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August 2018
5-HT6 receptor agonist and memory-enhancing properties of hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Xiao-fei Chen, Zeng-liang Jin, Ying Gong, Nan Zhao, Xiao-yun Wang, Yu-hua Ran, You-zhi Zhang, Li-ming Zhang, Yun-Feng Li Most current antidepressants are lacking a pro-cognition effect or even impair cognition as a side effect, and there are few effective psychopharmacological options that improve cognitive dysfunction in depression. Our previous studies revealed that hypidone hydrochloride (YL-0919), a novel 5-HT1A receptor partial agonist and SSRI, has antidepressant- and anxiolytic-like effects. Here, further studies found that YL-0919, but not vilazodone (a 5-HT1A receptor partial agonist and SSRI), exerted a significant memory-enhancing effect in the Morris water maze, object recognition test and step-down passive avoidance task. Because the 5-HT6 receptor has emerged as an interesting drug target to improve cognition, we investigated the target profile of YL-0919 using radioligand binding assays, [35S]-GTP
August 2018
Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Natalie S. McGuier, Jennifer A. Rinker, Reginald Cannady, Diana B. Fulmer, Sara R. Jones, Michaela Hoffman, Patrick J. Mulholland Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode KV7 channels influence alcohol intake and dependence. KV7 channels are a class of slowly activating voltage-dependent K+ channels that regulate neuronal excitability. Studies indicate that the KV7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and KV7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA KV7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective KV7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that KV7.4 channels are a critical mediator of excessive alcohol drinking.
August 2018
Synaptic transmission and excitability during hypoxia with inflammation and reoxygenation in hippocampal CA1 neurons
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Yoon-Sil Yang, Sook Jin Son, Joon Ho Choi, Jong-Cheol Rah Although a number of experimental and clinical studies have shown that hypoxia typically accompanies acute inflammatory responses, the combinatorial effect of the two insults on basic neural function has not been thoroughly investigated. Previous studies have predominantly suggested that hypoxia reduces network activity; however, several studies suggest the opposite effect. Of note, inflammation is known to increase neural activity. In the current study, we examined the effects of limited oxygen in combination with an inflammatory stimulus, as well as the effects of reoxygenation, on synaptic transmission and excitability. We observed a significant reduction of both synaptic transmission and excitability when hypoxia and inflammation occurred in combination, whereas reoxygenation caused hyperexcitability of neurons. Further, we found that the observed reduction in synaptic transmission was due to compromised presynaptic release efficiency based on an adenosine-receptorľdependent increase in synaptic facilitation. Excitability changes in both directions were attributable to dynamic regulation of the hyperpolarization-activated cation current (Ih) and to changes in the input resistance and the voltage difference between resting membrane potential and action potential threshold. We found that zatebradine, an Ih current inhibitor, reduced the fluctuation in excitability, suggesting that it may have potential as a drug to ameliorate reperfusion brain injury.
August 2018
Altered brain activity during withdrawal from chronic alcohol is associated with changes in IL-6 signal transduction and GABAergic mechanisms in transgenic mice with increased astrocyte expression of IL-6
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Donna L. Gruol, Salvador Huitron-Resendiz, Amanda J. Roberts Interleukin-6 (IL-6) is an important neuroimmune factor that is increased in the brain by alcohol exposure/withdrawal and is thought to play a role in the actions of alcohol on the brain. To gain insight into IL-6/alcohol/withdrawal interactions and how these interactions affect the brain, we are studying the effects of chronic binge alcohol exposure on transgenic mice that express elevated levels of IL-6 in the brain due to increased astrocyte expression (IL-6 tg) and their non-transgenic (non-tg) littermate controls. IL-6/alcohol/withdrawal interactions were identified by genotypic differences in spontaneous brain activity in electroencephalogram (EEG) recordings from the mice, and by Western blot analysis of protein activation or expression in hippocampus obtained from the mice after the final alcohol withdrawal period. Results from EEG studies showed frequency dependent genotypic differences in brain activity during withdrawal. For EEG frequencies that were affected by alcohol exposure/withdrawal in both genotypes, the nature of the effect was similar, but differed across withdrawal cycles. Differences between IL-6 tg and non-tg mice were also observed in Western blot studies of the activated form of STAT3 (phosphoSTAT3), a signal transduction partner of IL-6, and subunits of GABAA receptors (GABAAR). Regression analysis revealed that pSTAT3 played a more prominent role during withdrawal in the IL-6 tg mice than in the non-tg mice, and that the role of GABAAR alpha-5 and GABAAR alpha-1 in brain activity varied across genotype and withdrawal. Taken together, our results suggest that IL-6 can significantly impact mechanisms involved in alcohol withdrawal.
August 2018
Inhibition of the hypercapnic ventilatory response by adenosine in the retrotrapezoid nucleus in awake rats
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): B
August 2018
Cooperative and dissociable involvement of the nucleus accumbens core and shell in the promotion and inhibition of actions during active and inhibitory avoidance
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Patrick T. Piantadosi, Dylan C.M. Yeates, Stan B. Floresco The flexible implementation of active and passive strategies to avoid danger is critical to survival. Conversely, the inappropriate allocation of these behaviors may underlie pathological avoidance in neuropsychiatric illnesses. The present study investigated whether these two poles of avoidance may be differentially regulated by subdivsions of the nucleus accumbens, the core (NAcC) and shell (NAcS), which are known to bi-directionally control flexible action selection during reward-seeking. In so doing, we developed a novel cued active/inhibitory avoidance task conducted in operant chambers that entailed presentations of two distinct, 15
August 2018
New insights on the effects of varenicline on nicotine reward, withdrawal and hyperalgesia in mice
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Deniz Bagdas, Yasmin Alkhlaif, Asti Jackson, F. Ivy Carroll, Joseph W. Ditre, M. Imad Damaj Varenicline, a partial agonist for
August 2018
Chloride cotransporter KCC2 is essential for GABAergic inhibition in the SCN
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): A.H.O. Olde Engberink, J.H. Meijer, S. Michel One of the principal neurotransmitters of the central nervous system is GABA. In the adult brain, GABA is predominantly inhibitory, but there is growing evidence indicating that GABA can shift to excitatory action depending on environmental conditions. In the mammalian central circadian clock of the suprachiasmatic nucleus (SCN) GABAergic activity shifts from inhibition to excitation when animals are exposed to long day photoperiod. The polarity of the GABAergic response (inhibitory versus excitatory) depends on the GABA equilibrium potential determined by the intracellular Cl
August 2018
Amphetamine improves mouse and human attention in the 5-choice continuous performance test
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): David A. MacQueen, Arpi Minassian, Johnny A. Kenton, Mark A. Geyer, William Perry, Jonathan L. Brigman, Jared W. Young Non-medical use of prescription stimulants amongst college students is common, with claims of cognitive and academic benefits. The mechanism, magnitude, and pervasiveness of the cognitive enhancing effects of stimulants in healthy adults remain poorly understood however. The present study determined the effects of dextroamphetamine (D-amp) on the 5-choice continuous performance test (5C-CPT) of attention in healthy young adult humans and mice. A mixed gender sample received placebo (n
August 2018
Activation of axon initial segmental GABAA receptors inhibits action potential generation in neocortical GABAergic interneurons
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Yanbo Jiang, Yujie Xiao, Xiaoxue Zhang, Yousheng Shu Ionotropic GABAA receptors expressing at the axon initial segment (AIS) of glutamatergic pyramidal cell (PC) in the cortex plays critical roles in regulating action potential generation. However, it remains unclear whether these receptors also express at the AIS of cortical GABAergic interneurons. In mouse prefrontal cortical slices, we performed experiments at the soma and AIS of the two most abundant GABAergic interneurons: parvalbumin (PV) and somatostatin (SST) positive neurons. Local application of GABA at the perisomatic axonal regions could evoke picrotoxin-sensitive currents with a reversal potential near the Cl
August 2018
Enhanced central histaminergic transmission attenuates compulsive-like behavior in mice
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Lokesh Verma, Disha Agrawal, Nishant S. Jain Present investigation demonstrated the effect of central histaminergic transmission on the compulsive-like marble burying and spontaneous alteration behavior (SAB) in mice. Result demonstrates that on enhancement of endogenous histaminergic transmission in mice achieved by central (i.c.v.) administration of histamine or central histamine neuronal releaser, H3 receptor antagonist or on intraperitoneal (i.p.) administration of histamine precursor, l-histidine significantly attenuated the number of marble buried in marble burying behavior (MBB) test as well as obliterated the persistent behavior induced by 5-HT1A receptor agonist, 8-OH-DPAT in T-Maze test. Furthermore, central injection of histamine H1 receptor agonist, FMPH or H2 receptors agonist, amthamine also attenuated the MBB in mice. On the other hand, prior i.c.v administration of H1 but not H2 receptor antagonist attenuated the effects exhibited in MBB test on mice by all the above agents capable of enhancing the endogenous central histaminergic transmission. Thus, the results of the present investigation delineate the attenuating effect of central histaminergic transmission predominantly via H1 receptor on compulsive-like behavior in mice.
August 2018
Chronic amphetamine enhances visual input to and suppresses visual output from the superior colliculus in withdrawal
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Amy C. Turner, Igor Kraev, Michael G. Stewart, Agata Stramek, Paul G. Overton, Eleanor J. Dommett Heightened distractibility is a core symptom of Attention Deficit Hyperactivity Disorder (ADHD). Effective treatment is normally with chronic orally administered psychostimulants including amphetamine. Treatment prevents worsening of symptoms but the site of therapeutic processes, and their nature, is unknown. Mounting evidence suggests that the superior colliculus (SC) is a key substrate in distractibility and a therapeutic target, so we assessed whether therapeutically-relevant changes are induced in this structure by chronic oral amphetamine. We hypothesized that amphetamine would alter visual responses and morphological measures. Six-week old healthy male rats were treated with oral amphetamine (2, 5 or 10
August 2018
Importance of kynurenine 3-monooxygenase for spontaneous firing and pharmacological responses of midbrain dopamine neurons: Relevance for schizophrenia
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Maximilian Tufvesson-Alm, Lilly Schwieler, Robert Schwarcz, Michel Goiny, Sophie Erhardt, G
August 2018
Anti-
August 2018
Sub-efficacious doses of phosphodiesterase 4 and 5 inhibitors improve memory in a mouse model of Alzheimer's disease
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Walter Gulisano, Maria Rosaria Tropea, Ottavio Arancio, Agostino Palmeri, Daniela Puzzo Cyclic nucleotides cAMP and cGMP cooperate to ensure memory acquisition and consolidation. Increasing their levels by phosphodiesterase inhibitors (PDE-Is) enhanced cognitive functions and rescued memory loss in different models of aging and Alzheimer's disease (AD). However, side effects due to the high doses used limited their application in humans. Based on previous studies suggesting that combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is improved synaptic plasticity and memory in physiological conditions, here we aimed to study whether this treatment was effective to counteract the AD phenotype in APPswe mice. We found that a 3-week chronic treatment with a combination of sub-efficacious doses of the cAMP-specific PDE4-I roflumilast (0.01
August 2018
Osteopontin attenuates inflammation via JAK2/STAT1 pathway in hyperglycemic rats after intracerebral hemorrhage
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Lei Gong, Anatol Manaenko, Ruiming Fan, Lei Huang, Budbazar Enkhjargal, DevinW. McBride, Yan Ding, Jiping Tang, Xiaoqiu Xiao, John H. Zhang Acute intracerebral hemorrhage (ICH) complicated by hyperglycemia is associated with aggravation of post-stroke inflammation, leading to exacerbation of brain edema and predicting poor neurological outcomes and higher mortality of patients. Osteopontin (OPN) is a neuroprotective glycoprotein, which is able to attenuate brain injury induced by hemorrhagic stroke. In the current study we investigated whether OPN will decrease the inflammatory post-ICH response as well as attenuate brain edema and neurological deficits in hyperglycemic rats. We employed a collagenase model of ICH on male Sprague-Dawley rats (ná=á148) rats and 50% of Dextrose was injected intraperitoneally (i.p) 3áh after ICH (ICHá+áHG). Intranasal administration of recombinant OPN (rOPN) was performed 1áh after ICH. The development of brain injury was evaluated by brain water content (BWC) and neurological deficits, western blot and immunohistochemistry study. Small interfering ribonucleic acid (siRNA) for integrin-
August 2018
Overexpression of miRNA-137 in the brain suppresses seizure activity and neuronal excitability: A new potential therapeutic strategy for epilepsy
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Wei Wang, Yi Guo, Liang He, Chengzhi Chen, Jing Luo, Yuanlin Ma, Jie Li, Yong Yang, Qin Yang, Chao Du, Yanke Zhang, Zhonggui Li, Xin Xu, Xin Tian, Xuefeng Wang miRNA-137 is an extremely abundant miRNA in the central nervous system and is thought to be closely related to synaptic plasticity. Here, we report a previously unrecognized role of miRNA-137 in epilepsy. The expression of miRNA-137 was decreased both in patients with temporal lobe epilepsy (TLE) and in two different mouse models of epilepsy. Overexpression of miRNA-137 induced by an intrahippocampal injection of a specific agomir prolonged the latency to spontaneous recurrent seizures (SRSs) and reduced seizure severity in a mouse model of pilocarpine-induced epilepsy. Elevated levels of miRNA-137 also prolonged the latency to full kindling and reduced the seizure severity in a mouse model of pentylenetetrazol (PTZ)-kindled epilepsy. Suppression of miRNA-137 levels decreased the latency to the first SRS or the latency to full kindling and increased the seizure severity in both epileptic mouse models. Whole-cell patch-clamp recordings showed that overexpression of miRNA-137 reduced the excitability of pyramidal neurons in the hippocampal CA3a region in a Mg2+-free-induced brain slice model of epileptiform activity. This effect may have been achieved by the regulation of the frequency of miniature inhibitory postsynaptic currents (mIPSCs) and presynaptic inhibitory neurotransmitter release. These results suggest that elevated levels of miRNA-137 may exert an antiepileptic effect via a presynaptic neurotransmission mechanism. These data may provide a new potential target and therapeutic strategy for treating epilepsy in the future.
August 2018
Dysregulation and restoration of homeostatic network plasticity in fragile X syndrome mice
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Kathryn A. Jewett, Kwan Young Lee, Daphne E. Eagleman, Stephanie Soriano, Nien-Pei Tsai Chronic activity perturbations in neurons induce homeostatic plasticity through modulation of synaptic strength or other intrinsic properties to maintain the correct physiological range of excitability. Although similar plasticity can also occur at the population level, what molecular mechanisms are involved remain unclear. In the current study, we utilized a multielectrode array (MEA) recording system to evaluate homeostatic neural network activity of primary mouse cortical neuron cultures. We demonstrated that chronic elevation of neuronal activity through the inhibition of GABA(A) receptors elicits synchronization of neural network activity and homeostatic reduction of the amplitude of spontaneous neural network spikes. We subsequently showed that this phenomenon is mediated by the ubiquitination of tumor suppressor p53, which is triggered by murine double minute-2 (Mdm2). Using a mouse model of fragile X syndrome, in which fragile X mental retardation protein (FMRP) is absent (Fmr1 knockout), we found that Mdm2-p53 signaling, network synchronization, and the reduction of network spike amplitude upon chronic activity stimulation were all impaired. Pharmacologically inhibiting p53 with Pifithrin-
August 2018
Plasminogen activator system homeostasis and its dysregulation by ethanol in astrocyte cultures and the developing brain
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Clare J. Wilhelm, Joel G. Hashimoto, Melissa L. Roberts, Xiaolu Zhang, Calla M. Goeke, Shelley H. Bloom, Marina Guizzetti In utero alcohol exposure can cause fetal alcohol spectrum disorders (FASD), characterized by structural brain abnormalities and long-lasting behavioral and cognitive dysfunction. Neuronal plasticity is affected by in utero alcohol exposure and can be modulated by extracellular proteolysis. Plasmin is a major extracellular serine-protease whose activation is tightly regulated by the plasminogen activator (PA) system. In the present study we explored the effect of ethanol on the expression of the main components of the brain PA system in sex-specific cortical astrocyte primary cultures inávitro and in the cortex and hippocampus of post-natal day (PD) 9 male and female rats. We find that ethanol alters the PA system in astrocytes and in the developing brain. In particular, the expression of tissue-type PA (tPA), encoded by the gene Plat, is consistently upregulated by ethanol in astrocytes inávitro and in the cortex and hippocampus inávivo. Astrocytes exhibit endogenous plasmin activity that is increased by ethanol and recombinant tPA and inhibited by tPA silencing. We also find that tPA is expressed by astrocytes of the developing cortex and hippocampus inávivo. All components of the PA system investigated, with the exception of Neuroserpin/Serpini1, are expressed at higher levels in astrocyte cultures than in the developing brain, suggesting that astrocytes are major producers of these proteins in the brain. In conclusion, astrocyte PA system may play a major role in the modulation of neuronal plasticity; ethanol-induced upregulation of tPA levels and plasmin activity may be responsible for altered neuronal plasticity in FASD.
15 July 2018
Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation
Publication date: August 2018
Source:Neuropharmacology, Volume 138 Author(s): Patrizia Ratano, Carla Petrella, Fabrizio Forti, Pamela Petrocchi Passeri, Maria Morena, Maura Palmery, Viviana Trezza, Cinzia Severini, Patrizia Campolongo The endocannabinoid system is a key modulator of memory consolidation for aversive experiences. We recently found that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases anandamide levels by inhibiting its hydrolysis, facilitates memory consolidation through a concurrent activation of both cannabinoid receptor type 1 (CB1) and 2 (CB2). Here, we investigated the role played on memory consolidation by the other major endocannabinoid, 2-arachidonoylglycerol (2-AG). To this aim, we tested the effects of pharmacological inhibition of monoacylglycerol lipase (MAGL) through systemic administration of the MAGL inhibitor JZL184 to rats immediately after training of the inhibitory avoidance task. Pharmacological enhancement of 2-AG tone facilitated memory consolidation through activation of CB2 receptor signaling. Moreover, we found that increased 2-AG signaling prevented the activation of the mammalian target of rapamycin (mTOR) signaling pathway in the hippocampus through a CB2-dependent mechanism. Our results identify a fundamental role for 2-AG and CB2 receptors in the modulation of memory consolidation for aversive experiences.

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15 July 2018
Mechanisms underlying anticonvulsant and proconvulsant actions of norepinephrine
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Maedeh Ghasemi, Nasrin Mehranfard Norepinephrine (NE) has been shown to exert a potent suppressant effect on seizure development. On the other hand, several lines of evidence have shown that increased NE level is proconvulsant under certain conditions. These data suggest that variations in NE levels could affect modulatory action of noradrenergic system on seizures. Less, however, is known about the mechanisms by which adrenergic pathways protect against seizures or promote seizures. Knowing the mechanisms involved in anti- or proconvulsive effects of NE may help to the development of new therapeutic candidates for patients with refractory epilepsy. Here, we present some possible mechanisms involved in actions of NE on seizures.
15 July 2018
Effects of monoamines on the intrinsic excitability of lateral orbitofrontal cortex neurons in alcohol-dependent and non-dependent female mice
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Sudarat Nimitvilai, Marcelo F. Lopez, John J. Woodward Changes in brain reward and control systems of frontal cortical areas including the orbitofrontal cortex (OFC) are associated with alcohol use disorders (AUD). The OFC is extensively innervated by monoamines, and drugs that target monoamine receptors have been used to treat a number of neuropsychiatric diseases, including AUDs. Recent findings from this laboratory demonstrate that D2,
15 July 2018
Temporally dissociable effects of ketamine on neuronal discharge and gamma oscillations in rat thalamo-cortical networks
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Maria Amat-Foraster, Anders A. Jensen, Niels Plath, Kjartan F. Herrik, Pau Celada, Francesc Artigas Background Sub-anesthetic doses of the non-competitive N-methyl- d -aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas. Methods Single units and local field potentials were recorded in chloral hydrate anesthetized male Wistar rats. The effects of cumulative ketamine doses (0.25ľ5
15 July 2018
Sucrose or sucrose and caffeine differentially impact memory and anxiety-like behaviours, and alter hippocampal parvalbumin and doublecortin
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Tanya J. Xu, Amy C. Reichelt Caffeinated sugar-sweetened "energy" drinks are a subset of soft drinks that are popular among young people worldwide. High sucrose diets impair cognition and alter aspects of emotional behaviour in rats, however, little is known about sucrose combined with caffeine. Rats were allocated to 2
15 July 2018
Inhibition of miR-21 ameliorates excessive astrocyte activation and promotes axon regeneration following optic nerve crush
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Hong-Jiang Li, Yuan-Bo Pan, Zhao-Liang Sun, Yi-Yu Sun, Xi-Tao Yang, Dong-Fu Feng Optic nerve injury is a leading cause of irreversible visual impairment worldwide and can even cause blindness. Excessive activation of astrocytes has negative effects on the repair and recovery of retinal ganglion cells following optic nerve injury. However, the molecular and cellular mechanisms underlying astrocyte activation after optic nerve injury remain largely unknown. In the present study, we explored the effects of microRNA-21 (miR-21) on axon regeneration and flash visual evoked potential (F-VEP) and the underlying mechanisms of these effects based on astrocyte activation in the rat model of optic nerve crush (ONC). To the best of our knowledge, this article is the first to report that inhibition of miR-21 enhances axonal regeneration and promotes functional recovery in F-VEP in the rat model of ONC. Furthermore, inhibition of miR-21 attenuates excessive astrocyte activation and glial scar formation, thereby promoting axonal regeneration by regulating the epidermal growth factor receptor (EGFR) pathway. In addition, we observed that the expression of tissue inhibitor of metalloproteinase-3, a target gene of miR-21, was inhibited during this process. Taken together, these findings demonstrate that inhibition of miR-21 regulates the EGFR pathway, ameliorating excessive astrocyte activation and glial scar progression and promoting axonal regeneration and alleviating impairment in F-VEP function in a model of ONC. This study's results suggest that miR-21 may represent a therapeutic target for optic nerve injury.

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15 July 2018
AMPA receptor positive allosteric modulators attenuate morphine tolerance and dependence
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Xiaoyu Hu, Xuebi Tian, Xiao Guo, Ying He, Haijun Chen, Jia Zhou, Zaijie Jim Wang Development of opioid tolerance and dependence hinders the use of opioids for the treatment of chronic pain. In searching for the mechanism and potential intervention for opioid tolerance and dependence, we studied the action of two positive allosteric modulators of the
15 July 2018
Differential effect of COMT gene methylation on the prefrontal connectivity in subjects with depression versus healthy subjects
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Kyoung-Sae Na, Eunsoo Won, June Kang, Aram Kim, Sunyoung Choi, Woo-Suk Tae, Yong-Ku Kim, Min-Soo Lee, Sook-Haeng Joe, Byung-Joo Ham Expression of the catechol-O-methyl transferase (COMT) gene mainly determines prefrontal dopaminergic availability. Deficient prefrontal dopaminergic activity leads to loss of interest, energy, and motivation, which are core symptoms of depression. Given the role of stress-environmental interactions in major depressive disorder (MDD), we investigated the impact of COMT gene methylation status on prefrontal connectivity. We measured COMT gene methylation and polymorphisms (Val158Met) at the rs4468 locus in peripheral blood samples of healthy controls (n
15 July 2018
Prenatal nicotine exposure alters postsynaptic AMPA receptors and glutamate neurotransmission within the laterodorsal tegmentum (LDT) of juvenile mice
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Filip S. Polli, Kristi A. Kohlmeier Despite dissemination of information regarding the harm on fetal development of smoking while pregnant, the number of pregnancies associated with nicotine exposure appears to have stagnated. Presence of nicotine during neural formulation is associated with a higher susceptibility of drug dependence, suggesting an altered development of neurons in circuits involved in saliency and motivation. The laterodorsal tegmental nucleus (LDT) plays a role in coding stimuli valence via afferents to mesolimbic nuclei. Accordingly, alterations in development of neural mechanisms in the LDT could be involved in vulnerability to drug dependency. Therefore, we examined the effect of prenatal nicotine exposure (PNE) on glutamatergic functioning of LDT neurons in mouse brain slices using whole-cell, patch clamp concurrent with fluorescence-based calcium imaging. PNE was associated with larger amplitudes of AMPA-induced currents, and greater AMPA-mediated rises in intracellular calcium. AMPA/NMDA ratios and the AMPA-current rectification index were lower and higher, respectively, consistent with changes in the functionality of AMPA receptors in the PNE, which was substantiated by a greater inhibition of evoked and spontaneous glutamatergic synaptic events by a selective inhibitor of GluA2-lacking AMPA receptors. Paired pulse ratios showed a decreased probability of glutamate release from presynaptic inputs, and fluorescent imaging indicated a decreased action potential-dependent calcium increase associated with PNE. When taken together, our data suggest that PNE alters LDT glutamatergic functioning, which could alter output to mesolimbic targets. Such an alteration could play a role in altered coding of relevancy of drug stimuli that could enhance risk for development of drug dependency.
15 July 2018
Pharmacological inhibition of Receptor Protein Tyrosine Phosphatase
15 July 2018
5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2/3 receptor antagonist in mice
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Kenichi Fukumoto, Michihiko Iijima, Takeo Funakoshi, Shigeyuki Chaki We previously reported that serotonergic transmission is involved in the antidepressant effects of metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists. However, the detailed underlying mechanisms had not yet been explored. In the present study, we investigated the role of the 5-HT1A receptor and its signaling cascade in the medial prefrontal cortex (mPFC) in the antidepressant effects of LY341495, an mGlu2/3 receptor antagonist. LY341495 significantly reduced the immobility time in the forced swimming test which sustained for 24áh after administration. The antidepressant effect of LY341495 was attenuated by either intraperitoneal or intra-mPFC injection of WAY100635, a 5-HT1A receptor antagonist. Among the signaling cascades mediated by the 5-HT1A receptor, the role of phosphoinositide-3 kinase (PI3K)/Akt signaling, which has a critical role in neuroplasticity, was investigated. The sustained antidepressant effect of LY341495 was blocked by intra-mPFC injection of LY294002, a PI3K inhibitor. LY341495 increased the phosphorylation of Akt in the mPFC, which was blocked by both intra-mPFC injection of WAY100635 and LY294002. Thus, LY341495 activates PI3K/Akt signaling, presumably via stimulation of the 5-HT1A receptor in the mPFC, to exert its sustained antidepressant effect. Involvement of mechanistic target of rapamycin complex-1 (mTORC1) signaling was also demonstrated, as the sustained antidepressant effects of LY341495 was attenuated by intra-mPFC injection of rapamycin, an mTORC1 inhibitor. Finally, the sustained antidepressant effect of LY341495 was also attenuated by silencing of the dorsal raphe nucleus (DRN) neurons. These results suggest that stimulation of the 5-HT1A receptor in the mPFC and its signaling cascade, PI3K/Akt/mTORC1 signaling mediate the sustained antidepressant effect of LY341495, and that activation of the DRN neurons is also involved in these processes.
15 July 2018
Disruption of SHP1/NMDA receptor signaling in spinal cord dorsal horn alleviated inflammatory pain
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Li Yang, Hu-Hu Bai, Zi-Yang Zhang, Jiang-Ping Liu, Zhan-Wei Suo, Xian Yang, Xiao-Dong Hu Src-homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) is one of the non-receptor-like phosphatases that are highly enriched in hematopoietic cells. Although accumulating evidence has implicated the protein tyrosine phosphatases in the regulation of nociceptive transmission and plasticity, it is largely unknown whether SHP1 was expressed in pain-related spinal cord dorsal horn and engaged in the synaptic modification of nociceptive signals. Here we found that SHP1 was present in spinal neurons of rats and functionally coupled to GluN2A subunit-containing N-methyl-d-aspartate subtype of glutamate receptors, one of the key players in central sensitization of nociceptive behaviors. SHP1 interacted with a membrane-proximal region within the cytoplasmic tail of GluN2A. This interaction was necessary to stimulate SHP1 activity and more importantly, restrict SHP1 signaling to specifically enhance the tyrosine phosphorylation of GluN2A during inflammatory pain. Electrophysiological and behavioral studies showed that SHP1 binding potentiated GluN2A currents and evoked GluN2A-dependent pain hypersensitivity. The siRNA-mediated knockdown of SHP1 or interference with SHP1/GluN2A interaction by a synthetic peptide alleviated inflammatory pain induced by either Complete Freund's Adjuvant or formalin. Our data implicated that SHP1 was a specific enhancer of GluN2A-mediated nociceptive synaptic transmission in spinal cord dorsal horn, and manipulation of SHP1 activity may serve as an effective strategy for the treatment of inflammatory pain.
15 July 2018
BDNF contributes to the neonatal incision-induced facilitation of spinal long-term potentiation and the exacerbation of incisional pain in adult rats
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Xu Ding, Ya-Jing Liang, Li Su, Fei-Fei Liao, Dong Fang, Jun Tai, Guo-Gang Xing Neonatal surgical injury exacerbates spinal microglial reactivity, modifies spinal synaptic function, leading to exaggerated pain hypersensitivity after adult repeated incision. Whether and how the alteration in microglial reactivity and synaptic plasticity are functionally related remain unclear. Previously, we and others have documented that spinal brain-derived neurotrophic factor (BDNF), secreted from microglia, contributes to long-term potentiation (LTP) in adult rodents with neuropathic pain. Here, we demonstrated that the mRNA and protein expression of spinal BDNF are significantly upregulated in adult rats subjected to neonatal incision and adult repeated incision (nIN-IN). Neonatal incision facilitates spinal LTP induced by BDNF or high frequency electrical stimulation after adult incision, including a decreased induction threshold and an increased magnitude of LTP. Coincidently, inhibition of spinal BDNF abrogates the LTP facilitation, alleviates the mechanical allodynia and thermal hyperalgesia in nIN-IN rats. By contrast, spinal application of exogenous BDNF in the adult rats with a single neonatal incision mimics the LTP facilitation and pain hypersensitivity, which have been found in nIN-IN rats. Exogenous BDNF-induced exacerbation of pain hypersensitivity could be blocked by BDNF inhibitor. In addition, blockade of microglial reactivity by intrathecal application of minocycline attenuates the elevation of BDNF and the LTP facilitation, and also, alleviates pain hypersensitivity in nIN-IN rats. In conclusion, spinal BDNF, at least partly derived from microglia, contributes to the neonatal incision-induced facilitation of spinal LTP and to the exacerbation of incisional pain in adult rats. Thus, spinal BDNF may combine the changes of microglial reactivity and synaptic plasticity in nIN-IN rats.
15 July 2018
Evaluation of reinforcing and aversive effects of voluntary
15 July 2018
Memantine ameliorates depressive-like behaviors by regulating hippocampal cell proliferation and neuroprotection in olfactory bulbectomized mice
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Kohei Takahashi, Osamu Nakagawasai, Wataru Nemoto, Shogo Kadota, Jinichi Isono, Takayo Odaira, Wakana Sakuma, Yuichiro Arai, Takeshi Tadano, Koichi Tan-No Our previous study suggested that the non-competitive N-methyl-d-aspartate receptor antagonist memantine (MEM) inhibits dopamine (DA) reuptake and turnover by inhibiting brain monoamine oxidase. Clinical studies have reported that MEM may improve depressive symptoms; however, specific mechanisms underlying this effect are unclear. We performed emotional behavior, tail suspension, and forced swimming tests to examine whether MEM has antidepressant effects in olfactory bulbectomized (OBX) mice, an animal model of depression. Subsequently, we investigated the effects of MEM on the distribution of tyrosine hydroxylase (TH), altered microglia morphometry, and astrocyte and cell proliferation in the hippocampus with immunohistochemistry. We also investigated MEM effects on the levels of norepinephrine (NE), DA, and their metabolites with high performance liquid chromatography, and of neurotrophic, proinflammatory, and apoptotic molecules in the hippocampus with western blotting. Forty-two days after surgery, OBX mice showed depressive-like behaviors, as well as decreased levels of monoamines, reduced cell proliferation, and lower levels of TH, phospho(p)-TH (ser31 and ser40), p-protein kinase A (PKA), p-DARPP-32, p-ERK1/2, p-CREB, brain-derived neurotrophic factor (BDNF), doublecortin, NeuN, and Bcl-2 levels. In contrast, the number of activated microglia and astrocytes and the levels of Iba1, GFAP, p-I
15 July 2018
Fibroblast growth factor 20 is protective towards dopaminergic neurons inávivo in a paracrine manner
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Eugene.L. Boshoff, Edward.J.R. Fletcher, Susan Duty Neuroprotective strategies are an unmet medical need for Parkinson's disease. Fibroblast growth factor 20 (FGF20) enhances survival of cultured dopaminergic neurons but little is known about its inávivo potential. We set out to examine whether manipulation of the FGF20 system affected nigrostriatal tract integrity in rats, to identify which fibroblast growth factor receptors (FGFRs) might reside on dopaminergic neurons and to discover the source of endogenous FGF20 in the substantia nigra (SN). Male Sprague Dawley rats were subject to a partial 6-OHDA lesion alongside treatment with exogenous FGF20 or an FGFR antagonist. Behavioural readouts and tyrosine-hydroxylase (TH) immunohistochemistry were used to evaluate nigrostriatal tract integrity. Fluorescent immunohistochemistry was used to examine FGFR subtype expression on TH-positive dopamine neurons and FGF20 cellular localisation within the SN. FGF20 (2.5
15 July 2018
Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer's disease and vascular dementia
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Andrew S. Murtishaw, Chelcie F. Heaney, Monica M. Bolton, Krystal Courtney D. Belmonte, Michael A. Langhardt, Jefferson W. Kinney Rationale Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain. Objective and methods The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia. Results Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40
15 July 2018
Functional connectivity, behavioral and dopaminergic alterations 24 hours following acute exposure to synthetic bath salt drug methylenedioxypyrovalerone
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Luis M. Colon-Perez, Jose A. Pino, Kaustuv Saha, Marjory Pompilus, Sherman Kaplitz, Nafisa Choudhury, Darin A. Jagnarine, Jean R. Geste, Brandon A. Levin, Isaac Wilks, Barry Setlow, Adriaan W. Bruijnzeel, Habibeh Khoshbouei, Gonzalo E. Torres, Marcelo Febo Among cathinone drugs known as bath salts, methylenedioxypyrovalerone (MDPV) exerts its potent actions via the dopamine (DA) system, and at intoxicating doses may produce adverse behavioral effects. Previous work by our group suggests that prolonged alterations in correlated neural activity between cortical and striatal areas could underlie, at least in part, the adverse reactions to this bath salt drug. In the present study, we assessed the effect of acute MDPV administration on brain functional connectivity at 1 and 24
15 July 2018
The neurokinin-1 receptor mediates escalated alcohol intake induced by multiple drinking models
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Michelle K. Sequeira, Britta S. Nelson, Hannah D. Fulenwider, Courtney E. King, Sadie E. Nennig, Jennifer B. Bohannon, Kejun Cheng, Kenner C. Rice, Markus Heilig, Jesse R. Schank We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures.
15 July 2018
Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Ruifeng Liu, Jonathan Crawford, Patrick M. Callahan, Alvin V. Terry, Christos Constantinidis, David T. Blake Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance.
15 July 2018
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15 July 2018
Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Jerry Zhao, Michel Baudry, Susan Jones Repeated activation of N-Methyl-d-aspartate receptors (NMDARs) causes a Ca2+-dependent reduction in NMDAR-mediated current in dopamine (DA) neurons of the substantia nigra pars compacta (SNc) in one week old rats; however, a Ca2+-dependent regulatory protein has not been identified. The role of the Ca2+-dependent cysteine protease, calpain, in mediating NMDAR current rundown was investigated. In brain slices from rats aged postnatal day 7ľ9 (ĹP7ĺ), bath application of either of the membrane permeable calpain inhibitors, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLN, 20
15 July 2018
Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Mehdi Farokhnia, Mikela B. Sheskier, Mary R. Lee, April N. Le, Erick Singley, Sofia Bouhlal, Timmy Ton, Zhen Zhao, Lorenzo Leggio Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA-B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA-B receptor, in combination with alcohol intake, may affect feeding- and stress-related neuroendocrine pathways remains unknown. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals received baclofen (30
15 July 2018
Intranasally delivered small interfering RNA-mediated suppression of scavenger receptor Mac-1 attenuates microglial phenotype switching and working memory impairment following hypoxia
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Sudeshna Das, K.P. Mishra, Lilly Ganju, S.B. Singh Brain, being the highest consumer of oxygen, is prone to increased risk of hypoxia-induced neurological insults. In response to hypoxia, microglia, the major resident immune cells of brain switches to an activated phenotype and promote inflammatory responses leading to tissue damage and loss of cognitive functions including working memory impairment. Till date, no proven clinical therapeutics is available to retard the progression of neurodegenerative memory impairment. In the present study, we investigated the therapeutic potential of intranasal small interfering RNA (siRNA) delivery in a mouse model of hypoxia-induced working memory impairment using microglial receptor, Mac-1 as a target gene. Here, we implicate Mac-1 scavenger receptor in microglial phenotype switching, neurodegeneration in prefrontal cortex, hippocampus and working memory impairment. RNA mediated silencing of Mac-1 in both inávitro and inávivo model showed significant impact of it on hypoxia induced altered expression of Mac-1 endogenous ligand, signaling cascade proteins, transcription factors and NADPH oxidase pathway. Efficient degradation of Mac-1 mRNA suppressed expression of M1 phenotypic markers, inflammatory chemokines, and cytokines, but on the other hand, it upregulated M2 phenotypic markers and anti-inflammatory cytokines. Neuronal viability and synaptic plasticity markers were also modulated significantly by this strategy. Behavioral study revealed significant downregulation in the number of working memory errors at a time-dependent manner after silencing the Mac-1 gene during continuous hypoxic exposure. The novel findings of this study for the very first time, unmasked the role of Mac-1 receptor in neurodegenerative disease progression under hypoxic condition and at the same time indicated the potential therapeutic value of this non-invasive siRNA delivery approach for treating working memory loss.

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15 July 2018
Pannexin-1 channel dysfunction in the medial prefrontal cortex mediates depressive-like behaviors induced by chronic social defeat stress and administration of mefloquine in mice
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Ming Ni, Jin-Gang He, Hai-Yun Zhou, Xiao-Jia Lu, Yuan-Lang Hu, Li Mao, Fang Wang, Jian-Guo Chen, Zhuang-Li Hu Mefloquine (MFQ) is widely used for the treatment of malaria clinically. Apart from antimalarial effect, psychiatric side effects such as depression and anxiety of MFQ have been reported. Interestingly, MFQ is also known as a broad-spectrum pannexin-1 (Panx1) inhibitor. Panx1 is a new gap junction channel in the brain which mediates efflux of adenosine triphosphate (ATP). Although exogenous ATP has been known to produce a potential antidepressant-like effect, little is known about the role of Panx1 in pathophysiology of depression, especially the depression induced by administration of MFQ. Here, we used the chronic social defeat stress (CSDS) model and found a decrease in the expression and function of Panx1 in the medial prefrontal cortex (mPFC) of susceptible mice. Furthermore, pharmacological blockade of Panx1 in the mPFC with carbenoxolone (CBX) (100ámM) or 10Panx (100á
15 July 2018
Exposure to cannabinoid agonist WIN 55,212-2 during early adolescence increases alcohol preference and anxiety in CD1 mice
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Jimena Laura Frontera, Victoria Mar
15 July 2018
Activation and blockade of basolateral amygdala 5-HT6 receptor produce anxiolytic-like behaviors in an experimental model of Parkinsonĺs disease
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Yi-Na Sun, Lu Yao, Li-Bo Li, Yong Wang, Cheng-Xue Du, Yuan Guo, Jian Liu Although the basolateral amygdala (BLA) and serotonin6 (5-HT6) receptor are involved in modulation of anxiety, their roles in Parkinsonĺ disease (PD)-related anxiety are still unknown. Thus we perform this study to examine the involvement of BLA 5-HT6 receptor on anxiety in unilateral 6-hydroxydopamine-induced PD rats. The lesion of the medial forebrain bundle (MFB) induced anxiety-like behaviors, and decreased the basal firing rate of BLA glutamate neurons and dopamine (DA) levels in tissues of the medial prefrontal cortex (mPFC), amygdala and ventral part of hippocampus (vHip) in rats. Activation of BLA 5-HT6 receptor by local infusion of WAY208466 induced anxiolytic-like effects and increased extracellular
15 July 2018
Self-administration of the synthetic cathinone MPDV enhances reward function via a nicotinic receptor dependent mechanism
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Jean R. Geste, Marjory Pompilus, Marcelo Febo, Adriaan W. Bruijnzeel Methylenedioxypyrovalerone (MDPV) is an addictive synthetic drug with severe side effects. Previous studies have shown that MDPV has positive reinforcing properties. However, little is known about the effect of MDPV self-administration on the state of the brain reward system and the neuronal mechanisms by which MDPV mediates its effects. The goal of the present studies was to determine the effect of MDPV self-administration on reward function and the role of cholinergic neurotransmission in the reinforcing effects of MDPV. To study the effect of MDPV self-administration on the brain reward system, rats were prepared with intravenous catheters and intracranial self-stimulation electrodes (ICSS). For 10 days, the reward thresholds were assessed immediately before (23
15 July 2018
Inhibition of striatal cholinergic interneuron activity by the Kv7 opener retigabine and the nonsteroidal anti-inflammatory drug diclofenac
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Rodrigo Manuel Paz, Cecilia Tubert, Agostina Stahl, Anal
15 July 2018
Dissociable contributions of dorsal and ventral striatal regions on a rodent cost/benefit decision-making task requiring cognitive effort
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): Mason M. Silveira, Melanie Tremblay, Catharine A. Winstanley Cognitive effort is a ubiquitous process, yet surprisingly little is known about the brain mechanisms responsible for evaluating it. Here, we utilize the rat Cognitive Effort Task (rCET) to probe the striatum's role in deciding between options that vary in the amount of cognitive effort required for success. In the rCET, animals choose to perform either an easy trial, in which the attentional demand is low but the potential reward is small, or a difficult trial which is more attentionally demanding but can yield twice the sugar pellets. Twenty-six male Long Evans rats were trained on the rCET and the effects of pharmacologically inactivating the dorsomedial striatum (DMS) and core region of the nucleus accumbens were determined. Temporary inactivation of the DMS decreased all animals' choice of the high-effort, high-reward option, impaired attentional accuracy, and robustly increased premature responding without impairing general indices of motor ability. The DMS therefore appears necessary for the integration of cognitive signals required for optimal performance. In stark contrast, following temporary inactivation of the ventral striatum, subjects were fundamentally unable to perform the task, as reflected by a drastic decrease in the number of trials initiated and an increase in omitted responses. Together, these data suggest the striatum is likely part of a larger cortico-limbic-striatal network whose function is to optimize decisions requiring cognitive effort costs, at least in the attentional domain, and that striatal subregions have dissociable roles in the adjudication and application of this form of cognitive effort.

Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABAA receptors: Improved bioavailability enhances anticonvulsant efficacy
Publication date: 15 July 2018
Source:Neuropharmacology, Volume 137 Author(s): J.M. Witkin, J.L. Smith, X. Ping, S.D. Gleason, M.M. Poe, G. Li, X. Jin, J. Hobbs, J.M. Schkeryantz, J.S. McDermott, A.I. Alatorre, J.N. Siemian, J.W. Cramer, D.C. Airey, K.R. Methuku, V.V.N.P.B. Tiruveedhula, T.M. Jones, J. Crawford, M.J. Krambis, J.L. Fisher, J.M. Cook, R. Cerne HZ-166 has previously been characterized as an
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