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Thrombosis Research
15 March 2018
Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Mohammad Zafar Imam, Andy Kuo, Sussan Ghassabian, Maree T. Smith Opioids evoke analgesia through activation of opioid receptors (predominantly the
15 March 2018
Post-reexposure administration of riluzole attenuates the reconsolidation of conditioned fear memory in rats
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Kie Akagi, Misa Yamada, Akiyoshi Saitoh, Jun-Ichiro Oka, Mitsuhiko Yamada Recently, we demonstrated that riluzole, which has been shown to block the glutamatergic system, facilitates fear extinction in rats. Here, we undertook experiments on contextual fear conditioning to clarify the actions of riluzole on the reconsolidation of fear memory in rats. We used the fast-acting benzodiazepine midazolam as a reconsolidation-inhibiting control drug. We demonstrated that riluzole (3 mg/kg) and midazolam (1 mg/kg) impaired the reconsolidation of contextual fear memory. Results from spontaneous recovery experiments also suggested that riluzole attenuated reconsolidation. Indeed, conditioned fear did not recover spontaneously 4 weeks after a short (3 min) reexposure and riluzole administration, whereas it recovered after a long (10 min) reexposure. Using western blotting, we demonstrated that a short reexposure increased the phosphorylation of cyclic adenosine monophosphate response element binding protein significantly in the dorsal part of hippocampus, but not in the medial prefrontal cortex. Interestingly, this phosphorylation was attenuated by riluzole with short reexposure. In addition, bilateral microinjection of riluzole (2
15 March 2018
Distinct roles of prelimbic and infralimbic proBDNF in extinction of conditioned fear
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Wei Sun, Xiaoliang Li, Lei An Brain-derived neurotrophic factor (BDNF) has been investigated for its positive role in regulation of fear acquisition and memory. The precursor of BDNF, proBDNF, has been identified as different protein from its mature form. The prelimbic (PL) and infralimbic (IL) sub-regions of the medial prefrontal cortex (mPFC) are functionally distinct in fear behavior. However, the role of PL and IL proBDNF in fear memory is unclear. Here, through the infusion of cleavage-resistant proBDNF and its antibody, we identified the dissociable roles of PL and IL proBDNF in fear expression and extinction memory as well as explored proBDNF's potential mechanism of action. The results suggest that the infusion of proBDNF in the IL facilitates induction of fear extinction, while infusion in the PL depresses fear expression. Blocking proBDNF by using its antibody disrupted the acquisition of fear extinction in the IL, but not the PL. Furthermore, proBDNF-induced extinction was sufficient for extinguishing new and older memories, and required NR2B, but not NR2A, -containing NMDA receptors. We also observed extinction-related proBDNF expression increased in the PL and IL during successful fear expression and extinction, respectively. Importantly, enhanced proBDNF was required for maintaining an extinguished behavior. The extinction effects of proBDNF did not involve degrading the original fear memory. Therefore, proBDNF in the IL and PL differentially contribute to the inhibitory control of fear extinction behavior. Our findings provide a strong link between proBDNF activity and deficits in fear extinction, a hallmark of several psychiatric disorders.
15 March 2018
Corticosterone impairs gap junctions in the prefrontal cortical and hippocampal astrocytes via different mechanisms
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Cong-Yuan Xia, Zhen-Zhen Wang, Zhao Zhang, Jiao Chen, Ying-Ying Wang, Yu-Xia Lou, Yan Gao, Piao Luo, Qian Ren, Guo-Hua Du, Nai-Hong Chen Increasing evidence has implicated astrocyte pathology in the etiopathology of major depressive disorder (MDD). In particular, dysfunction of gap junctions in astrocytes is a potential target for MDD treatment. However, the mechanism underlying stress-induced dysfunction of gap junctions is still unknown. We therefore studied the mechanism of stress-induced dysfunction of gap junctions in prefrontal cortical and hippocampal astrocytes. Corticosterone (CORT) was used to induce stress conditions; CORT damaged the function of gap junctions, which resulted from less distribution of connexin43 (Cx43) on membranes and the enhanced phosphorylation of Cx43 at S368. Moreover, CORT downregulated the biosynthesis of Cx43 but increased the degradation of Cx43. Interestingly, both autophagy and the proteasome system were involved in the degradation of Cx43 in prefrontal cortical astrocytes, but only the proteasome system was involved in the degradation of Cx43 in hippocampal astrocytes. CORT significantly induced the formation of annular gap junction vesicles in prefrontal cortical astrocytes; however, Cx43 mainly presented as small dots in the hippocampal astrocytes. Furthermore, CORT increased N-Cadherin expression and the interactions of Cx43 with ZO-1/drebrin in prefrontal cortical astrocytes, but these interactions were oppositely modulated in hippocampal astrocytes. In conclusion, this study clarified the alternations of the Cx43 life cycle in the prefrontal cortical and hippocampal astrocytes exposed to CORT, which may contribute to our understanding of the mechanisms underlying stress-induced dysfunction of gap junctions.
15 March 2018
Acute administration of roflumilast enhances immediate recall of verbal word memory in healthy young adults
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): M.A. Van Duinen, A. Sambeth, P.R.A. Heckman, S. Smit, M. Tsai, G. Lahu, T. Uz, A. Blokland, J. Prickaerts The need for new and effective treatments for dementia remains indisputably high. Phosphodiesterase inhibitors (PDE-Is) have proven efficacy as cognitive enhancers based on their positive effects in numerous preclinical studies. Especially the PDE4 subfamily is of interest due to its expression in the hippocampus, the key structure for memory formation. The current study investigates the memory enhancing effects of the clinically approved PDE4-I roflumilast in a test battery including the Verbal Learning Task (VLT) combined with electroencephalography (EEG) recording. This acute study was conducted according to a double-blind, randomized, placebo-controlled, 4-way crossover design. Three capsulated dosages of roflumilast HCl (Daxas) and a placebo were administered in four study periods. Administration occurred 1 h before testing to reach maximal plasma concentrations. Memory performance was assessed using a 30 word Verbal Learning Task. The number of words recalled both immediately and after 45 min and 24 h were included as outcome measures. EEG was recorded during the cognitive tasks on the first day. Different event-related potentials (ERPs) were considered with special emphasis on P600, as this peak has been related to word learning. Memory performance was significantly improved after acute administration of 100 
15 March 2018
Differential neuromodulatory role of endocannabinoids in the rodent trigeminal sensory ganglion and cerebral cortex relevant to pain processing
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Francesca Eroli, Inge C.M. Loonen, Arn M.J.M. van den Maagdenberg, Else A. Tolner, Andrea Nistri Endocannabinoids are suggested to control pain, even though their clinical use is not fully validated and the underlying mechanisms are incompletely understood. To clarify the targets of endocannabinoid actions, we studied how activation of the endocannabinoid CB1 receptor (CB1R) affects neuronal responses in two in vitro preparations of rodents, namely the trigeminal sensory ganglion (TG) in culture and a coronal slice of the cerebral cortex. On TG small-medium size neurons, we tested whether submicromolar concentrations of the endogenous CB1R agonist anandamide (AEA) modulated inhibitory GABAA receptors and excitatory ATP-gated P2X3 receptors. AEA reversibly depressed GABA-mediated membrane currents without altering P2X3 receptor responses. The AEA antagonism was non-competitive, prevented by the CB1R antagonist AM-251, mimicked by the other cannabinoids 2-arachidonylglycerol and WIN 55,212-2, and insensitive to TRPV1 blocker capsazepine. AEA inhibited the potentiation of GABAergic responses by the cAMP activator forskolin, in line with the canonical inhibition of cAMP synthesis by CB1Rs. In the cerebral cortex, AEA or WIN 55,212-2 did not affect electrically-evoked local field potentials or characteristics of cortical spreading depolarization (CSD) elicited by high potassium application. The GABAA receptor blocker gabazine, however, strongly enhanced field potentials without affecting CSD properties, suggesting that CSD was not dominantly controlled by GABAergic mechanisms. Our data propose that, despite the widespread expression of CB1Rs peripherally and centrally, the functional effects of AEA are region-specific and depend on CB1R coupling to downstream effectors. Future studies concerned with the mechanisms of AEA analgesia should perhaps be directed to discrete subcortical nuclei processing trigeminal inputs.
15 March 2018
Online effects of transcranial direct current stimulation on prefrontal metabolites in gambling disorder
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Maya Dickler, Christophe Lenglos, Emmanuelle Renauld, Francine Ferland, Richard A. Edden, Jean Leblond, Shirley Fecteau Gambling disorder is characterized by persistent maladaptive gambling behaviors and is now considered among substance-related and addictive disorders. There is still unmet therapeutic need for these clinical populations, however recent advances indicate that interventions targeting the Glutamatergic/GABAergic system hold promise in reducing symptoms in substance-related and addictive disorders, including gambling disorder. There is some data indicating that transcranial direct current stimulation may hold clinical benefits in substance use disorders and modulate levels of brain metabolites including glutamate and GABA. The goal of the present work was to test whether this non-invasive neurostimulation method modulates key metabolites in gambling disorder. We conducted a sham-controlled, crossover, randomized study, blinded at two levels in order to characterize the effects of transcranial direct current stimulation over the dorsolateral prefrontal cortex on neural metabolites levels in sixteen patients with gambling disorder. Metabolite levels were measured with magnetic resonance spectroscopy from the right dorsolateral prefrontal cortex and the right striatum during active and sham stimulation. Active as compared to sham stimulation elevated prefrontal GABA levels. There were no significant changes between stimulation conditions in prefrontal glutamate + glutamine and N-acetyl Aspartate, or in striatal metabolite levels. Results also indicated positive correlations between metabolite levels during active, but not sham, stimulation and levels of risk taking, impulsivity and craving. Our findings suggest that transcranial direct current stimulation can modulate GABA levels in patients with gambling disorder which may represent an interesting future therapeutic avenue.
15 March 2018
Neurogranin in the nucleus accumbens regulates NMDA receptor tolerance and motivation for ethanol seeking
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Ashlie N. Reker, Alfredo Oliveros, John M. Sullivan, Lailun Nahar, David J. Hinton, Taehyun Kim, Robert C. Bruner, Doo-Sup Choi, Nicholas E. Goeders, Hyung W. Nam Dysfunction of N-methyl-d-aspartate receptor (NMDAR) signaling in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng), a calmodulin-binding protein, is exclusively expressed in the post-synapse, and mediates NMDAR driven synaptic plasticity by regulating the calcium-calmodulin (Ca2+-CaM) pathway. To study the functional role of Ng in AUD, we administrated behavior tests including Pavlovian instrument transfer (PIT), operant conditioning, and rotarod test using Ng null mice (Ng–/– mice). We used adeno-associated virus (AAV)-mediated Ng expression and pharmacological manipulation to validate behavioral responses in Ng–/– mice. The results from our multidisciplinary approaches demonstrated that deficit of Ng increases tolerance to NMDAR inhibition and elicit faster cue reactivity during PIT without changes in ethanol reward. Operant conditioning results demonstrated that Ng–/– mice self-administered significantly more ethanol and displayed reduced sensitivity to aversive motivation. We identified that ethanol exposure decreases mGluR5 (metabotropic glutamate receptor 5) expression in the NAc of Ng–/– mice and pharmacological inhibition of mGluR5 reverses NMDAR desensitization in Ng–/– mice. Together these findings specifically suggest that accumbal Ng plays an essential role in the counterbalance between NMDAR and mGluR5 signaling; which alters NMDAR resistance, and thereby altering aversive motivation for ethanol and may ultimately contribute to susceptibility for alcohol addiction.
15 March 2018
Syringaresinol suppresses excitatory synaptic transmission and picrotoxin-induced epileptic activity in the hippocampus through presynaptic mechanisms
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Young Seon Cho, Woo Seok Song, Sang Ho Yoon, Kyeong-Yeol Park, Myoung-Hwan Kim Many neuromodulating drugs acting on the nervous system originate from botanical sources. These plant-derived substances modulate the activity of receptors, ion channels, or transporters in neurons. Their properties make the substances useful for medicine and research. Here, we show that the plant lignan (+)-syringaresinol (SYR) suppresses excitatory synaptic transmission via presynaptic modulation. Bath application of SYR rapidly reduced the slopes of the field excitatory postsynaptic potentials (fEPSPs) at the hippocampal Schaffer collateral (SC)-CA1 synapse in a dose-dependent manner. SYR preferentially affected excitatory synapses, while inhibitory synaptic transmission remained unchanged. SYR had no effect on the conductance or the desensitization of AMPARs but increased the paired-pulse ratios of synaptic responses at short (20–200 ms) inter-stimulus intervals. These presynaptic changes were accompanied by a reduction of the readily releasable pool size. Pretreatment of hippocampal slices with the Gi/o protein inhibitor N-ethylmaleimide (NEM) abolished the effect of SYR on excitatory synaptic transmission, while the application of SYR significantly decreased Ca2+ currents and hyperpolarized the resting membrane potentials of hippocampal neurons. In addition, SYR suppressed picrotoxin-induced epileptiform activity in hippocampal slices. Overall, our study identifies SYR as a new neuromodulating agent and suggests that SYR suppresses excitatory synaptic transmission by modulating presynaptic transmitter release.
15 March 2018
GLP-1 action in the mouse bed nucleus of the stria terminalis
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Diana L. Williams, Nicole A. Lilly, Ian J. Edwards, Pallas Yao, James E. Richards, Stefan Trapp Glucagon-like peptide-1 (GLP-1) injected into the brain reduces food intake. Similarly, activation of preproglucagon (PPG) cells in the hindbrain which synthesize GLP-1, reduces food intake. However, it is far from clear whether this happens because of satiety, nausea, reduced reward, or even stress. Here we explore the role of the bed nucleus of the stria terminalis (BNST), an area involved in feeding control as well as stress responses, in GLP-1 responses. Using cre-expressing mice we visualized projections of NTS PPG neurons and GLP-1R-expressing BNST cells with AAV-driven Channelrhodopsin-YFP expression. The BNST displayed many varicose YFP+ PPG axons in the ventral and less in the dorsal regions. Mice which express RFP in GLP-1R neurons had RFP+ cells throughout the BNST with the highest density in the dorsal part, suggesting that PPG neuron-derived GLP-1 acts in the BNST. Indeed, injection of GLP-1 into the BNST reduced chow intake during the dark phase, whereas injection of the GLP-1 receptor antagonist Ex9 increased feeding. BNST-specific GLP-1-induced food suppression was less effective in mice on high fat (HF, 60%) diet, and Ex9 had no effect. Restraint stress-induced hypophagia was attenuated by BNST Ex9 treatment, further supporting a role for endogenous brain GLP-1. Finally, whole-cell patch clamp recordings of RFP+ BNST neurons demonstrated that GLP-1 elicited either a depolarizing or hyperpolarizing reversible response that was of opposite polarity to that under dopamine. Our data support a physiological role for BNST GLP-1R in feeding, and suggest complex cellular responses to GLP-1 in this nucleus.

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15 March 2018
Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Brendan J. Tunstall, Chelsea P. Ho, Jianjing Cao, Jana
15 March 2018
Fear extinction in an obsessive-compulsive disorder animal model: Influence of sex and estrous cycle
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Adriano Edgar Reimer, Amanda Ribeiro de Oliveira, Juliana Belo Diniz, Marcelo Queiroz Hoexter, Euripedes Constantino Miguel, Mohammed Ragib Milad, Marcus Lira Brand
15 March 2018
DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease.
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Tom H. Johnston, Eboo Versi, Patrick A. Howson, Paula Ravenscroft, Susan H. Fox, Michael P. Hill, Bruce E. Reidenberg, Ronald Corey, Jonathan M. Brotchie L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease.
15 March 2018
Synaptic adaptations to chronic ethanol intake in male rhesus monkey dorsal striatum depend on age of drinking onset
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Verginia C. Cuzon Carlson, Kathleen A. Grant, David M. Lovinger One in 12 adults suffer with alcohol use disorder (AUD). Studies suggest the younger the age in which alcohol consumption begins the higher the probability of being diagnosed with AUD. Binge/excessive alcohol drinking involves a transition from flexible to inflexible behavior likely involving the dorsal striatum (caudate and putamen nuclei). A major focus of this study was to examine the effect of age of drinking onset on subsequent chronic, voluntary ethanol intake and dorsal striatal circuitry. Data from rhesus monkeys (n
15 March 2018
Targeted inhibition of RAGE reduces amyloid-
15 March 2018
Endogenous dopamine and endocannabinoid signaling mediate cocaine-induced reversal of AMPAR synaptic potentiation in the nucleus accumbens shell
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Anna E. Ingebretson, Matthew C. Hearing, Ethan D. Huffington, Mark J. Thomas Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within meso-corticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During a 10–14 day period of abstinence from cocaine, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, rapidly reverses and depotentiates enhanced AMPAR signaling. To understand how re-exposure to cocaine alters AMPAR synaptic transmission, we investigated the roles of dopamine and endocannabinoid (eCB) signaling in modifying synaptic strength in the NAc shell. Using patch-clamp recordings from NAc slices prepared after 10–14 days of abstinence from repeated cocaine, we found that AMPAR-mediated depotentiation is rapidly induced in the NAc shell within 20 min of cocaine re-exposure ex vivo, and persists for up to five days before synapses return to levels of potentiation observed during abstinence. In cocaine-treated animals, global dopamine receptor activation was both necessary and sufficient for the cocaine-evoked depotentiation of AMPAR synaptic function. Additionally, we identified that CB1 receptors are engaged by endogenous endocannabinoids (eCBs) during re-exposure to cocaine ex vivo. Overall, these results indicate the central role that dopamine and eCB signaling mechanisms play in modulating cocaine-induced AMPAR plasticity in the NAc shell.
15 March 2018
Adipose-derived stem cells decrease pain in a rat model of oxaliplatin-induced neuropathy: Role of VEGF-A modulation
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Lorenzo Di Cesare Mannelli, Barbara Tenci, Laura Micheli, Alessia Vona, Francesca Corti, Matteo Zanardelli, Andrea Lapucci, Ann Maria Clemente, Paola Failli, Carla Ghelardini Oxaliplatin therapy of colorectal cancer induces a dose-dependent neuropathic syndrome in 50% of patients. Pharmacological treatments may offer limited relief; scientific efforts are needed for new therapeutic approaches. Therefore we evaluated in a preclinical setting the pain relieving properties of mesenchymal stem cells and its secretome. Rat adipose stem cells (rASCs) were administered in a rat model of oxaliplatin-induced neuropathy. A single intravenous injection of rASCs reduced oxaliplatin-dependent mechanical hypersensitivity to noxious and non-noxious stimuli taking effect 1 h after administration, peaking 6 h thereafter and lasting 5 days. Cell-conditioned medium was ineffective. Repeated rASCs injections every 5 days relieved pain each time with a comparable effect. Labeled rASCs were detected in the bloodstream 1 and 3 h after administration and found in the liver 24 h thereafter. In oxaliplatin-treated rats, the plasma concentration of vascular endothelial growth factor (pan VEGF-A) was increased while the isoform VEGF165b was upregulated in the spinal cord. Both alterations were reverted by rASCs. The anti-VEGF-A monoclonal antibody bevacizumab (intraperitoneally) reduced oxaliplatin-dependent pain. Studying the peripheral and central role of VEGF165b in pain, we determined that the intraplantar and intrathecal injection of the growth factor induced a pro-algesic effect. In the oxaliplatin neuropathy model, the intrathecal infusion of bevacizumab, anti-rat VEGF165b antibody and rASCs reduced pain. Adult adipose mesenchymal stem cells could represent a novel approach in the treatment of neuropathic pain. The regulation of VEGF-A is suggested as an effective mechanism in the complex response orchestrated by stem cells against neuropathy.

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15 March 2018
New Cav2 calcium channel gating modifiers with agonist activity and therapeutic potential to treat neuromuscular disease
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Man Wu, Hayley V. White, Blake A. Boehm, Christopher J. Meriney, Kaylan Kerrigan, Michael Frasso, Mary Liang, Erika M. Gotway, Madeleine R. Wilcox, Jon W. Johnson, Peter Wipf, Stephen D. Meriney Voltage-gated calcium channels (VGCCs) are critical regulators of many cellular functions, including the activity-dependent release of chemical neurotransmitter from nerve terminals. At nerve terminals, the Cav2 family of VGCCs are closely positioned with neurotransmitter-containing synaptic vesicles. The relationship between calcium ions and transmitter release is such that even subtle changes in calcium flux through VGCCs have a strong influence on the magnitude of transmitter released. Therefore, modulators of the calcium influx at nerve terminals have the potential to strongly affect transmitter release at synapses. We have previously developed novel Cav2-selective VGCC gating modifiers (notably GV-58) that slow the deactivation of VGCC current, increasing total calcium ion flux. Here, we describe ten new gating modifiers based on the GV-58 structure that extend our understanding of the structure-activity relationship for this class of molecules and extend the range of modulation of channel activities. In particular, we show that one of these new compounds (MF-06) was more efficacious than GV-58, another (KK-75) acts more quickly on VGCCs than GV-58, and a third (KK-20) has a mix of increased speed and efficacy. A subset of these new VGCC agonist gating modifiers can increase transmitter release during action potentials at neuromuscular synapses, and as such, show potential as therapeutics for diseases with a presynaptic deficit that results in neuromuscular weakness. Further, several of these new compounds can be useful tool compounds for the study of VGCC gating and function.

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15 March 2018
GLP-1 receptor agonists downregulate aberrant GnT-III expression in Alzheimer's disease models through the Akt/GSK-3
15 March 2018
Cannabinoid-1 receptor neutral antagonist reduces binge-like alcohol consumption and alcohol-induced accumbal dopaminergic signaling
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Andrea Balla, Bin Dong, Borehalli M. Shilpa, Kiran Vemuri, Alexandros Makriyannis, Subhash C. Pandey, Henry Sershen, Raymond F. Suckow, K. Yaragudri Vinod Binge alcohol (ethanol) drinking is associated with profound adverse effects on our health and society. Rimonabant (SR141716A), a CB1 receptor inverse agonist, was previously shown to be effective for nicotine cessation and obesity. However, studies using rimonabant were discontinued as it was associated with an increased risk of depression and anxiety. In the present study, we examined the pharmacokinetics and effects of AM4113, a novel CB1 receptor neutral antagonist on binge-like ethanol drinking in C57BL/6J mice using a two-bottle choice drinking-in-dark (DID) paradigm. The results indicated a slower elimination of AM4113 in the brain than in plasma. AM4113 suppressed ethanol consumption and preference without having significant effects on body weight, ambulatory activity, preference for tastants (saccharin and quinine) and ethanol metabolism. AM4113 pretreatment reduced ethanol-induced increase in dopamine release in nucleus accumbens. Collectively, these data suggest an important role of CB1 receptor-mediated regulation of binge-like ethanol consumption and mesolimbic dopaminergic signaling, and further points to the potential utility of CB1 neutral antagonists for the treatment of binge ethanol drinking.
15 March 2018
Vesicular glutamate transporter 1 (VGLUT1)-mediated glutamate release and membrane GluA1 activation is involved in the rapid antidepressant-like effects of scopolamine in mice
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Hanjie Yu, Mengmeng Li, Dongsheng Zhou, Dan Lv, Qi Liao, Zhongze Lou, Mengxin Shen, Zhen Wang, Ming Li, Xiao Xiao, Yanhua Zhang, Chuang Wang Emerging data have identified certain drugs such as scopolamine as rapidly acting antidepressants for major depressive disorder (MDD) that increase glutamate release and induce neurotrophic factors through
15 March 2018
Ginsenoside Rb1 confers neuroprotection via promotion of glutamate transporters in a mouse model of Parkinson's disease
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Yun-Long Zhang, Yan Liu, Xin-Pan Kang, Chun-Yan Dou, Ren-Gong Zhuo, Shu-Qiong Huang, Li Peng, Lei Wen Ginsenoside Rb1 has been demonstrated to protect dopaminergic (DA) neurons from death in vitro. However, the neuroprotective effects and underlying mechanism of Rb1 in treating Parkinson's disease (PD) remain uncharacterized. In this study, we explored the effects of Rb1 on the movement disorder and the underlying mechanisms based on the glutamatergic transmission and excitotoxicity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Here, for the first time, we report that Rb1 treatment ameliorates motor deficits, prevents DA neuron death, and suppresses
15 March 2018
Adenosine monophosphate-activated protein kinase modulation by berberine attenuates mitochondrial deficits and redox imbalance in experimental diabetic neuropathy
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Veera Ganesh Yerra, Anil Kumar Kalvala, Bhoomika Sherkhane, Aparna Areti, Ashutosh Kumar Adenosine monophosphate-activated protein kinase (AMPK) has been studied for its myriad metabolic and mitochondrial benefits in several chronic diseases. Recent studies have uncovered its therapeutic potential against mitochondrial dysfunction in cultured dorsal root ganglion (DRG) neurons isolated from streptozotocin (STZ) induced diabetic rats. The present study is aimed at evaluating the pharmacological efficacy of berberine (BRB), a natural AMPK activator against experimental diabetic neuropathy (DN) phenotype developed in STZ (55
15 March 2018
Low doses of prenatal ethanol exposure and maternal separation alter HPA axis function and ethanol consumption in adult male rats
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): F. Biggio, G. Talani, V. Locci, M.G. Pisu, G. Boero, B. Ciarlo, D.R. Grayson, M. Serra Adverse maternal behaviors during pregnancy and unfavorable postnatal experiences during development are associated with an increased risk of developing psychiatric disorders, as well as, a vulnerability to alcohol addiction in adulthood. Here, we examined the effects of combined ethanol exposure during late pregnancy and postnatal maternal separation (MS) on HPA responsiveness, anxiety behavior and preference for alcohol consumption in adult male rats. Animals exposed to both conditions revealed a decrease in blood levels of allopregnanolone accompanied by increased anxiety behavior. In addition, basal blood levels of corticosterone were markedly decreased in all experimental groups while increases in the foot-shock-induced corticosterone levels were more pronounced in MS animals. Finally, evaluating EtOH drinking behavior, MS animals exhibited a remarkable EtOH preference even at low doses (0.1–1%). Altogether, these data suggest that adverse conditions, alone or in combination, may alter anxiety–like states as well as modify behavior towards alcohol consumption.
15 March 2018
Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Tito Borner, Claudia G. Liberini, Thomas A. Lutz, Thomas Riediger The cancer anorexia-cachexia syndrome (CACS) is a frequent and severe condition in cancer patients. Currently, no pharmacological treatment is approved for the therapy of CACS. Centrally, glucagon-like peptide-1 (GLP-1) is expressed in the nucleus tractus solitarii (NTS) and is implicated in malaise, nausea and food aversion. The NTS is reciprocally connected to brain sites implicated in the control of energy balance including the area postrema (AP), which mediates CACS in certain tumour models. Given the role of GLP-1 as a mediator of anorexia under acute sickness conditions, we hypothesized that brainstem GLP-1 signalling might play a role in the mediation of CACS. Using hepatoma tumour-bearing (TB) rats, we first tested whether the chronic delivery of the GLP-1R antagonist exendin-9 (Ex-9) into the fourth ventricle attenuates CACS. Second, we investigated whether a genetic knockdown of GLP-1 expression in the NTS ameliorates CACS. Ex-9 attenuated anorexia, body weight loss, muscle and fat depletion compared to TB controls. Similarly, TB animals with a knockdown of GLP-1 expression in the NTS had higher food intake, reduced body weight loss, and higher lean and fat mass compared to TB controls. Our study identifies brainstem GLP-1 as crucial mediator of CACS in hepatoma TB rats. The GLP-1R represents a promising target against CACS and possibly other forms of disease-related anorexia/cachexia.
15 March 2018
Reduced expression of Na+/Ca2+ exchangers is associated with cognitive deficits seen in Alzheimer's disease model mice
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Shigeki Moriguchi, Satomi Kita, Masahiro Fukaya, Makoto Osanai, Ryo Inagaki, Yuzuru Sasaki, Hisanao Izumi, Kyoji Horie, Junji Takeda, Takashi Saito, Hiroyuki Sakagami, Takaomi C. Saido, Takahiro Iwamoto, Kohji Fukunaga Na+/Ca2+ exchangers (NCXs) are expressed primarily in the plasma membrane of most cell types, where they mediate electrogenic exchange of one Ca2+ for three Na+ ions, depending on Ca2+ and Na+ electrochemical gradients across the membrane. Three mammalian NCX isoforms (NCX1, NCX2, and NCX3) are each encoded by a distinct gene. Here, we report that NCX2 and NCX3 protein and mRNA levels are relatively reduced in hippocampal CA1 of APP23 and APP-KI mice. Likewise, NCX2 +/
15 March 2018
C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Konstantin Petrov, Irina Zueva, Irina Kovyazina, Igor Sedov, Sofya Lushchekina, Alexandra Kharlamova, Oksana Lenina, Sergei Koshkin, Yurii Shtyrlin, Evgeny Nikolsky, Patrick Masson C-547, a potent slow-binding inhibitor of acetylcholinesterase (AChE) was intravenously administered to rat (0.05
15 March 2018
Liraglutide ameliorates cognitive decline by promoting autophagy via the AMP-activated protein kinase/mammalian target of rapamycin pathway in a streptozotocin-induced mouse model of diabetes
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Fei-Juan Kong, Jia-Hua Wu, Shui-Ya Sun, Lei-Lei Ma, Jia-Qiang Zhou Diabetic cognitive dysfunction has gained widespread attention for its deleterious impact on individuals with diabetes. However, few clinical interventions are available to prevent the disorder. The glucagon-like peptide-1 analog liraglutide exerts neuroprotective effects in several models of neurodegenerative diseases. We investigated the effect of liraglutide pretreatment on diabetes-induced cognitive decline and explored the underlying mechanisms in vivo and in vitro. Liraglutide pretreatment prevented diabetes-induced cognitive impairment as assessed by the Morris Water Maze test, and alleviated neuronal injuries and ultrastructural damage to synapses in the hippocampal CA1 region. Furthermore, liraglutide promoted autophagy as indicated by enhanced expression of the autophagy markers Microtubule-associated protein 1 light chain 3 (LC3)-II and Beclin 1, decreased expression of p62, and increased formation of autophagic vacuoles and LC3-II aggregates. In vitro, liraglutide treatment elevated phosphorylated (p)-AMP-activated protein kinase (AMPK) levels and reduced p-mammalian target of rapamycin (p-mTOR) expression. Additionally, the AMPK inhibitor Compound C exhibited an inhibitory effect on liraglutide-induced increased LC3-II expression and p62 degradation. Liraglutide exhibits neuroprotective effects against diabetes-induced hippocampal neuronal injuries and cognitive impairment by promoting autophagy via the AMPK/mTOR pathway.
15 March 2018
Enhanced incentive motivation in obesity-prone rats is mediated by NAc core CP-AMPARs
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Rifka C. Derman, Carrie R. Ferrario Studies in humans suggest that stronger incentive motivational responses to Pavlovian food cues may drive over-consumption leading to and maintaining obesity, particularly in susceptible individuals. However, whether this enhanced incentive motivation emerges as a consequence of obesity or rather precedes obesity is unknown. Moreover, while human imaging studies have provided important information about differences in striatal responsiveness between susceptible and non-susceptible individuals, the neural mechanisms mediating these behavioral differences are unknown. The Nucleus Accumbens (NAc) mediates cue-triggered reward seeking and activity in the NAc is enhanced in obesity-susceptible populations. Therefore here, we used selectively-bred obesity-prone and obesity-resistant rats to examine intrinsic differences in incentive motivation, and the role of NAc AMPARs in the expression of these behaviors prior to obesity. We found that obesity-prone rats exhibit robust cue-triggered food-seeking (Pavlovian-to-instrumental transfer, PIT). Using intra-NAc infusion of AMPAR antagonists, we show that this behavior is selectively mediated by CP-AMPARs in the NAc core. Additionally, biochemical data suggest that this is due in part to experience-induced increases in CP-AMPAR surface expression in the NAc of obesity-prone rats. In contrast, in obesity-resistant rats PIT was weak and unreliable and training did not increase NAc AMPAR surface expression. Collectively, these data show that food cues acquire greater incentive motivational control in obesity-susceptible populations prior to the development of obesity. This provides support to the idea that enhanced intrinsic incentive motivation may be a contributing factor, rather than a consequence of obesity. In addition, these data demonstrate a novel role for experience-induced up-regulation of NAc CP-AMPARs in PIT, pointing to potential mechanistic parallels between the processes leading to addiction and to obesity.
15 March 2018
Chronic paroxetine treatment prevents disruption of methamphetamine-sensitive circadian oscillator in a transgenic mouse model of Huntington's disease
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Koliane Ouk, Juliet Aungier, Marc Cuesta, A. Jennifer Morton Circadian abnormalities seen in Huntington's disease (HD) patients are recapitulated in several HD transgenic mouse models. In mice, alongside the master clock located in the suprachiasmatic nucleus (SCN), two other oscillators may influence circadian behaviour. These are the food-entrainable oscillator (FEO) and the methamphetamine-sensitive circadian oscillator (MASCO). SCN- and MASCO- (but not FEO-) driven rhythms are progressively disrupted in the R6/2 mouse model of HD. MASCO-driven rhythms are induced by chronic treatment with low dose of methamphetamine and characterised by an increase in period length to greater than 24
15 March 2018
SLOH, a carbazole-based fluorophore, mitigates neuropathology and behavioral impairment in the triple-transgenic mouse model of Alzheimer's disease
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Xiaoli Wu, Jayasankar Kosaraju, Wei Zhou, Kin Yip Tam Alzheimer's disease (AD) is a progressive neurodegenerative dysfunction characterized by memory impairment and brings a heavy burden to old people both in developing and developed countries. Amyloid hypothesis reveals that aggregation and deposition of amyloid plaques are the cause of AD neurodegeneration. SLOH, a carbazole-based fluorophore, is reported to inhibit amyloid beta (A
15 March 2018
MiR-134 modulates chronic stress-induced structural plasticity and depression-like behaviors via downregulation of Limk1/cofilin signaling in rats
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Cuiqin Fan, Xiuzhi Zhu, Qiqi Song, Peng Wang, Zhuxi Liu, Shu Yan Yu Increasing evidence has suggested that depression is a neuropsychiatric condition associated with neuroplasticity within specific brain regions. However, the mechanisms by which neuroplasticity exerts its effects in depression remain largely uncharacterized. In the present study we show that chronic stress effectively induces depression-like behaviors in rats, an effect which was associated with structural changes in dendritic spines and synapse abnormalities within neurons of the ventromedial prefrontal cortex (vmPFC). Moreover, unpredictable chronic mild stress (UCMS) exposure significantly increased the expression of miR-134 within the vmPFC, an effect which was paralleled with a decrease in the levels of expression and phosphorylation of the synapse-associated proteins, LIM-domain kinase 1 (Limk1) and cofilin. An intracerebral infusion of the adenovirus associated virus (AAV)-miR-134-sponge into the vmPFC of stressed rats, which blocks mir-134 function, significantly ameliorated neuronal structural abnormalities, biochemical changes and depression-like behaviors. Chronic administration of ginsenoside Rg1 (40
1 March 2018
TIGAR inhibits ischemia/reperfusion-induced inflammatory response of astrocytes
Publication date: 15 March 2018
Source:Neuropharmacology, Volume 131 Author(s): Jieyu Chen, Ding-Mei Zhang, Xing Feng, Jian Wang, Yuan-Yuan Qin, Tian Zhang, Qiao Huang, Rui Sheng, Zhong Chen, Mei Li, Zheng-Hong Qin The inflammatory response of glial cells contributes to neuronal damage or repair after brain ischemia/reperfusion insult. We previously demonstrated a protective role of TP53-induced glycolysis and apoptosis regulator (TIGAR) in ischemic neuronal injury through increasing the flow of pentose phosphate pathway (PPP). The present study investigated the possible role of TIGAR in ischemia/reperfusion-induced inflammatory response of astrocytes. Male ICR mice were subjected to middle cerebral artery occlusion for 2
1 March 2018
Editorial board/Subscription info
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130

1 March 2018
The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Alexandre Seillier, Andrea Giuffrida Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo.
1 March 2018
Sucrose withdrawal induces depression and anxiety-like behavior by Kir2.1 upregulation in the nucleus accumbens
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Seonil Kim, Jiayi Shou, Sinedu Abera, Edward B. Ziff Dieting induces depression and anxiety among other emotional symptoms. Animal models indicate that repeated access to palatable foods such as sugar induces depression and anxiety-like behavior when the food is no longer available. However, the neurobiological mechanisms of how dietary restriction influences mood have not been fully understood. We used the two-bottle sucrose choice paradigm as an overeating and withdrawal model. Withdrawal after lengthy sucrose overeating elicited depression and anxiety-like behavior, which was reversed by sucrose reinstatement. In the nucleus accumbens (NAc) of sucrose withdrawal animals, dopamine levels and cAMP response element binding protein (CREB) activity were significantly reduced, while the inwardly rectifying K+ channel, Kir2.1, was significantly elevated. In addition, overexpression of Kir2.1 selectively in neurons expressing dopamine D1 receptors was sufficient to induce negative mood-linked behavior in the absence of sucrose overeating experience. As elevated K+ channels reduce neuronal excitability, a sucrose withdrawal-induced increase in Kir2.1 expression is able to decrease NAc activity, which provides a cellular basis for depression and anxiety-like behavior in animals.
1 March 2018
Pharmacological validation of voluntary gait and mechanical sensitivity assays associated with inflammatory and neuropathic pain in mice
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Andrew J. Shepherd, Durga P. Mohapatra The urgent need for more effective analgesic treatment options has prompted a re-evaluation of the behavioral tests used to assess pain in pre-clinical research, with an emphasis on inclusion of more voluntary, un-evoked behavioral assessments of pain. In order to validate voluntary gait analysis and a voluntary mechanical conflict-avoidance assay, we tested mouse models of neuropathy (spared nerve injury) and inflammation (complete Freund's adjuvant) alongside reflexive measures of mechanical and thermal hypersensitivity. To establish whether the observed changes in behavioral responses were pain-related, known analgesics (buprenorphine, gabapentin, carprofen) were also administered. Spared nerve injury persistently altered several gait indices, whereas complete Freund's adjuvant caused only transient changes. Furthermore, known analgesics could not reverse these gait changes, despite demonstrating their previously established efficacy in reflexive measures of mechanical and thermal hypersensitivity. In contrast, the mechanical conflict-avoidance assay demonstrated aversion in mice with neuropathy and inflammation-induced hypersensitivity, which could both be reversed by analgesics. We conclude that voluntary gait changes in rodent neuropathic and inflammatory pain models are not necessarily indicative of pain-related adaptations. On the other hand, mechanical conflict-avoidance represents a valid operant assay for quantifying pain-related behaviors in mice that can be reversed by known analgesics.
1 March 2018
Behavioral and biochemical sensitivity to low doses of ketamine: Influence of estrous cycle in C57BL/6 mice
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Amanda M. Dossat, Katherine N. Wright, Caroline E. Strong, Mohamed Kabbaj Rationale Low-dose ketamine is a rapid-acting antidepressant, to which female rodents are more sensitive as compared to males. However, the mechanism mediating this sex difference in ketamine sensitivity remains elusive. Objectives We sought to determine whether male and female mice differ in their behavioral sensitivity to low doses of ketamine, and uncover how ovarian hormones influence females’ ketamine sensitivity. We also aimed to uncover some of the molecular mechanism(s) in mood-related brain regions that mediate sex differences in ketamine antidepressant effects. Methods Male and female mice (freely-cycling, diestrus 1 [D1], proestrus [Pro], or D1 treated with an estrogen receptor (ER)
1 March 2018
Functional role for cortical-striatal circuitry in modulating alcohol self-administration
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Anel A. Jaramillo, Patrick A. Randall, Spencer Stewart, Brayden Fortino, Kalynn Van Voorhies, Joyce Besheer The cortical-striatal brain circuitry is heavily implicated in drug-use. As such, the present study investigated the functional role of cortical-striatal circuitry in modulating alcohol self-administration. Given that a functional role for the nucleus accumbens core (AcbC) in modulating alcohol-reinforced responding has been established, we sought to test the role of cortical brain regions with afferent projections to the AcbC: the medial prefrontal cortex (mPFC) and the insular cortex (IC). Long-Evans rats were trained to self-administer alcohol (15% alcohol (v/v)+2% sucrose (w/v)) during 30 min sessions. To test the functional role of the mPFC or IC, we utilized a chemogenetic technique (hM4Di-Designer Receptors Activation by Designer Drugs) to silence neuronal activity prior to an alcohol self-administration session. Additionally, we chemogenetically silenced mPFC
1 March 2018
Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Levi M. Smith, Rong Zhu, Stephen M. Strittmatter Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1
1 March 2018
Melanin-Concentrating Hormone acts through hypothalamic kappa opioid system and p70S6K to stimulate acute food intake
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Amparo Romero-Pic
1 March 2018
Fingolimod anti-inflammatory and neuroprotective effects modulation of RAGE axis in multiple sclerosis patients
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Zohara Sternberg, Channa Kolb, Kailash Chadha, Adam Nir, Raphael Nir, Rayan George, Joseph Johnson, Jinhee Yu, David Hojnacki Background We investigated Fingolimod treatment effects on the RAGE (receptor for advanced glycation endproducts) axis in multiple sclerosis (MS) patients. The primary outcome of the study was whether Fingolimod treatment increases serum levels of the soluble RAGE isoforms, sRAGE and esRAGE – both being considered putative endogenous inhibitors of RAGE signaling. Additional variables were serum levels of RAGE ligands, the high mobility group box (HMGB)1 and pentosidine. Methods Serum levels of the study variables were measured by ELISA, and compared between baseline (before Fingolimod treatment) and 6 and 12 months post-drug treatment in 17 relapsing MS patients. Fingolimod treatment effects on MS disease progression were assessed by comparing pre- and post-Fingolimod values of the EDSS and rate of clinical relapse, and changes in the T1-and T2-enahncing lesions on the MRI scan.methods Results Twelve months treatment with Fingolimod increased serum levels of sRAGE and esRAGE by 32.4% (P = 0.004) and 48.5% (P = 0.007) respectively. In addition, Fingolimod treatment reduced serum levels of HMGB1 by 71.6% (P = 0.02) and pentosidine serum levels by 41.3% (P = 0.12). EDSS remained stable (baseline: 3.57 ± 1.56; post-Fingolimod: 3.54 ± 1.2, P = 0.96) and the rate of clinical relapse decreased near significantly (P = 0.094). T1-and T2-enhancing lesions remained stable, showing no significant changes pre-vs. post-Fingolimod treatment. Conclusion Fingolimod mediates modulation of the RAGE axis which apparently contributes to the Fingolimod's anti-inflammatory and neuroprotective effects. These findings may provide a rationale for the clinical efficacy of Fingolimod in pathological states other than MS, where dysregulation of the RAGE axis plays a role.
1 March 2018
Protopanaxadiol derivative DDPU improves behavior and cognitive deficit in AD mice involving regulation of both ER stress and autophagy
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Xiaodan Guo, Jianlu Lv, Jian Lu, Lei Fan, Xi Huang, Lihong Hu, Jiaying Wang, Xu Shen Alzheimer's disease (AD) is a progressively neurodegenerative disease with typical hallmarks of amyloid
February 2018
Peripheral 5-HT3 mediates mirror-image pain by a cross-talk with acid-sensing ion channel 3
Publication date: 1 March 2018
Source:Neuropharmacology, Volume 130 Author(s): Yeu-Shiuan Su, Hao-Ruei Mei, Chun-Hung Wang, Wei-Hsin Sun Mirror-image pain (MIP), which occurs along with complex regional pain syndrome, rheumatoid arthritis and chronic migraine, is characterized by increased pain sensitivity of healthy body regions other than the actual injured or inflamed sites. A high level of peripheral inflammation may activate central or peripheral glia, triggering mirror-image pain. However, which receptors mediate inflammatory signals to contribute glial activation remains unclear. Intraplantarly injecting mice with 5-hydroxytryptamine (5-HT) or acidic buffer (proton) caused only unilateral hyperalgesia, but co-injection of 5-HT/acid induced bilateral hyperalgesia (MIP). Blocking 5-HT3 or acid-sensing ion channel 3 (ASIC3) abolished satellite glial activation, inhibiting MIP. Interestingly, intraplantar administration of a 5-HT3 agonist induced MIP, and 5-HT3–mediated MIP can be reversed by a 5-HT3 antagonist or an ASIC3 blocker. Similar results were found using a ASIC3 agonist. Furthermore, 5-HT3 was observed to co-localize with ASIC3 in DRG neurons; 5-HT3 activation-induced an increase in intracellular calcium that was inhibited by an ASIC3 blocker and vice versa. A cross-talk between 5-HT3 and ASIC3 mediates satellite glial activation, thereby triggering mirror-image pain.

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February 2018
Editorial board/Subscription info
Publication date: February 2018
Source:Neuropharmacology, Volume 129

February 2018
Long lasting effects of chronic WIN55,212-2 treatment on mesostriatal dopaminergic and cannabinoid systems in the rat brain
Publication date: February 2018
Source:Neuropharmacology, Volume 129 Author(s): Panagiotis Perdikaris, Martha Tsarouchi, Eleni Fanarioti, Evangelos Natsaridis, Ada Mitsacos, Panagiotis Giompres Cannabinoid administration modulates dopamine transmission via an indirect, multisynaptic mechanism that includes the activation of cannabinoid type-1 receptor (CB1R). The present study evaluated in rodents, the effects of acute and chronic (20 days) WIN55,212-2 administration, a non-selective CB1R agonist, on dopamine uptake and synthesis in the mesolimbic and nigrostriatal dopaminergic pathways and associate them to its effects on the endocannabinoid system. The effect of spontaneous withdrawal, after different abstinence periods (7 days, 20 days), was also assessed. Acute and chronic administration of WIN55,212-2 decreased dopamine transporter (DAT) binding and mRNA levels, as well as tyrosine hydroxylase (TH) mRNA expression in the substantia nigra (SN) and ventral tegmental area (VTA). In the striatum, chronic WIN55,212-2 administration led to decreased protein expression of DAT and TH, whereas no alterations were observed after acute administration, suggesting a diminished dopamine uptake and synthesis after chronic agonist treatment. Furthermore, after chronic agonist treatment, we observed reduced CB1R binding and mRNA levels in SN and striatum, providing evidence for a possible regulatory role of the endocannabinoid system on dopaminergic function. Seven days after WIN55,212-2 cessation, we observed a rebound increase in mRNA, binding and total protein levels of DAT and TH in VTA, SN and striatum proposing the existence of a biphasic expression pattern, which was also observed in CB1R binding levels. Within the 20-day period of abstinence, TH mRNA and protein levels and CB1R binding levels remain increased. The above results indicate that chronic CB1R agonist treatment induces long-lasting control of the mesostriatal dopaminergic activity.

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February 2018
Protracted motivational dopamine-related deficits following adolescence sugar overconsumption
Publication date: February 2018
Source:Neuropharmacology, Volume 129 Author(s): Fabien Naneix, Florence Darlot, V
February 2018
A novel curcumin derivative for the treatment of diabetic neuropathy
Publication date: February 2018
Source:Neuropharmacology, Volume 129 Author(s): Daniel J. Daugherty, Alexandra Marquez, Nigel A. Calcutt, David Schubert Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNF
February 2018
Methamphetamine-induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist RO5263397
Publication date: February 2018
Source:Neuropharmacology, Volume 129 Author(s): Zhaoxia Xue, Justin N. Siemian, Bernard N. Johnson, Yanan Zhang, Jun-Xu Li Impulsivity is an important personality trait associated with several clinical syndromes including drug abuse. While repeated drug exposure is known to increase certain behavioral responses, such as locomotion, to subsequent drug exposure, few studies have examined whether such sensitization develops for impulsive behavior. In the current study we tested the effects of methamphetamine acutely, during the course of, and upon discontinuation of chronic methamphetamine treatment on impulsive behavior in two models, the 5-choice serial reaction time task (5-CSRTT) and the delay-discounting task which measure impulsive action and impulsive choice, respectively. We also examined whether the trace amine-associated receptor 1 (TAAR1) agonist RO5263397 attenuated methamphetamine-induced effects in parallel tests. Acute methamphetamine dose-dependently increased premature responses in the 5-CSRTT and shifted the delay function upward in delay discounting. Up to 40 days of methamphetamine treatment did not significantly alter the dose-effect curve of methamphetamine-induced premature responses, but produced a significant effect in the delay-discounting task. RO5263397 attenuated acute methamphetamine-induced premature responses, but this effect became non-significant over the course of chronic treatment. RO5263397 did not significantly alter the delay-discounting performance. Discontinuation of methamphetamine treatment increased premature responses, which was attenuated by RO5263397, but did not significantly alter the delay discounting function. These results suggest that acute discontinuation from prolonged methamphetamine treatment increases impulsivity, which can be reduced by a TAAR1 agonist.

Rescue of glutamate transport in the lateral habenula alleviates depression- and anxiety-like behaviors in ethanol-withdrawn rats
Publication date: February 2018
Source:Neuropharmacology, Volume 129 Author(s): Seungwoo Kang, Jing Li, Alex Bekker, Jiang-Hong Ye Alcoholism and psychiatric disorders like depression and anxiety are often comorbid. Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol na
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