Dissecting the influence of two structural substituents on the differential neurotoxic effects of methamphetamine and mephedrone on dopamine nerve endings with the use of 4-methylmethamphetamine and methcathinone (original) (raw)
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Neurotoxicology and teratology, 2017
The rise in popularity of substituted methcathinones (aka "bath salts") has increased the focus on their neurotoxic effects. Two commonly abused methcathinones, 3,4-methylenedioxymethcathinone (methylone, MDMC) and 3,4-methylenedioxypyrovalerone (MDPV), are often concomitantly ingested with the illicit drug 3,4-methylenedioxymethamphetamine (MDMA). To examine potential neurotoxic effects of these drug combinations, C57BL/6J mice were administered 4 i.p. injection of the drugs, at 2h intervals, either singularly: MDMA 15 or 30mg/kg, methylone 20mg/kg, MDPV 1mg/kg; or in combination: methylone/MDMA 20/15mg/kg, MDPV/MDMA 1/15mg/kg. Drug effects on thermoregulation were characterized and striatal tissue analyzed after 2 or 7days for dopamine (DA) and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. Two days following drug administration, DA and TH were decreased only in the MDMA 30mg/kg group, whereas GFAP expression was dose-depe...
Journal of Neurochemistry, 2010
The toxic potential of methamphetamine (METH) toward brain dopamine (DA) neurons is well established (Lew et al. 1997; Riddle et al. 2006; Cadet and Krasnova 2009). Despite considerable research, the precise mechanism(s) by which METH induces degeneration of DA axon terminals remain(s) to be identified. However, a substantial body of data has implicated endogenous brain DA as a mediator of METH neurotoxicity (see Gibb et al. 1994; Volz et al. 2007; Kuhn et al. 2008; for reviews). For example, drugs that deplete brain DA [e.g. alpha-methyl-para-tyrosine (AMPT)] afford neuroprotection (Gibb and Kogan 1979; Schmidt et al. 1985), and drugs that replenish DA stores [e.g. L-dihydroxyphenylalanine (L-DOPA)] reinstate METH neurotoxicity (Gibb and Kogan 1979; Thomas et al. 2008). These observations have led to that DA mediates METH neurotoxicity (Volz et al. 2007; Guillot et al. 2008; Thomas et al. 2008; Kita et al. 2009). As evidence implicating DA in METH neurotoxicity has accrued, the importance of body temperature in the development and extent of METH neurotoxicity has become apparent (see Sharma et al. 2007; Bowyer et al. 2008; Krasnova and Cadet 2009). In particular, higher body temperatures enhance toxicity, whereas lower body temperatures generally afford neuroprotection (Bowyer et al. 1992; Ali et al. 1994; Albers and Sonsalla 1995; Cappon et al. 1997; Miller and O'Callaghan 2003). Notably, temperature effects may have direct bearing on studies demonstrating a protective effect of dopaminergic drugs, because most drugs that alter DA neurotransmission also cause alterations in core temperature in METH-treated animals.
4-Methylmethcathinone (mephedrone): neuropharmacological effects of a designer stimulant of abuse
The Journal of pharmacology and experimental therapeutics, 2011
The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant "binge" treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transpo...
Neurotoxicity induced by mephedrone: An up-to-date review
Current Neuropharmacology, 2016
Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-HT and DA systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health.
European Neuropsychopharmacology, 2013
The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats. Young-adult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4 or 10 mg/kg) or MDMA (10 mg/kg) on two consecutive days weekly for 3 weeks or as a single acute injection (for neurochemical analysis). Locomotor activity (LMA), novel object discrimination (NOD), conditioned emotional response (CER) and prepulse inhibition of the acoustic startle response (PPI) were measured following intermittent drug administration. Dopamine, 5-hydroxytryptamine (5-HT) and their major metabolites were measured in striatum, frontal cortex and hippocampus by high performance liquid chromatography 7 days after intermittent dosing and 2 h after acute injection. Cathinone (1, 4 mg/kg), mephedrone (10 mg/kg) and MDMA (10 mg/kg) induced hyperactivity following the first and sixth injections and sensitization to cathinone and mephedrone occurred with chronic dosing. All drugs impaired NOD and mephedrone (10 mg/kg) reduced freezing in response to contextual re-exposure during the CER retention trial. Acute MDMA reduced hippocampal 5-HT and 5-HIAA but the only significant effect on dopamine, 5-HT and their metabolites following chronic dosing was altered hippocampal 3, 4-dihydroxyphenylacetic acid (DOPAC), following mephedrone (4, 10 mg/kg) and MDMA. At the doses examined, mephedrone, cathinone, and MDMA induced similar effects on behaviour and www.elsevier.com/locate/euroneuro 0924-977X/$ -see front matter & (M.V. King). European Neuropsychopharmacology (2013) 23, 1085-1095 failed to induce neurotoxic damage when administered intermittently over 3 weeks.
The role of dopamine receptors in the neurotoxicity of methamphetamine
Journal of Internal Medicine, 2013
Ares-Santos S, Granado N, Moratalla R (Instituto Cajal, Consejo Superior de Investigaciones Cient ıficas, CSIC, Madrid; CIBERNED, ISCIII, Madrid; Universidad Complutense de Madrid, Madrid, Spain). The role of dopamine receptors inthe neurotoxicity of methamphetamine. (Review). J Intern Med 2013; 273: 437-453.
British Journal of Pharmacology, 2013
BACKGROUND AND PURPOSE Bath salts is the street name for drug combinations that contain synthetic cathinone analogues, among them possibly mephedrone (MEPH) and certainly methylenedioxypyrovalerone (MDPV). In animal studies, cathinone and certain cathinone analogues release dopamine (DA), similar to the action of amphetamine (AMPH) and methamphetamine (METH). AMPH and METH act on the human DA transporter (hDAT); thus, we investigated MEPH and MDPV acting at hDAT. EXPERIMENTAL APPROACH We recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and exposed to: DA, METH, a known hDAT stimulant and DA releaser, MEPH, MDPV, MEPH + MDPV, or cocaine, a known hDAT inhibitor. KEY RESULTS DA, METH and MEPH induce an inward current (depolarizing) when the oocyte is held near the resting potential (-60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward (hyperpolarizing) current similar to cocaine, therefore acting as an inhibitory non-substrate blocker. CONCLUSIONS AND IMPLICATIONS Two components of bath salts, MEPH and MDPV, produce opposite effects at hDAT that are comparable with METH and cocaine, respectively. In our assay, MEPH is nearly as potent as METH; however, MDPV is much more potent than cocaine and its effect is longer lasting. When applied in combination, MEPH exhibits faster kinetics than MDPV, viz., the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts containing MEPH (or a similar drug) and MDPV might then be expected initially to release DA and subsequently prevent its reuptake via hDAT. Such combined action possibly underlies some of the reported effects of bath salts abuse.
Neuropsychopharmacology, 2012
The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.
Pharmacology, neurobiology and neurotoxicity of methamphetamine
El Mednifico Journal, 2014
Methamphetamine (MA) is a synthetic, powerfully addictive central nervous system stimulant drug, derived from amphetamine. It is used for both medicinal and illegal recreational proposes. MA causes an increase in activity, decrease in appetite, and a strong feeling of euphoria. MA exerts powerful effects on several neurochemical systems throughout the brainincluding dopamine, GABA and GLU. MA is highly lipophilic, which allows rapid and efficient transport across the blood-brain barrier and results in increased CNS penetration. It causes massive release of newly synthesized catecholamines, and blocks their reuptake from the synapse in several areas of the brain, including the nucleus accumbens, the prefrontal cortex and the striatum. This review presents: (i) an overview of the neurochemical and pharmacological effects of MA administration, (ii) a summary of the clinical effects of MA administration and (iii) evidence of MA's neurotoxic effects. Due to its toxic potential, It is very important to develop research strategies towards prospective designs looking at large cohorts of young people belonging to a risk group for recreational drug use. (El Med J 2:1; 2014