Glucocorticoid receptor modulators decrease alcohol self-administration in male rats
Neuropharmacology. 2021 Feb 26:108510. doi: 10.1016/j.neuropharm.2021.108510. Online ahead of print.ABSTRACTAlcohol use disorder (AUD) is associated with the dysregulation of brain stress and reward systems, including glucocorticoid receptors (GRs). The mixed glucocorticoid/progesterone receptor antagonist mifepristone and selective GR antagonist CORT113176 have been shown to selectively reduce alcohol consumption in alcohol-dependent rats. Mifepristone has also been shown to decrease alcohol consumption and craving for alcohol in humans with AUD. The present study tested the effects of the GR modulators CORT118335, CORT12...
Source: Neuropharmacology - March 1, 2021 Category: Drugs & Pharmacology Authors: M Adrienne McGinn Brendan J Tunstall Joel E Schlosburg Adriana Gregory-Flores Olivier George Giordano de Guglielmo Barbara J Mason Hazel J Hunt George F Koob Leandro F Vendruscolo Source Type: research

Clozapine attenuates mitochondrial dysfunction, inflammatory gene expression, and behavioral abnormalities in an animal model of schizophrenia
Neuropharmacology. 2021 Feb 23:108503. doi: 10.1016/j.neuropharm.2021.108503. Online ahead of print.ABSTRACTBeyond abnormalities in the neurotransmitter hypothesis, recent evidence suggests that mitochondrial dysfunction and immune-inflammatory responses contribute to the pathophysiology of schizophrenia. The prefrontal cortex (PFC) undergoes maturation and development during adolescence, which is a critical time window in life that is vulnerable to environmental adversities and the development of psychiatric disorders such as schizophrenia. Applying eight weeks of post-weaning social isolation stress (PWSI) to rats, as an...
Source: Neuropharmacology - February 26, 2021 Category: Drugs & Pharmacology Authors: Shayan Amiri Rana Dizaji Majid Momeny Evan Gauvin Mir-Jamal Hosseini Source Type: research

Alcohol reduces the activity of somatostatin interneurons in the mouse prefrontal cortex: a neural basis for its disinhibitory effect?
Neuropharmacology. 2021 Feb 23:108501. doi: 10.1016/j.neuropharm.2021.108501. Online ahead of print.ABSTRACTThe prefrontal cortex (PFC) is involved in executive ("top-down") control of behavior and its function is especially susceptible to the effects of alcohol, leading to behavioral disinhibition that is associated with alterations in decision making, response inhibition, social anxiety and working memory. The circuitry of the PFC involves a complex interplay between pyramidal neurons (PNs) and several subclasses of inhibitory interneurons (INs), including somatostatin (SST)-expressing INs. Using in vivo calciu...
Source: Neuropharmacology - February 26, 2021 Category: Drugs & Pharmacology Authors: Miao Li David Cabrera-Garcia Michael C Salling Edmund Au Guang Yang Neil L Harrison Source Type: research

Clozapine attenuates mitochondrial dysfunction, inflammatory gene expression, and behavioral abnormalities in an animal model of schizophrenia
Neuropharmacology. 2021 Feb 23:108503. doi: 10.1016/j.neuropharm.2021.108503. Online ahead of print.ABSTRACTBeyond abnormalities in the neurotransmitter hypothesis, recent evidence suggests that mitochondrial dysfunction and immune-inflammatory responses contribute to the pathophysiology of schizophrenia. The prefrontal cortex (PFC) undergoes maturation and development during adolescence, which is a critical time window in life that is vulnerable to environmental adversities and the development of psychiatric disorders such as schizophrenia. Applying eight weeks of post-weaning social isolation stress (PWSI) to rats, as an...
Source: Neuropharmacology - February 26, 2021 Category: Drugs & Pharmacology Authors: Shayan Amiri Rana Dizaji Majid Momeny Evan Gauvin Mir-Jamal Hosseini Source Type: research

Alcohol reduces the activity of somatostatin interneurons in the mouse prefrontal cortex: a neural basis for its disinhibitory effect?
Neuropharmacology. 2021 Feb 23:108501. doi: 10.1016/j.neuropharm.2021.108501. Online ahead of print.ABSTRACTThe prefrontal cortex (PFC) is involved in executive ("top-down") control of behavior and its function is especially susceptible to the effects of alcohol, leading to behavioral disinhibition that is associated with alterations in decision making, response inhibition, social anxiety and working memory. The circuitry of the PFC involves a complex interplay between pyramidal neurons (PNs) and several subclasses of inhibitory interneurons (INs), including somatostatin (SST)-expressing INs. Using in vivo calciu...
Source: Neuropharmacology - February 26, 2021 Category: Drugs & Pharmacology Authors: Miao Li David Cabrera-Garcia Michael C Salling Edmund Au Guang Yang Neil L Harrison Source Type: research

Clozapine attenuates mitochondrial dysfunction, inflammatory gene expression, and behavioral abnormalities in an animal model of schizophrenia
Neuropharmacology. 2021 Feb 23:108503. doi: 10.1016/j.neuropharm.2021.108503. Online ahead of print.ABSTRACTBeyond abnormalities in the neurotransmitter hypothesis, recent evidence suggests that mitochondrial dysfunction and immune-inflammatory responses contribute to the pathophysiology of schizophrenia. The prefrontal cortex (PFC) undergoes maturation and development during adolescence, which is a critical time window in life that is vulnerable to environmental adversities and the development of psychiatric disorders such as schizophrenia. Applying eight weeks of post-weaning social isolation stress (PWSI) to rats, as an...
Source: Neuropharmacology - February 26, 2021 Category: Drugs & Pharmacology Authors: Shayan Amiri Rana Dizaji Majid Momeny Evan Gauvin Mir-Jamal Hosseini Source Type: research

Alcohol reduces the activity of somatostatin interneurons in the mouse prefrontal cortex: a neural basis for its disinhibitory effect?
Neuropharmacology. 2021 Feb 23:108501. doi: 10.1016/j.neuropharm.2021.108501. Online ahead of print.ABSTRACTThe prefrontal cortex (PFC) is involved in executive ("top-down") control of behavior and its function is especially susceptible to the effects of alcohol, leading to behavioral disinhibition that is associated with alterations in decision making, response inhibition, social anxiety and working memory. The circuitry of the PFC involves a complex interplay between pyramidal neurons (PNs) and several subclasses of inhibitory interneurons (INs), including somatostatin (SST)-expressing INs. Using in vivo calciu...
Source: Neuropharmacology - February 26, 2021 Category: Drugs & Pharmacology Authors: Miao Li David Cabrera-Garcia Michael C Salling Edmund Au Guang Yang Neil L Harrison Source Type: research

PARP-DNA trapping ability of PARP inhibitors jeopardizes astrocyte viability: implications for CNS disease therapeutics
This study provides unique insight into the selective use of PARP inhibitors to treat neurodegenerative disorders whereby inhibition of PARP enzymatic activity must occur without deleteriously trapping PARP onto DNA.PMID:33631119 | DOI:10.1016/j.neuropharm.2021.108502 (Source: Neuropharmacology)
Source: Neuropharmacology - February 25, 2021 Category: Drugs & Pharmacology Authors: Asha Sinha Sachin Katyal Tiina M Kauppinen Source Type: research

PARP-DNA trapping ability of PARP inhibitors jeopardizes astrocyte viability: implications for CNS disease therapeutics
This study provides unique insight into the selective use of PARP inhibitors to treat neurodegenerative disorders whereby inhibition of PARP enzymatic activity must occur without deleteriously trapping PARP onto DNA.PMID:33631119 | DOI:10.1016/j.neuropharm.2021.108502 (Source: Neuropharmacology)
Source: Neuropharmacology - February 25, 2021 Category: Drugs & Pharmacology Authors: Asha Sinha Sachin Katyal Tiina M Kauppinen Source Type: research

Alcohol exposure in utero disrupts cortico-striatal coordination required for behavioral flexibility
Neuropharmacology. 2021 Feb 19:108471. doi: 10.1016/j.neuropharm.2021.108471. Online ahead of print.ABSTRACTDeficits in behavioral flexibility are a hallmark of multiple psychiatric, neurological, and substance use disorders. These deficits are often marked by decreased function of the prefrontal cortex (PFC); however, the genesis of such executive deficits remains understudied. Here we report how the most preventable cause of developmental disability, in utero exposure to alcohol, alters cortico-striatal circuit activity leading to impairments in behavioral flexibility in adulthood. We utilized a translational touch-scree...
Source: Neuropharmacology - February 23, 2021 Category: Drugs & Pharmacology Authors: Kristin Marquardt James F Cavanagh Jonathan L Brigman Source Type: research

Alcohol exposure in utero disrupts cortico-striatal coordination required for behavioral flexibility
Neuropharmacology. 2021 Feb 19:108471. doi: 10.1016/j.neuropharm.2021.108471. Online ahead of print.ABSTRACTDeficits in behavioral flexibility are a hallmark of multiple psychiatric, neurological, and substance use disorders. These deficits are often marked by decreased function of the prefrontal cortex (PFC); however, the genesis of such executive deficits remains understudied. Here we report how the most preventable cause of developmental disability, in utero exposure to alcohol, alters cortico-striatal circuit activity leading to impairments in behavioral flexibility in adulthood. We utilized a translational touch-scree...
Source: Neuropharmacology - February 23, 2021 Category: Drugs & Pharmacology Authors: Kristin Marquardt James F Cavanagh Jonathan L Brigman Source Type: research

Alcohol exposure in utero disrupts cortico-striatal coordination required for behavioral flexibility
Neuropharmacology. 2021 Feb 19:108471. doi: 10.1016/j.neuropharm.2021.108471. Online ahead of print.ABSTRACTDeficits in behavioral flexibility are a hallmark of multiple psychiatric, neurological, and substance use disorders. These deficits are often marked by decreased function of the prefrontal cortex (PFC); however, the genesis of such executive deficits remains understudied. Here we report how the most preventable cause of developmental disability, in utero exposure to alcohol, alters cortico-striatal circuit activity leading to impairments in behavioral flexibility in adulthood. We utilized a translational touch-scree...
Source: Neuropharmacology - February 23, 2021 Category: Drugs & Pharmacology Authors: Kristin Marquardt James F Cavanagh Jonathan L Brigman Source Type: research

Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor
This study aims to determine the effect of MDMA on the KYN pathway and on AhR activity and to establish their role in the long-term serotonergic neurotoxicity induced by the drug in rats. Our results show that MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while administration of exogenous ...
Source: Neuropharmacology - February 19, 2021 Category: Drugs & Pharmacology Authors: C Abuin-Mart ínez R Vidal M D Guti érrez-López M P érez-Hernández P Gim énez-Gómez N Morales-Puerto E O'Shea M I Colado Source Type: research

Promising vulnerability markers of substance use and misuse: A review of human neurobehavioral studies
Neuropharmacology. 2021 Feb 16:108500. doi: 10.1016/j.neuropharm.2021.108500. Online ahead of print.ABSTRACTSubstance use often begins, and noticeably escalates, during adolescence. Identifying predictive neurobehavioral vulnerability markers of substance use and related problems may improve targeted prevention and early intervention initiatives. This review synthesizes 44 longitudinal studies and explores the utility of developmental imbalance models and neurobehavioral addiction frameworks in predicting neural and cognitive patterns that are associated with prospective substance use initiation and escalation among young ...
Source: Neuropharmacology - February 19, 2021 Category: Drugs & Pharmacology Authors: Briana Lees Alexis M Garcia Jennifer Debenham Anna E Kirkland Brittany E Bryant Louise Mewton Lindsay M Squeglia Source Type: research

Sex differences in progestogen- and androgen-derived neurosteroids in vulnerability to alcohol and stress-related disorders
Neuropharmacology. 2021 Feb 15:108499. doi: 10.1016/j.neuropharm.2021.108499. Online ahead of print.ABSTRACTStress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, ...
Source: Neuropharmacology - February 18, 2021 Category: Drugs & Pharmacology Authors: MacKenzie R Peltier Terril L Verplaetse Yann S Mineur Ralitza Geuorguieva Ismene Petrakis Kelly P Cosgrove Marina R Picciotto Sherry A McKee Source Type: research

Modulation of human T-type calcium channels by synthetic cannabinoid receptor agonists in vitro
CONCLUSIONS AND IMPLICATIONS: SCRAs are potent agonists of CB1 receptors and can be extremely toxic, but observed toxicity also resembles symptoms associated with altered Cav3.2 activity. Many SCRAs tested were potent modulators of Cav3.2, raising the possibility that SC toxicity may be due in part to Cav3.2 modulation. This potent T-type channel modulation suggests the possibility of SCRAs as a new drug class with potential to treat diseases associated with altered T-type channel activity.PMID:33600843 | DOI:10.1016/j.neuropharm.2021.108478 (Source: Neuropharmacology)
Source: Neuropharmacology - February 18, 2021 Category: Drugs & Pharmacology Authors: Chris Bladen Somayeh Mirlohi Marina Santiago Mitchell Longworth Michael Kassiou Sam Banister Mark Connor Source Type: research

Increased kynurenine concentration attenuates serotonergic neurotoxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in rats through activation of aryl hydrocarbon receptor.
This study aims to determine the effect of MDMA on the KYN pathway and on AhR activity and to establish their role in the long-term serotonergic neurotoxicity induced by the drug in rats. Our results show that MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while administration of exogenous ...
Source: Neuropharmacology - February 16, 2021 Category: Drugs & Pharmacology Authors: Abuin-Martínez C, Vidal R, Gutiérrez-López MD, Pérez-Hernández M, Giménez-Gómez P, Morales-Puerto N, O'Shea E, Colado MI Tags: Neuropharmacology Source Type: research

Promising vulnerability markers of substance use and misuse: A review of human neurobehavioral studies.
Abstract Substance use often begins, and noticeably escalates, during adolescence. Identifying predictive neurobehavioral vulnerability markers of substance use and related problems may improve targeted prevention and early intervention initiatives. This review synthesizes 44 longitudinal studies and explores the utility of developmental imbalance models and neurobehavioral addiction frameworks in predicting neural and cognitive patterns that are associated with prospective substance use initiation and escalation among young people. A total of 234 effect sizes were calculated and compared. Findings suggest that ab...
Source: Neuropharmacology - February 16, 2021 Category: Drugs & Pharmacology Authors: Lees B, Garcia AM, Debenham J, Kirkland AE, Bryant BE, Mewton L, Squeglia LM Tags: Neuropharmacology Source Type: research

Sex differences in progestogen- and androgen-derived neurosteroids in vulnerability to alcohol and stress-related disorders.
Abstract Stress and trauma exposure disturbs stress regulation systems and thus increases the vulnerability for stress-related disorders which are characterized by negative affect, including major depressive disorder, anxiety disorders and posttraumatic stress disorder. Similarly, stress trauma exposure results in increased vulnerability to problematic alcohol use and alcohol use disorder, especially among women, who are more likely to drink to cope with negative affect than their male counterparts. Given these associations, the relationship between stress-related disorders and alcohol use is generally stronger am...
Source: Neuropharmacology - February 15, 2021 Category: Drugs & Pharmacology Authors: Peltier MR, Verplaetse TL, Mineur YS, Geuorguieva R, Petrakis I, Cosgrove KP, Picciotto MR, McKee SA Tags: Neuropharmacology Source Type: research

Modulation of Human T-type Calcium Channels by Synthetic Cannabinoid Receptor Agonists in vitro.
CONCLUSIONS AND IMPLICATIONS: SCRAs are potent agonists of CB1 receptors and can be extremely toxic, but observed toxicity also resembles symptoms associated with altered Cav3.2 activity. Many SCRAs tested were potent modulators of Cav3.2, raising the possibility that SC toxicity may be due in part to Cav3.2 modulation. This potent T-type channel modulation suggests the possibility of SCRAs as a new drug class with potential to treat diseases associated with altered T-type channel activity. PMID: 33600843 [PubMed - as supplied by publisher] (Source: Neuropharmacology)
Source: Neuropharmacology - February 15, 2021 Category: Drugs & Pharmacology Authors: Bladen C, Mirlohi S, Santiago M, Longworth M, Kassiou M, Banister S, Connor M Tags: Neuropharmacology Source Type: research

Synergistic efficacy and diminished adverse effect profile of composite treatment of several ADHD medications.
Abstract Although attention-deficit/hyperactivity disorder (ADHD) is widely studied, problems regarding the adverse effect risks and non-responder problems still need to be addressed. Combination pharmacotherapy using standard dose regimens of existing medication is currently being practiced mainly to augment the therapeutic efficacy of each drug. The idea of combining different pharmacotherapies with different molecular targets to alleviate the symptoms of ADHD and its comorbidities requires scientific evidence, necessitating the investigation of their therapeutic efficacy and the mechanisms underlying the profes...
Source: Neuropharmacology - February 12, 2021 Category: Drugs & Pharmacology Authors: Park D, Mabunga DFN, Adil KJ, Ryu O, Valencia S, Kim R, Kim HJ, Cheong JH, Kwon KJ, Kim HY, Han SH, Jeon SJ, Shin CY Tags: Neuropharmacology Source Type: research

Activation of PPG neurons following acute stressors differentially involves hindbrain serotonin in male rats.
In this study, we investigated the roles of 5-HT2C and 5-HT3 receptors in mediating the activation of PPG neurons in the nucleus tractus solitarius (NTS) following exposure to three different acute stressors: lithium chloride (LiCl), noncontingent cocaine (Coc), and novel restraint stress (RES). Results showed that increased c-Fos expression in PPG neurons following LiCl and RES-but not Coc-is dependent on hindbrain 5-HT2C and 5-HT3 receptor signaling. Additionally, stressors that depend on 5-HT signaling to activate PPG neurons (i.e., LiCl and RES) increased c-Fos expression in 5-HT-expressing neurons within the caudal ra...
Source: Neuropharmacology - February 10, 2021 Category: Drugs & Pharmacology Authors: Leon RM, Borner T, Stein LM, Urrutia NA, De Jonghe BC, Schmidt HD, Hayes MR Tags: Neuropharmacology Source Type: research

Class I HDAC inhibition improves object recognition memory consolidation through BDNF/TrkB pathway in a time-dependent manner.
Abstract There is increasing evidence showing that HDACs regulates BDNF (brain-derived neurotrophic factor) expression through its interaction with the Bdnf gene promoter, a key regulator to consolidate memory. Although the nuclear mechanisms regulated by HDACs that control BDNF expression have been partially described recently, the temporal events for memory consolidation remain unknown. Hence, in this work, we studied the temporal pattern for the activation of the BDNF/TrkB pathway through class I HDAC inhibition to enhance object recognition memory (ORM) consolidation. To this end, we inhibited class I HDAC int...
Source: Neuropharmacology - February 10, 2021 Category: Drugs & Pharmacology Authors: Gerardo RM, Elvi GL, Oscar UM, Ernesto SR, Federico BR Tags: Neuropharmacology Source Type: research

Sex differences in vulnerability to addiction.
This article reviews the evidence for sex differences in vulnerability to addiction with an emphasis on the neural mechanisms underlying these differences. Sex differences in the way that the gonadal hormone, estradiol, interacts with the ascending telencephalic dopamine system results in sex differences in motivated behaviors, including drug seeking. In rodents, repeated psychostimulant exposure enhances incentive sensitization to a greater extent in females than males. Estradiol increases females' motivation to attain psychostimulants and enhances the value of drug related cues, which ultimately increases their susceptib...
Source: Neuropharmacology - February 7, 2021 Category: Drugs & Pharmacology Authors: Quigley JA, Logsdon MK, Turner CA, Gonzalez I, Leonardo N, Becker JB Tags: Neuropharmacology Source Type: research

Aged rhesus monkeys: cognitive performance categorizations and preclinical drug testing.
Abstract Rodent models have facilitated major discoveries in neurobiology, however, the low success rate of novel medications in clinical trials have led to questions about their translational value in neuropsychiatric drug development research. For age-related disorders of cognition such as Alzheimer' disease (AD) there is interest in moving beyond transgenic amyloid-β and/or tau-expressing rodent models and focusing more on natural aging and dissociating "healthy" from "pathological" aging to identify new therapeutic targets and treatments. In complex disorders such as AD, it can also be...
Source: Neuropharmacology - February 6, 2021 Category: Drugs & Pharmacology Authors: Plagenhoef MR, Callahan PM, Beck WD, Blake DT, Terry AV Tags: Neuropharmacology Source Type: research

Oxytocin mediates neuroprotection against hypoxic-ischemic injury in hippocampal CA1 neuron of neonatal rats.
This study combined immunohistochemistry with electrophysiological recordings of hippocampal CA1 neurons to investigate the role of oxytocin in an in vitro model of hypoxi c-ischemic (HI) injury (oxygen and glucose deprivation, OGD) in postnatal day 7-10 rats. Immunohistochemical analysis showed that oxytocin largely reduced the relative intensity of TOPRO-3 staining following OGD in the hippocampal CA1 region. Whole-cell patch-clamp recording revealed that the OGD-induced onset time of anoxic depolarization (AD) was significantly delayed by oxytocin. This protective effect of oxytocin was blocked by pretreatment with [d(C...
Source: Neuropharmacology - February 5, 2021 Category: Drugs & Pharmacology Authors: Wu Z, Xie C, Kuang H, Wu J, Chen X, Liu H, Liu T Tags: Neuropharmacology Source Type: research

Linking the CHRNA5 SNP to drug abuse liability: from circuitry to cellular mechanisms.
Abstract Genetics are known to be a significant risk factor for drug abuse. In human populations, the single nucleotide polymorphism (SNP) D398N in the gene CHRNA5 has been associated with addiction to nicotine, opioids, cocaine, and alcohol. In this paper, we review findings from studies in humans, rodent models, and cell lines and provide evidence that collectively suggests that the Chrna5 SNP broadly influences the response to drugs of abuse in a manner that is not substance-specific. This finding has important implications for our understanding of the role of the cholinergic system in reward and addiction vuln...
Source: Neuropharmacology - February 1, 2021 Category: Drugs & Pharmacology Authors: Brynildsen JK, Blendy JA Tags: Neuropharmacology Source Type: research

Caffeine exposure in utero is associated with structural brain alterations and deleterious neurocognitive outcomes in 9-10 year old children.
Abstract Caffeine, a very widely used and potent neuromodulator, easily crosses the placental barrier, but relatively little is known about the long-term impact of gestational caffeine exposure (GCE) on neurodevelopment. Here, we leverage magnetic resonance imaging (MRI) data, collected from a very large sample of 9157 children, aged 9-10 years, as part of the Adolescent Brain and Cognitive Developmentsm (ABCD ®) study, to investigate brain structural outcomes at 27 major fiber tracts as a function of GCE. Significant relationships between GCE and fractional anisotropy (FA) measures in the inferior fronto-occi...
Source: Neuropharmacology - January 30, 2021 Category: Drugs & Pharmacology Authors: Christensen ZP, Freedman EG, Foxe JJ Tags: Neuropharmacology Source Type: research

Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones.
pez-Arnau R Abstract The emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, they are quickly replaced by new structurally related alternatives. The main goal of the present study was to characterize the pharmacological profile, the psychostimulant and rewarding properties of novel cathinones (pentedrone, N-ethyl-pentedrone, α-PVP, N,N-diethyl-pentedrone and α-PpVP) which only differs in their amino terminal substitution. Rat synaptosomes were used for [3H]dopamine uptake experiments. HEK293 transfected cells (hDAT, hSERT, hOCT; human dopamine, serotonin an...
Source: Neuropharmacology - January 30, 2021 Category: Drugs & Pharmacology Authors: Duart-Castells L, Nadal-Gratacós N, Muralter M, Puster B, Berzosa X, Estrada-Tejedor R, Niello M, Bhat S, Pubill D, Camarasa J, Sitte HH, Escubedo E, López-Arnau R Tags: Neuropharmacology Source Type: research

Factors Mediating Pain-Related Risk for Opioid Use Disorder.
Abstract Pain is a complex experience with far-reaching organismal influences ranging from biological factors to those that are psychological and social. Such influences can serve as pain-related risk factors that represent susceptibilities to opioid use disorder. This review evaluates various pain-related risk factors to form a consensus on those that facilitate opioid abuse. Epidemiological findings represent a high degree of co-occurrence between chronic pain and opioid use disorder that is, in part, driven by an increase in the availability of opioid analgesics and the diversion of their use in a non-medical c...
Source: Neuropharmacology - January 29, 2021 Category: Drugs & Pharmacology Authors: Nazarian A, Negus SS, Martin TJ Tags: Neuropharmacology Source Type: research

Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/ β-catenin signaling in mice.
Lithium alleviates blood-brain barrier breakdown after cerebral ischemia and reperfusion by upregulating endothelial Wnt/β-catenin signaling in mice. Neuropharmacology. 2021 Jan 29;:108474 Authors: Ji YB, Gao Q, Tan XX, Huang XW, Ma YZ, Fang C, Wang SN, Qiu LH, Cheng YX, Guo FY, Chang J Abstract Although upregulation of endothelial Wnt/β-catenin signaling may be used to treat blood-brain barrier (BBB) breakdown caused by cerebral ischemia/reperfusion injury, no agents based on this mechanism are available clinically. Lithium, a medication used for treating bipolar mood disorders, upregulates...
Source: Neuropharmacology - January 29, 2021 Category: Drugs & Pharmacology Authors: Ji YB, Gao Q, Tan XX, Huang XW, Ma YZ, Fang C, Wang SN, Qiu LH, Cheng YX, Guo FY, Chang J Tags: Neuropharmacology Source Type: research

Exposure of R6/2 mice in an enriched environment augments P42 therapy efficacy on Huntington's disease progression.
We reported that, in the R6/2 mouse model of HD, P42 rescued striatal TrkB level but marginally increased cortical BDNF. In the present study, our aim was to address P42 neuroprotection in presence of an external input of BDNF. We combined P42 administration with environmental enrichment (EE), induced by training in the Hamlet test. We examined the consequences of P42+EE combination on different phenotypes in R6/2 HD mice: motor and cognitive performances, recorded at early and late pathological stages, and analyzed aggregated mHtt and BDNF levels in forebrain structures. Hamlet exploration (i.e., entries in Run, Hide, Eat...
Source: Neuropharmacology - January 28, 2021 Category: Drugs & Pharmacology Authors: Couly S, Carles A, Denus M, Benigno-Anton L, Maschat F, Maurice T Tags: Neuropharmacology Source Type: research

Role of peripheral and central sensitization in the anti-hyperalgesic effect of hecogenin acetate, an acetylated sapogenin, complexed with β-cyclodextrin: Involvement of NFκB and p38 MAPK pathways.
Role of peripheral and central sensitization in the anti-hyperalgesic effect of hecogenin acetate, an acetylated sapogenin, complexed with β-cyclodextrin: Involvement of NFκB and p38 MAPK pathways. Neuropharmacology. 2021 Jan 28;:108395 Authors: Santos Passos FR, Pereira EWM, Heimfarth L, Monteiro BS, Barbosa Gomes de Carvalho YM, Siqueira-Lima P, Melo Coutinho HD, Antunes de Souza Araújo A, Guedes da Silva Almeida JR, Barreto RSS, Picot L, Quintans-Júnior LJ, Quintans JSS Abstract Neuropathic pain develops due to injury to the somatosensory system, affecting the patient's qua...
Source: Neuropharmacology - January 28, 2021 Category: Drugs & Pharmacology Authors: Santos Passos FR, Pereira EWM, Heimfarth L, Monteiro BS, Barbosa Gomes de Carvalho YM, Siqueira-Lima P, Melo Coutinho HD, Antunes de Souza Araújo A, Guedes da Silva Almeida JR, Barreto RSS, Picot L, Quintans-Júnior LJ, Quintans JSS Tags: Neuropharmacology Source Type: research

Vortioxetine attenuates the effects of early-life stress on depression-like behaviors and monoamine transporters in female mice.
In this study, adopting the early-life stress (ELS) paradigm of limited bedding and nesting material, we found that ELS induced depression-like behaviors only in adult female mice, as evaluated by sucrose preference and tail suspension tests. We then examined the ELS effects on monoamine neurotransmission (transporters for monoamine reuptake and release) in depression-related brain regions in female mice. We found that ELS resulted in widespread changes of the expression levels of these transporters in four brain regions. Moreover, systemic 21-day treatment with vortioxetine, a novel multimodal antidepressant, successfully...
Source: Neuropharmacology - January 21, 2021 Category: Drugs & Pharmacology Authors: Liu X, Sun YX, Zhang CC, Zhang XQ, Zhang Y, Wang T, Ma YN, Wang H, Su YA, Li JT, Si TM Tags: Neuropharmacology Source Type: research

Sexually Dimorphic Neuroimmune Response to Chronic Opioid Treatment and Withdrawal.
Abstract Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant o...
Source: Neuropharmacology - January 21, 2021 Category: Drugs & Pharmacology Authors: Kumar M, Rainville JR, Williams K, Lile JA, Hodes GE, Vassoler FM, Turner JR Tags: Neuropharmacology Source Type: research

Combined 5-HT2A and mGlu2 modulation for the treatment of dyskinesia and psychosis in Parkinson's disease.
uot P Abstract Antagonising the serotonin 2A (5-HT2A) receptor is an efficacious way to alleviate dyskinesia and psychosis in Parkinson's disease (PD). However, previous research indicates that there might be a limit to the effects conferred by this approach. 5-HT2A receptors were shown to form hetero-dimers with metabotropic glutamate 2 (mGlu2) receptors, in which 5-HT2A blockade and mGlu2 activation elicit equivalent effects at the downstream signalling level. We have previously shown that mGlu2 activation reduces both dyskinesia and psychosis-like behaviours (PLBs) induced by L-3,4-dihydroxyphenylalanine (L-DOP...
Source: Neuropharmacology - January 21, 2021 Category: Drugs & Pharmacology Authors: Kwan C, Frouni I, Nuara SG, Belliveau S, Kang W, Hamadjida A, Bédard D, Beaudry F, Panisset M, Gourdon JC, Huot P Tags: Neuropharmacology Source Type: research

Vulnerability to addiction.
acute;n-García E Abstract Addiction is a chronic brain disease that has dramatic health and socioeconomic consequences worldwide. Multiple approaches have been used during decades to clarify the neurobiological basis of this disease and to identify novel potential treatments. This review summarizes the main brain networks involved in the vulnerability to addiction and specific innovative technological approaches to investigate these neural circuits. First, the evolution of the definition of addiction across the Diagnostic and Statistical Manual of Mental Disorders (DSM) is revised. We next discuss several i...
Source: Neuropharmacology - January 19, 2021 Category: Drugs & Pharmacology Authors: Maldonado R, Calvé P, García-Blanco A, Domingo-Rodriguez L, Senabre E, Martín-García E Tags: Neuropharmacology Source Type: research

Genetically Selected Alcohol-Preferring msP Rats to Study Alcohol Use Disorder: Anything Lost in Translation?
Abstract For several decades, genetically selected alcohol-preferring rats have been successfully used to mimic and study alcohol use disorders (AUD). These rat lines have been instrumental in advancing our understanding of the neurobiology of alcoholism and enabling pharmacological studies to evaluate drug efficacy on alcohol drinking and relapse. Moreover, the results of these studies have identified genetic variables that are linked to AUD vulnerability. This is an up-to-date review that focuses on genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. To support the translational relevance of...
Source: Neuropharmacology - January 18, 2021 Category: Drugs & Pharmacology Authors: Borruto AM, Stopponi S, Li H, Weiss F, Roberto M, Ciccocioppo R Tags: Neuropharmacology Source Type: research

Novel compounds with dual S1P receptor agonist and histamine H3 receptor antagonist activities act protective in a mouse model of multiple sclerosis.
In this study, we have synthesized a piperidine derivative of the oxazolo-oxazole compounds, denoted ST-1505, and its ring-opened analogue ST-1478, and characterized their in-vitro and in-vivo functions. Notably, the 3-piperidinopropyloxy moiety resembles a structural motif of pitolisant, a drug with histamine H3R antagonistic/inverse agonist activity approved for the treatment of narcolepsy. Both novel compounds exerted H3R affinities, and in addition, ST-1505 was characterised as a dual S1P1+3 agonist, whereas ST-1478 was a dual S1P1+5 agonist. Both multitargeting compounds were also active in mice and reduced the lympho...
Source: Neuropharmacology - January 15, 2021 Category: Drugs & Pharmacology Authors: Imeri F, Tanturovska BS, Zivkovic A, Enzmann G, Schwalm S, Pfeilschifter J, Homann T, Kleuser B, Engelhardt B, Stark H, Huwiler A Tags: Neuropharmacology Source Type: research

(3 α,5α)3-Hydroxypregnan-20-one (3α,5α-THP) regulation of hypothalamic and extrahypothalamic corticotropin releasing factor (CRF): Sexual dimorphism and brain region specificity in Sprague Dawley rats.
In this study, we explored 3α,5α-THP regulation of hypothalamic and extrahypothalamic CRF mRNA and peptide expression, in male and female Sprague Dawley rats following vehicle or 3α,5α-THP administration (15 mg/kg). In the hypothalamus, we found sex differences in CRF mRNA expression (females +74%, p
Source: Neuropharmacology - January 15, 2021 Category: Drugs & Pharmacology Authors: Boero G, Tyler RE, Todd CA, O'Buckley TK, Balan I, Besheer J, Morrow AL Tags: Neuropharmacology Source Type: research

Effects of the NKCC1 inhibitors bumetanide, azosemide, and torasemide alone or in combination with phenobarbital on seizure threshold in epileptic and nonepileptic mice.
scher W Abstract The sodium-potassium-chloride (Na-K-Cl) cotransporter NKCC1 is found in the plasma membrane of a wide variety of cell types, including neurons, glia and endothelial cells in the brain. Increased expression of neuronal NKCC1 has been implicated in several brain disorders, including neonatal seizures and epilepsy. The loop diuretic and NKCC inhibitor bumetanide has been evaluated as an antiseizure agent alone or together with approved antiseizure drugs such as phenobarbital (PB) in pre-clinical and clinical studies with varying results. The equivocal efficacy of bumetanide may be a result of its poo...
Source: Neuropharmacology - January 12, 2021 Category: Drugs & Pharmacology Authors: Hampel P, Römermann K, Gailus B, Johne M, Gericke B, Kaczmarek E, Löscher W Tags: Neuropharmacology Source Type: research

Mambalgin-1 pain-relieving peptide locks the hinge between α4 and α5 helices to inhibit rat Acid-Sensing Ion Channel 1a.
Mambalgin-1 pain-relieving peptide locks the hinge between α4 and α5 helices to inhibit rat Acid-Sensing Ion Channel 1a. Neuropharmacology. 2021 Jan 12;:108453 Authors: Salinas M, Kessler P, Douguet D, Sarraf D, Tonali N, Thai R, Servent D, Lingueglia E Abstract Acid-sensing ion channels (ASICs) are proton-gated cationic channels involved in pain and other processes, underscoring the potential therapeutic value of specific inhibitors such as the three-finger toxin mambalgin-1 (Mamb-1) from snake venom. A low-resolution structure of the human-ASIC1a/Mamb-1 complex obtained by cryo-electron ...
Source: Neuropharmacology - January 12, 2021 Category: Drugs & Pharmacology Authors: Salinas M, Kessler P, Douguet D, Sarraf D, Tonali N, Thai R, Servent D, Lingueglia E Tags: Neuropharmacology Source Type: research

Molecular Imaging of the Serotonin Transporter Availability and Occupancy by Antidepressant Treatment in Late-Life Depression.
Abstract Patients with late-life depression (LLD) have a more variable response to pharmacotherapy relative to patients with mid-life depression. Degeneration of the serotonergic system and lower occupancy of the initial target for antidepressant medications, the serotonin transporter (5-HTT) may contribute to variability in treatment response. The focus of this study was to test the hypotheses that lower cortical and limbic 5-HTT availability in LLD patients relative to controls and less 5-HTT occupancy by antidepressant medications would be associated with less improvement in mood and cognition with treatment in...
Source: Neuropharmacology - January 12, 2021 Category: Drugs & Pharmacology Authors: Smith GS, Kuwabara H, Gould NF, Nassery N, Savonenko A, Joo JH, Bigos K, Kraut M, Brasic J, Holt DP, Hall AW, Mathews WB, Dannals RF, Nandi A, Workman CI Tags: Neuropharmacology Source Type: research

Allosteric modulation of the cannabinoid 2 receptor confers seizure resistance in mice.
Abstract Mounting evidence suggests that modulation of cannabinoid 2 receptors (CB2Rs) is therapeutic in mouse models of neurological disorders, including neuropathic pain, neurodegenerative disease, and stroke. We previously showed that reducing CB2R activity increases seizure susceptibility in mice. In the present study, we evaluated the therapeutic potential of the CB2R positive allosteric modulator, Ec21a, against induced seizures in mice. The pharmacokinetic profile of Ec21 demonstrated a similar distribution in brain and plasma, with detection up to 12 hours following injection. Ec21a increased resistance to...
Source: Neuropharmacology - January 12, 2021 Category: Drugs & Pharmacology Authors: Shapiro L, Gado F, Manera C, Escayg A Tags: Neuropharmacology Source Type: research

The endocannabinoid 2-arachidonoylglycerol and dual ABHD6/MAGL enzyme inhibitors display neuroprotective and anti-inflammatory actions in the in vivo retinal model of AMPA excitotoxicity.
Abstract The endocannabinoid system has been shown to be a putative therapeutic target for retinal disease. Here, we aimed to investigate the ability of the endocannabinoid 2-arachidonoylglycerol (2-AG) and novel inhibitors of its metabolic enzymes, α/β-hydrolase domain-containing 6 (ABHD6) and monoacylglycerol lipase (MAGL), a) to protect the retina against excitotoxicity and b) the mechanisms involved in the neuroprotection. Sprague-Dawley rats, wild type and Akt2-/- C57BL/6 mice were intravitreally administered with phosphate-buffered saline or (RS)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropion...
Source: Neuropharmacology - January 12, 2021 Category: Drugs & Pharmacology Authors: Kokona D, Spyridakos D, Tzatzarakis M, Papadogkonaki S, Filidou E, Arvanitidis KI, Kolios G, Lamani M, Makriyannis A, Malamas MS, Thermos K Tags: Neuropharmacology Source Type: research

Characterization of opioidergic mechanisms related to the anti-migraine effect of vagus nerve stimulation.
Abstract Vagus nerve stimulation (VNS) is a promising neuromodulation approach used in the treatment of migraine, whose therapeutic mechanism is largely unknown. Previous studies suggest that VNS's anti-nociceptive effects may, in part, involved engaging opioidergic mechanisms. We used a validated preclinical model of head pain, with good translational outcomes in migraine, acute intracranial-dural stimulation, and has responded to invasive VNS. We tested the effects of μ (MOR), δ (DOR) and κ (KOR) opioid receptor agonists in this model, and subsequently the effects of opioid receptor antagonists ag...
Source: Neuropharmacology - January 11, 2021 Category: Drugs & Pharmacology Authors: Hu B, Akerman S, Goadsby PJ Tags: Neuropharmacology Source Type: research

Kappa opioid receptor activation in the amygdala disinhibits CRF neurons to generate pain-like behaviors.
This study shows for the first time that KOR activation increases activity of amygdala CRF neurons through synaptic disinhibition, resulting in averse-affective pain-like behaviors. Blocking KOR receptors may therefore represent a novel therapeutic strategy. PMID: 33444637 [PubMed - as supplied by publisher] (Source: Neuropharmacology)
Source: Neuropharmacology - January 11, 2021 Category: Drugs & Pharmacology Authors: Hein M, Ji G, Tidwell D, D'Souza P, Kiritoshi T, Yakhnitsa V, Navratilova E, Porreca F, Neugebauer V Tags: Neuropharmacology Source Type: research

Modulation of single cell circadian response to NMDA by diacylglycerol lipase inhibition reveals a role of endocannabinoids in light entrainment of the suprachiasmatic nucleus.
, Sumová A Abstract Suprachiasmatic nucleus (SCN) of the hypothalamus is the master clock that drives circadian rhythms in physiology and behavior and adjusts their timing to external cues. Neurotransmitter glutamate and glutamatergic receptors sensitive to N-methyl-D-aspartate (NMDA) play a dual role in the SCN by coupling astrocytic and neuronal single cell oscillators and by resetting their phase in response to light. Recent reports suggested that signaling by endogenous cannabinoids (ECs) participates in both of these functions. We have previously shown that ECs, such as 2-arachidonoylglycerol (2-AG), a...
Source: Neuropharmacology - January 11, 2021 Category: Drugs & Pharmacology Authors: Sládek M, Liška K, Houdek P, Sumová A Tags: Neuropharmacology Source Type: research

Phosphodiesterase type 1 inhibition alters medial prefrontal cortical activity during goal-driven behaviour and partially reverses neurophysiological deficits in the rat phencyclidine model of schizophrenia.
Abstract Positive modulation of cAMP signalling by phosphodiesterase (PDE) inhibitors has recently been explored as a potential target for the reversal of cognitive and behavioural deficits implicating the corticoaccumbal circuit. Previous studies show that PDE type 1 isoform B (PDE1B) inhibition may improve memory function in rodent models; however, the contribution of PDE1B inhibition to impulsivity, attentional and motivational functions as well as its neurophysiological effects have not been investigated. To address this, we recorded single unit activity in medial prefrontal cortex (mPFC) and nucleus accumbens...
Source: Neuropharmacology - January 11, 2021 Category: Drugs & Pharmacology Authors: Hayes J, Laursen B, Eneberg E, Kehler J, Rasmussen LK, Langgard M, Bastlund JF, Gerdjikov TV Tags: Neuropharmacology Source Type: research

mGlu5 function in the nucleus accumbens core during the incubation of methamphetamine craving.
Abstract Many studies have demonstrated that negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGlu5) reduce cocaine and methamphetamine seeking in extinction-reinstatement animal models of addiction. Less is known about effects of mGlu5 NAMs in abstinence models, particularly for methamphetamine. We used the incubation of drug craving model, in which cue-induced craving progressively intensifies after withdrawal from drug self-administration, to conduct the first studies of the following aspects of mGlu5 function in the rat nucleus accumbens (NAc) core during abstinence from methamphetami...
Source: Neuropharmacology - January 11, 2021 Category: Drugs & Pharmacology Authors: Murray CH, Christian DT, Milovanovic M, Loweth JA, Hwang EK, Caccamise AJ, Funke JR, Wolf ME Tags: Neuropharmacology Source Type: research