoletti, S. Maccari S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties. Here, the drug was assessed in the perinatal stress (PRS) rat model, known to have a high predictive validity with monoaminergic antidepressants. The effects of a chronic treatment (i.p.) with S 47445 were investigated on risk-taking, motivational and cognitive behavior. S 47445 (1 and 10
June 2018
Nucleus accumbens GLT-1a overexpression reduces glutamate efflux during reinstatement of cocaine-seeking but is not sufficient to attenuate reinstatement
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Carly N. Logan, Amber L. LaCrosse, Lori A. Knackstedt Cocaine use disorder is a chronically relapsing disease without FDA-approved treatments. Using a rodent model of cocaine relapse, we and others have previously demonstrated that the beta-lactam antibiotic ceftriaxone attenuates cue- and cocaine-primed reinstatement of cocaine-seeking. Ceftriaxone restores cocaine-induced deficits in both system xc- and GLT-1 expression and function in the nucleus accumbens core (NAc). We recently demonstrated that restoration of GLT-1 expression in the NAc is necessary for ceftriaxone to attenuate reinstatement of cocaine-seeking. Here we used an adeno-associated virus (AAV) to overexpress GLT-1a in the NAc to investigate whether such restoration is sufficient to attenuate cue- and cocaine-primed reinstatement. Rats self-administered cocaine for two weeks and received injections of either AAV-GFAP-GLT-1a or AAV-GFAP-eGFP in the NAc following the last day of self-administration. Rats then underwent three weeks of extinction training (during which time transduction and expression occurred) before undergoing a cue- or cocaine-primed reinstatement test. Microdialysis for the quantification of glutamate efflux in the NAc was conducted during the cocaine-primed test. Rats that received AAV-GFAP-GLT-1a reinstated cue-primed cocaine-seeking in a similar manner as rats that received the control AAV-GFAP-eGFP. Upregulation of GLT-1a attenuated glutamate efflux during a cocaine-primed reinstatement test, but was not sufficient to attenuate reinstatement. We confirmed that GLT-1a upregulation resulted in functional upregulation of glutamate transport and expression, without affecting sodium-independent glutamate uptake, indicating system xc-was not altered. These results indicate that upregulation of NAc GLT-1 transporters alone is not sufficient to prevent the reinstatement of cocaine-seeking and implicate additional mechanisms in regulating glutamate efflux.
June 2018
Effects of drugs of abuse on channelrhodopsin-2 function
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Dominic A. Gioia, Minfu Xu, Wesley N. Wayman, John J. Woodward Channelrhodopsins are light activated ion channels used extensively over the past decade to probe the function of genetically defined neuronal populations and distinct neural circuits with high temporal and spatial precision. The widely used Channelrhodopsin-2 variant (ChR2) is an excitatory opsin that undergoes conformational changes in response to blue light, allowing non-selective passage of protons and cations across the plasma membrane thus leading to depolarization. In the addiction neuroscience field, opsins such as ChR2 provide a means to disambiguate the overlapping circuitry involved in mediating the reinforcing and aversive effects of drugs of abuse as well as to determine the plasticity that can occur in these circuits during the development of dependence. Although ChR2 has been widely used in animal models of drug and alcohol self-administration, direct effects of drugs of abuse on ChR2 function may confound its use and lead to misinterpretation of data. As a variety of neuronal ion channels are primary targets of various drugs of abuse, it is critical to determine whether ChR2-mediated currents are modulated by these drugs. In this study, we performed whole-cell electrophysiological recordings in HEK293
June 2018
Modality-specific peripheral antinociceptive effects of
June 2018
CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Matthew E. Tracy, Vesna Tesic, Tamara Timic Stamenic, Srdjan M. Joksimovic, Nicolas Busquet, Vesna Jevtovic-Todorovic, Slobodan M. Todorovic Recent data have implicated voltage-gated calcium channels in the regulation of the excitability of neurons within the mesolimbic reward system. While the attention of most research has centered on high voltage L-type calcium channel activity, the presence and role of the low voltage-gated T-type calcium channel (T-channels) has not been well explored. Hence, we investigated T-channel properties in the neurons of the ventral tegmental area (VTA) utilizing wild-type (WT) rats and mice, CaV3.1 knock-out (KO) mice, and TH-eGFP knock-in (KI) rats in acute horizontal brain slices of adolescent animals. In voltage-clamp experiments, we first assessed T-channel activity in WT rats with characteristic properties of voltage-dependent activation and inactivation, as well as characteristic crisscrossing patterns of macroscopic current kinetics. T-current kinetics were similar in WT mice and WT rats but T-currents were abolished in CaV3.1 KO mice. In ensuing current-clamp experiments, we observed the presence of hyperpolarization-induced rebound burst firing in a subset of neurons in WT rats, as well as dopaminergic and non-dopaminergic neurons in TH-eGFP KI rats. Following the application of a pan-selective T-channel blocker TTA-P2, rebound bursting was significantly inhibited in all tested cells. In a behavioral assessment, the acute locomotor increase induced by a MK-801 (Dizocilpine) injection in WT mice was abolished in CaV3.1 KO mice, suggesting a tangible role for 3.1
June 2018
Role of nitric oxide and WNK-SPAK/OSR1-KCC2 signaling in daily changes in GABAergic inhibition in the rat dorsal raphe neurons
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Mi Jung Kim, Hye Jin Yang, Younghoon Kim, Insug Kang, Sung Soo Kim, Young-Wuk Cho Serotonergic neurons in the dorsal raphe nucleus (DRN) act as wake-inducing neurons in the sleep-wake cycle and are controlled by gamma-aminobutyric acid (GABA) synaptic inputs. We investigated daily changes in GABAergic inhibition of the rat DRN neurons and the role of nitric oxide (NO) and cation-chloride co-transporters in the GABAergic action. Neuronal NO synthase (nNOS) was co-expressed in 74% of serotonergic DRN neurons and nNOS expression was higher during daytime (the sleep cycle) than that during nighttime (the wake cycle). GABAergic hyperpolarization of DRN neurons produced by GABAA receptor agonist muscimol was greater and the equilibrium potential of muscimol showed a hyperpolarizing shift during daytime compared to that during nighttime. Expression levels of potassium-chloride co-transporter 2 (KCC2) were higher during daytime than that during nighttime, whereas there were no changes in sodium-potassium-chloride co-transporter 1 (NKCC1) expression. With-no-lysine kinase (WNK) isoform 1 was more highly expressed during daytime than that during nighttime. Total Ste20-related proline alanine rich kinase (SPAK) and oxidative stress response kinase 1 (OSR1) were also higher during daytime than during nighttime, while there were no changes in phosphorylated SPAK and OSR1. Consistent with the findings during the sleep-wake cycle, exávivo treatment of DRN slices with a NO donor sodium nitroprusside (SNP) increased the expression of KCC2, WNK1, WNK2, WNK3, SPAK, and OSR1, whilst decreasing phosphorylated SPAK. These results suggest that GABAergic synaptic inhibition of DRN serotonergic neurons shows daily changes during the sleep-wake cycle, which might be regulated by daily changes in nNOS-derived NO and WNK-SPAK/OSR1-KCC2 signaling.
June 2018
Brain tissue oxygen regulation in awake and anesthetized neonates
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Daniil P. Aksenov, Andrey V. Dmitriev, Michael J. Miller, Alice M. Wyrwicz, Robert A. Linsenmeier Inhaled general anesthetics are used commonly in adults and children, and a growing body of literature from animals and humans suggests that exposure to anesthesia at an early age can impact brain development. While the origin of these effects is not well understood, it is known that anesthesia can disrupt oxygen regulation in the brain, which is critically important for maintaining healthy brain function. Here we investigated how anesthesia affected brain tissue oxygen regulation in neonatal rabbits by comparing brain tissue oxygen and single unit activity in the awake and anesthetized states. We tested two common general anesthetics, isoflurane and sevoflurane, delivered in both air and 80% oxygen. Our findings show that general anesthetics can greatly increase brain tissue PO2 in neonates, especially when combined with supplemental oxygen. Although isoflurane and sevoflurane belong to the same class of anesthetics, notable differences were observed in their effects upon neuronal activity and spontaneous respiration. Our findings point to the need to consider the potential effects of hyperoxia when supplemental oxygen is utilized, particularly in children and neonates.

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June 2018
Activation of 5-HT2C (but not 5-HT1A) receptors in the amygdala enhances fear-induced antinociception: Blockade with local 5-HT2C antagonist or systemic fluoxetine
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): L
June 2018
Propranolol produces short-term facilitation of extinction in a rabbit model of post-traumatic stress disorder
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Lauren B. Burhans, Carrie A. Smith-Bell, Bernard G. Schreurs Post-traumatic stress disorder (PTSD) is a learning-based anxiety disorder with significant public health challenges due to difficulties in treating the complex, multiple symptomology. We have developed an animal model of PTSD, based on Pavlovian eyeblink conditioning in rabbits, that addresses two key features: conditioned responses (CRs) to cues associated with an aversive event and a form of conditioned hyperarousal referred to as conditioning-specific reflex modification (CRM). We have found previously that unpaired extinction is ideal for reducing both CRs and CRM simultaneously and shows sensitivity to systemic serotonergic and glutamatergic manipulations. The following study aimed to extend our work to examine the role of the noradrenergic system, dysregulation of which is strongly implicated as part of the neurobiology of PTSD and which may also play a role in the balance shift from fear reconsolidation to extinction during treatment. The goal of the following two studies was to examine whether the
June 2018
Periaqueductal gray glutamatergic, cannabinoid and vanilloid receptor interplay in defensive behavior and aversive memory formation
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Franklin P. Back, Antonio P. Carobrez Stimulation of the midbrain periaqueductal gray matter (PAG) in humans elicits sensations of fear and impending terror, and mediates predator defensive responses in rodents. In rats, pharmacological stimulation of the dorsolateral portion of the PAG (dlPAG) with N-Methyl-d-Aspartate (NMDA) induces aversive conditioning that acts as an unconditioned stimulus (US). In the present work, we investigated the interplay between the vanilloid TRPV1 and cannabinoid CB1 receptors in the NMDA-dlPAG defensive response and in subsequent aversive learning. Rats were subjected to dlPAG NMDA infusion in an olfactory conditioned stimulus (CS) task allowing the evaluation of immediate and long-term defensive behavioral responses during CS presentation. The results indicated that an intermediate dose of NMDA (50
June 2018
Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Patrick D. Skosnik, Mih
June 2018
Lacosamide protects striatal and hippocampal neurons from inávitro ischemia without altering physiological synaptic plasticity
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Petra Mazzocchetti, Michela Tantucci, Guendalina Bastioli, Valeria Calabrese, Massimiliano Di Filippo, Alessandro Tozzi, Paolo Calabresi, Cinzia Costa Lacosamide ([(R)-2-acetamido-N-benzyl-3-methoxypropanamide], LCM), is an antiepileptic that exerts anticonvulsant activity by selectively enhancing slow sodium channel inactivation. By inhibiting seizures and neuronal excitability it might therefore be a good candidate to stabilize neurons and protect them from energetic insults. Using electrophysiological analyses, we have investigated in mice the possible neuroprotective effect of LCM against inávitro ischemia obtained by oxygen and glucose deprivation (ODG), in striatal and hippocampal tissues, two brain structures particularly susceptible to ischemic injury and of pivotal importance for different form of learning and memory. We also explored in these regions the influence of LCM on firing discharge and on long-term synaptic plasticity. We found that in both areas LCM reduced the neuronal firing activity in a use-dependent manner without influencing the physiological synaptic transmission, confirming its anticonvulsant effects. Moreover, we found that this AED is able to protect, in a dose dependent manner, striatal and hippocampal neurons from energy metabolism failure produced by OGD. This neuroprotective effect does not imply impairment of long-term potentiation of striatal and hippocampal synapses and suggests that LCM might exert additional beneficial therapeutic effects beyond its use as antiepileptic.
June 2018
Cocaine evokes a profile of oxidative stress and impacts innate antiviral response pathways in astrocytes
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Irma E. Cisneros, Mert Erdenizmenli, Kathryn A. Cunningham, Slobodan Paessler, Kelly T. Dineley HIV-1 and Zika virus (ZIKV) represent RNA viruses with neurotropic characteristics. Infected individuals suffer neurocognitive disorders aggravated by environmental toxins, including drugs of abuse such as cocaine, exacerbating HIV-associated neurocognitive disorders through a combination of astrogliosis, oxidative stress and innate immune signaling; however, little is known about how cocaine impacts the progression of ZIKV neural perturbations. Impaired innate immune signaling is characterized by weakened antiviral activation of interferon signaling and alterations in inflammatory signaling, factors contributing to cognitive sequela associated with cocaine in HIV-1/ZIKV infection. We employed cellular/molecular biology techniques to test if cocaine suppresses the efficacy of astrocytes to initiate a Type 1 interferon response to HIV-1/ZIKV, inávitro. We found cocaine activated antiviral signaling pathways and type I interferon in the absence of inflammation. Cocaine pre-exposure suppressed antiviral responses to HIV-1/ZIKV, triggering antiviral signaling and phosphorylation of interferon regulatory transcription factor 3 to stimulate type I interferon gene transcription. Our data indicate that oxidative stress is a major driver of cocaine-mediated astrocyte antiviral immune responses. Although astrocyte antiviral signaling is activated following detection of foreign pathogenic material, oxidative stress and increased cytosolic double-stranded DNA (dsDNA) can drive antiviral signaling via stimulation of pattern recognition receptors. Pretreatment with the glial modulators propentofylline (PPF) or pioglitazone (PIO) reversed cocaine-mediated attenuation of astrocyte responses to HIV-1/ZIKV. Both PPF/PIO protected against cocaine-mediated generation of reactive oxygen species (ROS), increased dsDNA, antiviral signaling pathways and increased type I interferon, indicating that cocaine induces astrocyte type I interferon signaling in the absence of virus and oxidative stress is a major driver of cocaine-mediated astrocyte antiviral immunity. Lastly, PPF and PIO have therapeutic potential to ameliorate cocaine-mediated dysregulation of astrocyte antiviral immunity possibly via a myriad of protective actions including decreases in reactive phenotype and damaging immune factors.

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June 2018
Antidepressant-like actions by silencing of neuronal ELAV-like RNA-binding proteins HuB and HuC in a model of depression in male mice
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Maria Domenica Sanna, Alessandro Quattrone, Nicoletta Galeotti Currently available antidepressant drugs often fail to achieve full remission and patients might evolve to treatment resistance, showing the need to achieve a better therapy of depressive disorders. Increasing evidence supports that post-transcriptional regulation of gene expression is important in neuronal development and survival and a relevant role is played by RNA binding proteins (RBP). To explore new therapeutic strategies, we investigated the role of the neuron-specific ELAV-like RBP (HuB, HuC, HuD) in a mouse model of depression. In this study, a 4-week unpredictable chronic mild stress (UCMS) protocol was applied to mice to induce a depressive-like phenotype. In the last 2 weeks of the UCMS regimen, silencing of HuB, HuC or HuD was performed by using specific antisense oligonucleotides (aODN). Treatment of UCMS-exposed mice with anti-HuB and anti-HuC aODN improved both anhedonia and behavioural despair, used as measures of depressive-like behaviour, without modifying the response of stressed mice to an anxiety-inducing environment. On the contrary, HuD silencing promoted an anxiolytic-like behaviour in UCMS-exposed mice without improving depressive-like behaviours. The antidepressant-like phenotype of anti-HuB and anti-HuC mice was not shown concurrently with the promotion of adult hippocampal neurogenesis in the dentate gyrus, and no increase in the BDNF and CREB content was detected. Conversely, in the CA3 hippocampal region, projection area of newly born neurons, HuB and HuC silencing increased the number of BrdU/NeuN positive cells. These results give the first indication of a role of nELAV in the modulation of emotional states in a mouse model of depression.
June 2018
The metabotropic glutamate receptor 5 radioligand [11C]AZD9272 identifies unique binding sites in primate brain
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Katarina Varn
June 2018
A novel pharmacological activity of caffeine in the cholinergic system
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Camila Fabiani, Ana Paula Murray, Jerem
June 2018
Dorsal CA1 interneurons contribute to acute stress-induced spatial memory deficits
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Jing-Ying Yu, Ping Fang, Chi Wang, Xing-Xing Wang, Kun Li, Qian Gong, Ben-Yan Luo, Xiao-Dong Wang Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs declarative memory. GABAergic interneurons coordinate neuronal network activity, but their involvement in stress-evoked memory loss remains to be elucidated. Here, we provide evidence that interneurons in area CA1 of the dorsal hippocampus partially modulate acute stress-induced memory deficits. In adult male mice, both acute forced swim stress and restraint stress impaired hippocampus-dependent spatial memory and increased the density of c-fos-positive interneurons in the dorsal CA1. Selective activation of dorsal CA1 interneurons by chemogenetics disrupted memory performance in the spatial object recognition task. In comparison, anxiety-related behavior, spatial working memory and novel object recognition memory remained intact when dorsal CA1 interneurons were overactivated. Moreover, chemogenetic activation of dorsal CA1 interneurons suppressed the activity of adjacent pyramidal neurons, whereas a single exposure to forced swim stress but not restraint stress increased the activity of CA1 pyramidal neurons. However, chemogenetic inhibition of dorsal CA1 interneurons led to spatial memory impairments and failed to attenuate acute stress-induced memory loss. These findings suggest that acute stress may overactivate interneurons in the dorsal CA1, which reduces the activity of pyramidal neurons and in turn disrupts long-term memory.
June 2018
The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamineľtriggered reinstatement of female rats
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Sergios Charntikov, Steven T. Pittenger, Cindy M. Pudiak, Rick A. Bevins N-acetylcysteine and bupropion are two promising candidate medications for treatment of substance use disorder. The effects of N-acetylcysteine or bupropion on methamphetamine self-administration of female rats are not well understood. To fill this gap, this study assessed the effects of N-acetylcysteine (0, 30, 60, or 120
June 2018
Inhalational anesthetics accelerate desensitization of acid-sensing ion channels
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Linda Lehmke, Mark Coburn, Manfred M
June 2018
Antidepressant-like effects of a novel curcumin derivative J147: Involvement of 5-HT1A receptor
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Lejing Lian, Ying Xu, Jianbo Zhang, Yingcong Yu, Naping Zhu, Xiaofei Guan, Hui Huang, Ruijie Chen, Jie Chen, Guilan Shi, Jianchun Pan Depression is a dysthymia disorder characterized by a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. J147, a curcumin analogue, increases brain derived neurotrophic factor (BDNF) levels and facilitates memory in animals. Because curcumin has the antidepressant-like activity, the present study investigated the potential antidepressant-like effects of J147 in the forced swimming test (FST) and tail suspension tests (TST) and the involvement of 5-HT receptors related to cAMP signaling. The results suggested that acute treatment of J147 at doses of 5 and 10
June 2018
Liver X receptor
June 2018
Maternal nicotine exposure effects on adolescent learning and memory are abolished in alpha(
1 May 2018
GluN2B/CaMKII mediates CFA-induced hyperalgesia via HDAC4-modified spinal COX2 transcription
Publication date: June 2018
Source:Neuropharmacology, Volume 135 Author(s): Cheng-Yuan Lai, Ming-Chun Hsieh, Yu-Cheng Ho, Gin-Den Chen, Dylan Chou, Ting Ruan, An-Sheng Lee, Hsueh-Hsiao Wang, Yat-Pang Chau, Hsien-Yu Peng, Cheng-Hung Lai Histone deacetylase 4 (HDAC4), which actively shuttles between the nucleus and cytoplasm, is an attractive candidate for a repressor mechanism in epigenetic modification. However, the potential role of HDAC4-dependent epigenetics in the neural plasticity underlying the development of inflammatory pain has not been well established. By injecting complete Freund's adjuvant (CFA) into the hind-paw of Sprague-Dawley rats (200ľ250
1 May 2018
Editorial Board
Publication date: 1 May 2018
Source:Neuropharmacology, Volume 133


Do ketone bodies mediate the anti-seizure effects of the ketogenic diet?
Publication date: 1 May 2018
Source:Neuropharmacology, Volume 133 Author(s): Timothy A. Simeone, Kristina A. Simeone, Carl E. Stafstrom, Jong M. Rho Although the mechanisms underlying the anti-seizure effects of the high-fat ketogenic diet (KD) remain unclear, a long-standing question has been whether ketone bodies (i.e.,
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