mephedrone and Disease-Models--Animal

Methamphetamine and mephedrone are designer drugs with high abuse liability and they share extensive similarities in their chemical structures and neuropharmacological effects. However, these drugs differ in one significant regard: methamphetamine elicits dopamine neurotoxicity and mephedrone does not. From a structural perspective, mephedrone has a β-keto group and a 4-methyl ring addition, both of which are lacking in methamphetamine. Our previous studies found that methcathinone, which contains only the β-keto substituent, is neurotoxic, while 4-methylmethamphetamine, which contains only the 4-methyl ring substituent, elicits minimal neurotoxicity. In the present study, it was hypothesized that the varying neurotoxic potential associated with these compounds is mediated by the drug-releasable pool of dopamine, which may be accessed by methamphetamine more readily than mephedrone, methcathinone, and 4-methylmethamphetamine. To test this hypothesis, l-DOPA and pargyline, compounds known to increase both the releasable pool of dopamine and methamphetamine neurotoxicity, were combined with mephedrone, 4-methylmethamphetamine and methcathinone. Methamphetamine was also tested because of its ability to increase releasable dopamine. All three regimens significantly enhanced striatal neurotoxicity and glial reactivity for 4-methylmethamphetamine. Methcathinone neurotoxicity and glial reactivity were enhanced only by l-DOPA. Mephedrone remained non-neurotoxic when combined with either l-DOPA or pargyline. Body temperature effects of each designer drug were not altered by the combined treatments. These results support the conclusion that the neurotoxicity of 4-methylmethamphetamine, methcathinone and methamphetamine may be differentially regulated by the drug-releasable pool of dopamine due to β-keto and 4-methyl substituents, but that mephedrone remains non-neurotoxic despite large increases in this pool of dopamine. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

Topics: Analysis of Variance; Animals; Body Temperature; Brain; Designer Drugs; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Drug Synergism; Female; Methamphetamine; Mice; Mice, Inbred C57BL; Neuroglia; Neurotoxicity Syndromes; Propiophenones; Tyrosine 3-Monooxygenase

According to the European Drug Report (2016), the use of synthetic cathinones, such as mephedrone, among young people has rapidly increased in the last years. Studies in humans indicate that psychostimulant drug use in adolescence increases risk of drug abuse in adulthood. Mephedrone by its interaction with transporters for dopamine (DAT) and serotonin (SERT) stimulates their release to the synaptic cleft. In animal studies, high repeated doses of mephedrone given to adolescent but not adult mice or rats induced toxic changes in 5-hydroxytryptamine (5-HT) neurons. The aim of our study was to investigate the effects of mephedrone given in adolescence on brain neurotransmission and possible neuronal injury in adult rats. Adolescent male rats were given mephedrone (5 mg/kg) for 8 days. In vivo microdialysis in adult rats showed an increase in dopamine (DA), 5-HT, and glutamate release in the nucleus accumbens and frontal cortex but not in the striatum in response to challenge dose in animals pretreated with mephedrone in adolescence. The 5-HT and 5-hydroxyindoleacetic acid contents decreased in the striatum and nucleus accumbens while DA turnover rates were decreased in the striatum and nucleus accumbens. The oxidative damage of DNA assessed with the alkaline comet assay was found in the cortex of adult rats. Therefore, the administration of repeated low doses of mephedrone during adolescence does not seem to induce injury to 5-HT and DA neurons. The oxidative stress seems to be responsible for possible damage of cortical cell bodies which causes maladaptive changes in serotonergic and dopaminergic neurons.

Topics: Age Factors; Analysis of Variance; Animals; Brain; Central Nervous System Stimulants; Comet Assay; Disease Models, Animal; Dopamine; Glutamic Acid; Male; Methamphetamine; Microdialysis; Neurotoxicity Syndromes; Rats; Rats, Wistar; Serotonin; Synaptic Transmission

Abuse of more than one psychoactive drug is becoming a global problem. Our experiments were designed to examine the effects of a concomitant administration of 3,4-methylenedioxy-methamphetamine (MDMA) and mephedrone on depression- and anxiety-like behaviors and cognitive processes in Swiss mice.. In order to investigate the drug interactions the forced swimming test (FST) - an animal model of depression, the passive avoidance (PA) test - a memory and learning paradigm, as well as the elevated plus maze (EPM) test - test for anxiety level were used.. The results revealed that a concomitant administration of non-effective doses of mephedrone (1mg/kg) and MDMA (1mg/kg) exerted marked antidepressive effects in the FST. Also a co-administration of mephedrone (2.5mg/kg) and MDMA (1mg/kg) displayed a pro-cognitive action in the PA paradigm. Furthermore, even though mephedrone and MDMA can, in general, exert some anxiogenic effects in mice, the concomitant administration of nonactive doses of both drugs (0.05 and 0.1mg/kg, respectively) in the EPM test, did not show any synergistic effect in our study.. The effects of mephedrone and MDMA combination on mammalian organisms were attempted to be evaluated in our study and the results are described in the present report. These results may help explain the reasons for and consequences of a concomitant administration of psychoactive substances with regards to the central nervous system, while being possibly useful in the treatment of polydrug intoxication.

Topics: Animals; Antidepressive Agents; Anxiety; Cognition; Depression; Disease Models, Animal; Drug Interactions; Male; Maze Learning; Memory; Methamphetamine; Mice; Motor Activity; N-Methyl-3,4-methylenedioxyamphetamine; Swimming

The purpose of the present study was to determine the effects of exposure to cocaine and mephedrone on conditioned place preference (CPP) and locomotion in the flatworm planaria. Planaria were treated with either cocaine or mephedrone at 1 or 10 μM. Planaria were exposed to 15 min of drug in their non-preferred place (either a rough- or smooth-floored petri dish) on alternate days, and were exposed to normal water in their preferred place on the following day. There were 5 days of conditioning to drug. Planaria were then tested for CPP on day 2, 6 and 13 after withdrawal. We found that animals exhibited CPP to cocaine at both 1 and 10 μM, but not to mephedrone. When examining locomotor activity we found that neither cocaine nor mephedrone treatment showed any evidence of evoking increased motility or locomotor sensitisation. Hypo-motility was seen on the first day of conditioning at concentrations of 10 μM for both cocaine and mephedrone, but had disappeared by the last day of conditioning. Examining chronic withdrawal, only 10 μM mephedrone had a significant effect on motility, decreasing locomotion on day 2 of withdrawal. Taken together we have shown that cocaine evoked CPP in planaria. We have also shown withdrawal depressing effects of mephedrone on motility.

Topics: Animals; Cocaine; Conditioning, Psychological; Disease Models, Animal; Locomotion; Methamphetamine; Planarians; Psychotropic Drugs; Substance Withdrawal Syndrome; Substance-Related Disorders

The use of cathinone-derivative designer drugs methylone and mephedrone has increased rapidly in recent years. Our aim was to investigate the possible long-term effects of these drugs on a range of behavioral tests in mice. Further, we investigated the long-term effects of these drugs on brain neurochemistry in both rats and mice.. We treated animals with a binge-like regimen of methylone or mephedrone (30 mg/kg, twice daily for 4 days) and, starting 2 weeks later, we performed behavioral tests of memory, anxiety and depression and measured brain levels of dopamine (DA), serotonin (5-HT), their metabolites and norepinephrine (NE). 5-HT and DA transporter (5-HTT and DAT) levels were also measured in rats by [(3)H]paroxetine and [(3)H]mazindol binding.. Mephedrone reduced working memory performance in the T-maze spontaneous alternation task but did not affect neurotransmitter levels aside from a 22% decrease in striatal homovanillic acid (HVA) levels in mice. Methylone had little effect on behavior or neurotransmitter levels in mice but produced a widespread depletion of 5-HT and 5-HTT levels in rats.. Both methylone and mephedrone appeared to have a long-term effect on either behavioral or biochemical gauges of neurotoxicity in rodents.

Topics: Animals; Anxiety; Brain; Depression; Designer Drugs; Disease Models, Animal; Dopamine; Dopamine Plasma Membrane Transport Proteins; Hindlimb Suspension; Male; Maze Learning; Memory Disorders; Methamphetamine; Mice; Mice, Inbred C57BL; Norepinephrine; Radioligand Assay; Rats; Rats, Wistar; Serotonin; Serotonin Plasma Membrane Transport Proteins

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) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.

Topics: Administration, Oral; Animals; Central Nervous System Stimulants; Corpus Striatum; Designer Drugs; Disease Models, Animal; Dopamine; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Hippocampus; Male; Methamphetamine; Public Health; Rats; Rats, Sprague-Dawley; Reward; Serotonin