scholarly journals Acute MDPV Binge Paradigm on Mice Emotional Behavior and Glial Signature

2021 ◽  
Vol 14 (3) ◽  
pp. 271
Author(s):  
Mafalda Campeão ◽  
Luciana Fernandes ◽  
Inês R. Pita ◽  
Cristina Lemos ◽  
Syed F. Ali ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Drugs Of Abuse ◽  
Time Window ◽  
Tail Suspension Test ◽  
Brain Regions ◽  
Emotional Behavior ◽  
Immune Modulators ◽  
Controlled Drugs ◽  
General Locomotor Activity ◽  
Synthetic Cathinone

3,4-Methylenedioxypyrovalerone (MDPV), a widely available synthetic cathinone, is a popular substitute for classical controlled drugs of abuse, such as methamphetamine (METH). Although MDPV poses public health risks, its neuropharmacological profile remains poorly explored. This study aimed to provide evidence on that direction. Accordingly, C57BL/6J mice were exposed to a binge MDPV or METH regimen (four intraperitoneal injections every 2 h, 10 mg/kg). Locomotor, exploratory, and emotional behavior, in addition to striatal neurotoxicity and glial signature, were assessed within 18–24 h, a known time-window encompassing classical amphetamine dopaminergic neurotoxicity. MDPV resulted in unchanged locomotor activity (open field test) and emotional behavior (elevated plus maze, splash test, tail suspension test). Additionally, striatal TH (METH neurotoxicity hallmark), Iba-1 (microglia), GFAP (astrocyte), RAGE, and TLR2/4/7 (immune modulators) protein densities remained unchanged after MDPV-exposure. Expectedly, and in sheer contrast with MDPV, METH resulted in decrease general locomotor activity paralleled by a significant striatal TH depletion, astrogliosis, and microglia arborization alterations (Sholl analysis). This comparative study newly highlights that binge MDPV-exposure comes without evident behavioral, neurochemical, and glial changes at a time-point where METH-induced striatal neurotoxicity is clearly evident. Nevertheless, neuropharmacological MDPV signature needs further profiling at different time-points, regimens, and brain regions.

scholarly journals Drugs of Abuse Can Entrain Circadian Rhythms

2007 ◽  
Vol 7 ◽  
pp. 203-212 ◽  
Author(s):  
Ann E. K. Kosobud ◽  
Andrea G. Gillman ◽  
Joseph K. Leffel ◽  
Norman C. Pecoraro ◽  
G. V. Rebec ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Circadian Rhythms ◽  
Drug Metabolism ◽  
Suprachiasmatic Nucleus ◽  
Drugs Of Abuse ◽  
Social Cues ◽  
Dark Cycle ◽  
Drug Reward ◽  
Locomotor Stimulation ◽  
Almost All

Circadian rhythms prepare organisms for predictable events during the Earth's 24-h day. These rhythms are entrained by a variety of stimuli. Light is the most ubiquitous and best known zeitgeber, but a number of others have been identified, including food, social cues, locomotor activity, and, most recently drugs of abuse. Given the diversity of zeitgebers, it is probably not surprising that genes capable of clock functions are located throughout almost all organs and tissues. Recent evidence suggests that drugs of abuse can directly entrain some circadian rhythms. We have report here that entrainment by drugs of abuse is independent of the suprachiasmatic nucleus and the light/dark cycle, is not dependent on direct locomotor stimulation, and is shared by a variety of classes of drugs of abuse. We suggest that drug-entrained rhythms reflect variations in underlying neurophysiological states. This could be the basis for known daily variations in drug metabolism, tolerance, and sensitivity to drug reward. These rhythms could also take the form of daily periods of increased motivation to seek and take drugs, and thus contribute to abuse, addiction and relapse.

scholarly journals Mesenchymal Stem/Stromal Cell Therapy in Blood–Brain Barrier Preservation Following Ischemia: Molecular Mechanisms and Prospects

2021 ◽  
Vol 22 (18) ◽  
pp. 10045
Author(s):  
Phuong Thao Do ◽  
Chung-Che Wu ◽  
Yung-Hsiao Chiang ◽  
Chaur-Jong Hu ◽  
Kai-Yun Chen
Keyword(s):  
Stem Cells ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Time Window ◽  
Brain Regions ◽  
Brain Barrier ◽  
Therapeutic Effects ◽  
Pathophysiological Mechanism ◽  
Cell Based Therapy ◽  
Blood Brain

Ischemic stroke is the leading cause of mortality and long-term disability worldwide. Disruption of the blood–brain barrier (BBB) is a prominent pathophysiological mechanism, responsible for a series of subsequent inflammatory cascades that exacerbate the damage to brain tissue. However, the benefit of recanalization is limited in most patients because of the narrow therapeutic time window. Recently, mesenchymal stem cells (MSCs) have been assessed as excellent candidates for cell-based therapy in cerebral ischemia, including neuroinflammatory alleviation, angiogenesis and neurogenesis promotion through their paracrine actions. In addition, accumulating evidence on how MSC therapy preserves BBB integrity after stroke may open up novel therapeutic targets for treating cerebrovascular diseases. In this review, we focus on the molecular mechanisms of MSC-based therapy in the ischemia-induced prevention of BBB compromise. Currently, therapeutic effects of MSCs for stroke are primarily based on the fundamental pathogenesis of BBB breakdown, such as attenuating leukocyte infiltration, matrix metalloproteinase (MMP) regulation, antioxidant, anti-inflammation, stabilizing morphology and crosstalk between cellular components of the BBB. We also discuss prospective studies to improve the effectiveness of MSC therapy through enhanced migration into defined brain regions of stem cells. Targeted therapy is a promising new direction and is being prioritized for extensive research.

scholarly journals Search and evaluation of pharmacodynamic and pharmacokinetic parameters of selective blocker of TRPA 1 ion channels from the group of substituted pyrazinopyrimidinones

2018 ◽  
Vol 4 (3) ◽  
pp. 49-62
Author(s):  
Evgeniya А. Beskhmelnitsyna ◽  
Dmitriy V. Kravchenko ◽  
Lev N. Sernov ◽  
Irina N. Dolzhikova ◽  
Tatyana V. Avtina ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Laboratory Animals ◽  
Absolute Bioavailability ◽  
Organ Distribution ◽  
Pharmacokinetic Parameters ◽  
In Vitro Tests ◽  
Activity Levels ◽  
General Locomotor Activity ◽  
Anti Inflammatory

Introduction. Doctors of almost all specialties have to deal with the problem of pain and its relief. According to the literature, almost 30 million people daily take analgesics from the group of non-opioid analgesics, but in more than half of them 4-6 hours after taking the medication, the severity of pain is unchanged. Objective. to search for the most active molecules potential selective inhibitors of the TRPA1 ion channel with further investigation of their pharmacodynamic effects, toxicological safety, pharmacokinetic parameters and organ distribution, as well as to assess their impact on the psychoemotional state, general locomotor activity levels and anxiety in laboratory animals. Materials and methods. According to the results of in vitro tests, the most active molecule under code ZC02-0012 was selected from the pool of candidates. Further its analgesic activity was evaluated using an acetic acid-induced writhing test and a hot plate test; its anti-inflammatory activity was studied in the acute exudative paw edema model; in the open field and elevated plus-maze tests the influence of ZC02-0012 on the general locomotor activity levels and the anxiety of the laboratory animals was studied. The pharmacokinetic parameters and organ distribution of the substance ZC02-0012 were studied using a liquid chromatograph with an operating pressure range of 0-60 mPa (Thermo Scientific Dionex UltiMate 3000). Results and discussion. According to the results of in vitro tests, it was found that IC50 of the TRPA1 selective inhibitor under laboratory code ZC02-0012 was 91.3 nmol. The preclinical studies showed that ZC02-0012 possessed pronounced analgesic and anti-inflammatory activities and absence of the influence on the behavior and anxiety of the laboratory animals. Absolute bioavailability of ZC02-0012 in rabbits was 47%, while ZC02-0012 was intensely distributed into organs and tissues with a high level of blood circulation. The highest content of ZC02-0012 is typical of liver, kidneys and lungs, the lowest – for muscle tissue. Most of the substance is undergone rapid biotransformation and excreted as metabolites.

Mental and behavioural disorders

2020 ◽  
pp. 333-365
Author(s):  
Fabrizio Benedetti
Keyword(s):  
Clinical Trials ◽  
Mental Disorders ◽  
Placebo Effect ◽  
Crucial Role ◽  
Drugs Of Abuse ◽  
Placebo Treatment ◽  
Brain Regions ◽  
Psychotherapeutic Interventions ◽  
Psychotherapeutic Outcome ◽  
The Brain

In this chapter some mental disorders are described. For example, in depression, fluoxetine treatment and a placebo treatment affect similar brain regions. In anxiety, patients’ expectations play a crucial role, as covert (unexpected) administration of anti-anxiety drugs is less effective than overt (expected) administration. The disruption of prefrontal executive control in Alzheimer’s disease decreases the magnitude of placebo responses. In addition, expectations appear to be particularly important when associated with the effects of drugs of abuse. Placebo effects appear to be powerful in psychotherapy as well, and the brain areas involved in the psychotherapeutic outcome are different from those involved in the placebo effect. As clinical trials for psychotherapeutic interventions represent a major problem, new recommendations are presented.

scholarly journals Effects of Cocaine Exposure on Astrocytic Glutamate Transporters and Relapse-Like Ethanol-Drinking Behavior in Male Alcohol-Preferring Rats

2020 ◽  
Vol 55 (3) ◽  
pp. 254-263 ◽  
Author(s):  
Alaa M Hammad ◽  
Youssef Sari
Keyword(s):  
Drugs Of Abuse ◽  
Drinking Behavior ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Brain Regions ◽  
Ethanol Intake ◽  
Free Access ◽  
Cocaine Exposure ◽  
Extracellular Glutamate ◽  
Lactam Antibiotic

Abstract Aim Glutamate has been considered as neurotransmitter that is critical in triggering relapse to drugs of abuse, including ethanol and cocaine. Extracellular glutamate concentrations are tightly regulated by several mechanisms, including reuptake through glutamate transporters. Glutamate transporter type 1 (GLT-1) is responsible for clearing the majority of extracellular glutamate. The astrocytic cystine/glutamate antiporter (xCT) regulates also glutamate homeostasis. In this study, we investigated the effects of cocaine exposure and ampicillin/sulbactam (AMP/SUL), a β-lactam antibiotic known to upregulate GLT-1 and xCT, on relapse-like ethanol intake and the expression of astrocytic glutamate transporters in mesocorticolimbic brain regions. Methods Male alcohol-preferring (P) rats had free access to ethanol for 5 weeks. On Week 6, rats were exposed to either cocaine (20 mg/kg, i.p.) or saline for 12 consecutive days. Ethanol bottles were then removed for 7 days; during the last 5 days, either AMP/SUL (100 or 200 mg/kg, i.p.) or saline was administered to the P rats. Ethanol bottles were reintroduced, and ethanol intake was measured for 4 days. Results Cocaine exposure induced an alcohol deprivation effect (ADE), which was associated in part by a decrease in the expression of GLT-1 and xCT in the nucleus accumbens (NAc) core. AMP/SUL (100 mg/kg, i.p.) attenuated the ADE, while AMP/SUL (200 mg/kg, i.p.) reduced ethanol intake during 4 days of ethanol re-exposure and upregulated GLT-1 and xCT expression in the NAc core, NAc shell and dorsomedial prefrontal cortex (dmPFC). Conclusion This study suggests that these astrocytic glutamate transporters might be considered as potential targets for the treatment of polysubstance abuse.

scholarly journals Electroacupuncture Alleviates Pain-Related Emotion by Upregulating the Expression of NPS and Its Receptor NPSR in the Anterior Cingulate Cortex and Hypothalamus

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Zitong Xu ◽  
JunFan Fang ◽  
Xuaner Xiang ◽  
HaiJu Sun ◽  
SiSi Wang ◽  
...  
Keyword(s):  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Emotional Behavior ◽  
Anterior Cingulate ◽  
Place Aversion ◽  
Elevated Expression ◽  
Peptide System ◽  
Affective Pain

Objective. Electroacupuncture (EA) is reported effective in alleviating pain-related emotion; however, the underlying mechanism of its effects still needs to be elucidated. The NPS-NPSR system has been validated for the involvement in the modulation of analgesia and emotional behavior. Here, we aimed to investigate the role of the NPS-NPSR system in the anterior cingulate cortex (ACC), hypothalamus, and central amygdala (CeA) in the use of EA to relieve affective pain modeled by complete Freund’s adjuvant- (CFA-) evoked conditioned place aversion (C-CPA). Materials and Methods. CFA injection combined with a CPA paradigm was introduced to establish the C-CPA model, and the elevated O-maze (EOM) was used to test the behavioral changes after model establishment. We further explored the expression of NPS and NPSR at the protein and gene levels in the brain regions of interest by immunofluorescence staining and quantitative real-time PCR. Results. We observed that EA stimulation delivered to the bilateral Zusanli (ST36) and Kunlun (BL60) acupoints remarkably inhibited sensory pain, pain-evoked place aversion, and anxiety-like behavior. The current study showed that EA significantly enhanced the protein expression of this peptide system in the ACC and hypothalamus, while the elevated expression of NPSR protein alone was just confined to the affected side in the CeA. Moreover, EA remarkably upregulated the mRNA expression of NPS in CeA, ACC, and hypothalamus and NPSR mRNA in the hypothalamus and CeA. Conclusions. These data suggest the effectiveness of EA in alleviating affective pain, and these benefits may at least partially be attributable to the upregulation of the NPS-NPSR system in the ACC and hypothalamus.

Opioidergic system and N-methyl D-aspartate receptor (NMDA-R) hypofunction: Translational implications for the pathophysiology of psychosis and drug addiction

2011 ◽  
Vol 26 (S2) ◽  
pp. 1231-1231
Author(s):  
E.F. Buonaguro ◽  
F. Marmo ◽  
L. Avvisati ◽  
G. Latte ◽  
R. Rossi ◽  
...  
Keyword(s):  
Drug Addiction ◽  
Drugs Of Abuse ◽  
Premotor Cortex ◽  
Region Of Interest ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Preclinical Model ◽  
Sprague Dawley ◽  
Somatosensory Cortices ◽  
Sprague Dawley Rats

Enkephalin is an opioidergic neuromodulator that has been implicated in long-term behavioural sensitization after administration of drugs of abuse. Enkephalin is also a molecular marker of GABAergic neurons in the striato-pallidal pathway that is involved in sensory-motor gating and has been considered dysfunctional in the pathophysiology of psychosis.In this study we investigated in male Sprague Dawley rats putative changes in Enkephalin transcripts by in situ hybridization after acute or subchronic administration of ketamine in either high or low subanaesthetic doses (50 mg/kg and 12 mg/kg respectively). Ketamine is a non-competitive NMDA-R antagonist that perturbs glutamate neurotransmission and provides a preclinical model of psychosis-like behaviour in rats.In the acute paradigm the expression of Enkephalin was reduced in the motor, premotor, somatosensory cortices as well as in anterior cingulate. In the subchronic paradigm Enkephalin expression was reduced in the premotor cortex, in the ventromedial caudate-putamen and in the shell of nucleus accumbens. Comparative analysis showed that the relative decrement in gene expression was not significantly different between the acute and subchronic paradigm for each region of interest.Changes in distribution of Enkephalin expression and correlation analysis of functionally related brain regions suggest that Enkephalin transcripts reduction may be implicated in the motivational aspects of drug addiction and may help explaining some aspects of the pathophysiology in ketamine-induced psychosis.

scholarly journals Synaptic plasticity in the mesolimbic dopamine system

2003 ◽  
Vol 358 (1432) ◽  
pp. 815-819 ◽  
Author(s):  
Mark J. Thomas ◽  
Robert C. Malenka
Keyword(s):  
Synaptic Plasticity ◽  
Drugs Of Abuse ◽  
Neural Circuit ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Mesolimbic Dopamine ◽  
Dopamine System ◽  
Mesolimbic Dopamine System

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

Ethylone: A synthetic cathinone emerging in Barcelona

2017 ◽  
Vol 41 (S1) ◽  
pp. s860-s860
Author(s):  
M. de Dios ◽  
E. Monteagudo ◽  
A. Trabsa ◽  
M. Grifell ◽  
L. Galindo ◽  
...  
Keyword(s):  
Illicit Drugs ◽  
Drugs Of Abuse ◽  
Sample Selection ◽  
Drug Market ◽  
Gas Chromatography Mass Spectrometry ◽  
Bath Salts ◽  
Energy Control ◽  
Report Analysis ◽  
Synthetic Cathinone ◽  
Competing Interest

IntroductionSynthetic cathinones, the active component in “bath salts”, have surfaced as a popular alternative to other illicit drugs of abuse, such as cocaine, MDMA (ecstasy), and methamphetamine, due to their potent psychostimulant and empathogenic effects.ObjectivesTo describe the presence of Ethylone in samples delivered to energy control from 2014 to 2015 in Spain.MethodsThe total number of samples analyzed from 2014 to 2015 was 8324. Only those samples containing ethylone were studied. They were analyzed by energy control, a Spanish harm reduction NGO that offers the possibility of analysing the substances that users report. Analysis was done by gas chromatography-mass spectrometry.ResultsFrom June 2014 to December 2015, 8324 samples were delivered to EC. From this samples 28 (0.336%) contained ethylone. Twelve (0.144%) were delivered as MDMA, representing a 0.783% of the samples delivered as such, and only one sample (0.012%) delivered as MDMA presented ethylene as an adulterant along with MDMA. Other 6 samples (0.072%) were delivered as ethylone and 10 samples (0.120%) were delivered as unknown pills.DiscussionEthylone consumption is found to be an emerging issue according to the results of our samples, an increase of such is found during 2015. This might be traduced as an increase of ethylone in the drug market, but a sample selection bias should be considered as samples were voluntary delivered by consumers. An alarming phenomenon is that in some occasions ethylone is sold as MDMA, but effects take longer to occur and last longer, which may lead to an overdose if used as MDMA.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Influence of acute exposure to a low dose of systemic insecticide fipronil on locomotor activity and emotional behavior in adult male mice

2020 ◽  
Author(s):  
Mizuki MAEDA ◽  
Toshifumi YOKOYAMA ◽  
Sayaka KITAUCHI ◽  
Tetsushi HIRANO ◽  
Youhei MANTANI ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Adult Male ◽  
Low Dose ◽  
Emotional Behavior ◽  
Acute Exposure ◽  
Male Mice ◽  
Systemic Insecticide
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