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      Gestational Exposure to the Synthetic Cathinone Methylenedioxypyrovalerone Results in Reduced Maternal Care and Behavioral Alterations in Mouse Pups

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          Abstract

          The member of synthetic cathinone family, methylenedioxypyrovalerone (MDPV), is a frequently used psychoactive drug of abuse. The objective of our study was to determine the effect of MDPV (administered from the 8th to the 14th day of gestation) on the behavior of neonatal and adolescent mice, as well as its effect on maternal care. We measured maternal care (pup retrieval test, nest building), locomotor activity (open field test), and motor coordination (grip strength test) of dams, whereas on pups we examined locomotor activity at postnatal day 7 and day 21 (open field test) and motor coordination on day 21 (grip strength test). On fresh-frozen brain samples of the dams we examined the expression of two important peptides implicated in the regulation of maternal behavior and lactation: tuberoinfundibular peptide 39 (TIP39) mRNA in the thalamic posterior intralaminar complex, and amylin mRNA in the medial preoptic nucleus. We detected decreased birth rate and survival of offspring, and reduced maternal care in the drug-treated animals, whereas there was no difference between the motility of treated and control mothers. Locomotor activity of the pups was increased in the MDPV treated group both at 7 and 21 days of age, while motor coordination was unaffected by MDPV treatment. TIP39 and amylin were detected in their typical location but failed to show a significant difference of expression between the drug-treated and control groups. The results suggest that chronic systemic administration of the cathinone agent MDPV to pregnant mice can reduce birth rate and maternal care, and it also enhances motility (without impairment of motor coordination) of the offspring.

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          Pharmacological characterization of designer cathinones in vitro.

          Designer β-keto amphetamines (e.g. cathinones, 'bath salts' and 'research chemicals') have become popular recreational drugs, but their pharmacology is poorly characterized. We determined the potencies of cathinones to inhibit DA, NA and 5-HT transport into transporter-transfected HEK 293 cells, DA and 5-HT efflux from monoamine-preloaded cells, and monoamine receptor binding affinity. Mephedrone, methylone, ethylone, butylone and naphyrone acted as non-selective monoamine uptake inhibitors, similar to cocaine. Mephedrone, methylone, ethylone and butylone also induced the release of 5-HT, similar to 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and other entactogens. Cathinone, methcathinone and flephedrone, similar to amphetamine and methamphetamine, acted as preferential DA and NA uptake inhibitors and induced the release of DA. Pyrovalerone and 3,4-methylenedioxypyrovalerone (MDPV) were highly potent and selective DA and NA transporter inhibitors but unlike amphetamines did not evoke the release of monoamines. The non-β-keto amphetamines are trace amine-associated receptor 1 ligands, whereas the cathinones are not. All the cathinones showed high blood-brain barrier permeability in an in vitro model; mephedrone and MDPV exhibited particularly high permeability. Cathinones have considerable pharmacological differences that form the basis of their suggested classification into three groups. The predominant action of all cathinones on the DA transporter is probably associated with a considerable risk of addiction. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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            Developmental consequences of fetal exposure to drugs: what we know and what we still must learn.

            Most drugs of abuse easily cross the placenta and can affect fetal brain development. In utero exposures to drugs thus can have long-lasting implications for brain structure and function. These effects on the developing nervous system, before homeostatic regulatory mechanisms are properly calibrated, often differ from their effects on mature systems. In this review, we describe current knowledge on how alcohol, nicotine, cocaine, amphetamine, Ecstasy, and opiates (among other drugs) produce alterations in neurodevelopmental trajectory. We focus both on animal models and available clinical and imaging data from cross-sectional and longitudinal human studies. Early studies of fetal exposures focused on classic teratological methods that are insufficient for revealing more subtle effects that are nevertheless very behaviorally relevant. Modern mechanistic approaches have informed us greatly as to how to potentially ameliorate the induced deficits in brain formation and function, but conclude that better delineation of sensitive periods, dose-response relationships, and long-term longitudinal studies assessing future risk of offspring to exhibit learning disabilities, mental health disorders, and limited neural adaptations are crucial to limit the societal impact of these exposures.
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              The toxicology of bath salts: a review of synthetic cathinones.

              Synthetic cathinones have recently emerged and grown to be popular drugs of abuse. Their dramatic increase has resulted in part from sensationalized media attention as well as widespread availability on the Internet. They are often considered "legal highs" and sold as "bath salts" or "plant food" and labeled "not for human consumption" to circumvent drug abuse legislation. Cathinone is a naturally occurring beta-ketone amphetamine analogue found in the leaves of the Catha edulis plant. Synthetic cathinones are derivatives of this compound. Those that are being used as drugs of abuse include butylone, dimethylcathinone, ethcathinone, ethylone, 3- and 4-fluoromethcathinone, mephedrone, methedrone, methylenedioxypyrovalerone (MDPV), methylone, and pyrovalerone. Synthetic cathinones are phenylalkylamines derivatives, and are often termed "bk-amphetamines" for the beta-ketone moiety. They may possess both amphetamine-like properties and the ability to modulate serotonin, causing distinct psychoactive effects. Desired effects reported by users of synthetic cathinones include increased energy, empathy, openness, and increased libido. Cardiac, psychiatric, and neurological signs and symptoms are the most common adverse effects reported in synthetic cathinone users who require medical care. Deaths associated with use of these compounds have been reported. Exposure to and use of synthetic cathinones are becoming increasingly popular despite a lack of scientific research and understanding of the potential harms of these substances. The clinical similarities to amphetamines and MDMA specifically are predictable based on the chemical structure of this class of agents. More work is necessary to understand the mechanisms of action, toxicokinetics, toxicodynamics, metabolism, clinical and psychological effects as well as the potential for addiction and withdrawal of these agents.
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                Author and article information

                Contributors
                Journal
                Front Neurosci
                Front Neurosci
                Front. Neurosci.
                Frontiers in Neuroscience
                Frontiers Media S.A.
                1662-4548
                1662-453X
                05 February 2018
                2018
                : 12
                : 27
                Affiliations
                [1] 1Department of Anatomy, Histology and Embryology, Semmelweis University , Budapest, Hungary
                [2] 2Laboratory of Sensorimotor Adaptation, Semmelweis University , Budapest, Hungary
                [3] 3MTA-ELTE Laboratory of Molecular and Systems Neurobiology, Institute of Biology, Hungarian Academy of Sciences and Eötvös Loránd University , Budapest, Hungary
                Author notes

                Edited by: Heather K. Caldwell, Kent State University, United States

                Reviewed by: Dora Reglodi, University of Pécs, Hungary; Wei-jiang Zhao, Shantou University, China

                *Correspondence: Ágota Ádám adam.agota@ 123456med.semmelweis-univ.hu

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Neuroscience

                Article
                10.3389/fnins.2018.00027
                5807393
                29459818
                43decd73-1cd8-4846-ba86-928e68049c73
                Copyright © 2018 Gerecsei, Csillag, Zachar, Gévai, Simon, Dobolyi and Ádám.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 November 2017
                : 12 January 2018
                Page count
                Figures: 10, Tables: 2, Equations: 0, References: 90, Pages: 14, Words: 10295
                Funding
                Funded by: Országos Tudományos Kutatási Alapprogramok 10.13039/501100003549
                Award ID: PD-105251
                Award ID: K-109077
                Categories
                Neuroscience
                Original Research

                Neurosciences
                new psychoactive substances,synthetic cathinone,bath salt,maternal care,methylenedioxypyrovalerone,locomotor activity,pregnancy

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