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Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats.

ABSTRACT: Synthetic cathinones, commonly referred to as 'bath salts', are a group of amphetamine-like drugs gaining popularity worldwide. 4-Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate-type releaser at monoamine transporters. Similar to other cathinone-related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R-mephedrone (R-MEPH) and S-mephedrone (S-MEPH).Here, we provide the first investigation into the neurochemical and behavioural effects of R-MEPH and S-MEPH. We analysed both enantiomers in rat brain synaptosome neurotransmitter release assays and also investigated their effects on locomotor activity (e.g. ambulatory activity and repetitive movements), behavioural sensitization and reward.Both enantiomers displayed similar potency as substrates (i.e. releasers) at dopamine transporters, but R-MEPH was much less potent than S-MEPH as a substrate at 5-HT transporters. Locomotor activity was evaluated in acute and repeated administration paradigms, with R-MEPH producing greater repetitive movements than S-MEPH across multiple doses. After repeated drug exposure, only R-MEPH produced sensitization of repetitive movements. R-MEPH produced a conditioned place preference whereas S-MEPH did not. Lastly, R-MEPH and S-MEPH produced biphasic profiles in an assay of intracranial self-stimulation (ICSS), but R-MEPH produced greater ICSS facilitation than S-MEPH.Our data are the first to demonstrate stereospecific effects of MEPH enantiomers and suggest that the predominant dopaminergic actions of R-MEPH (i.e. the lack of serotonergic actions) render this stereoisomer more stimulant-like when compared with S-MEPH. This hypothesis warrants further study.

SUBMITTER: Gregg RA

PROVIDER: S-EPMC4301696 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats.

Gregg Ryan A RA Baumann Michael H MH Partilla John S JS Bonano Julie S JS Vouga Alexandre A Tallarida Christopher S CS Velvadapu Venkata V Smith Garry R GR Peet M Melissa MM Reitz Allen B AB Negus S Stevens SS Rawls Scott M SM

British journal of pharmacology 20141215 3

<h4>Background and purpose</h4>Synthetic cathinones, commonly referred to as 'bath salts', are a group of amphetamine-like drugs gaining popularity worldwide. 4-Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate-type releaser at monoamine transporters. Similar to other cathinone-related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R-mephedrone (R-MEPH) and S-mephedrone (S-M ...[more]

PMID: 25255824

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Project description:A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71-84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone-but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.

Project description:Methylmercury (MeHg+) is a known neurotoxin that causes progressive motor neuron degeneration in the central nervous system. Axonal degeneration, oligodendrocyte degeneration, and myelin basic protein (MBP) deficits are among the neuropathological abnormalities caused by MeHg+ in amyotrophic lateral sclerosis (ALS). This results in demyelination and motor neuron death in both humans and animals. Previous experimental studies have confirmed that overexpression of the extracellular signalling regulated kinase (ERK1/2) signalling contributes to glutamate excitotoxicity, inflammatory response of microglial cells, and oligodendrocyte (OL) dysfunction that promotes myelin loss. Alpha-mangostin (AMG), an active ingredient obtained from the tree "Garcinia mangostana Linn," has been used in experimental animals to treat a variety of brain disorders, including Parkinson's and Huntington's disease memory impairment, Alzheimer's disease, and schizophrenia, including Parkinson's disease and Huntington's disease memory impairment, Alzheimer's disease, and schizophrenia. AMG has traditionally been used as an antioxidant, anti-inflammatory, and neuroprotective agent.Accordingly, we investigated the therapeutic potential of AMG (100 and 200 mg/kg) in experimental rats with methylmercury (MeHg+)-induced neurotoxicity. The neuroprotective effect of AMG on behavioural, cellular, molecular, and other gross pathological changes, such as histopathological alterations in MeHg+ -treated rat brains, is presented. The neurological behaviour of experimental rats was evaluated using a Morris water maze (MWM), open field test (OFT), grip strength test (GST), and force swim test (FST). In addition, we investigate AMG's neuroprotective effect by restoring MBP levels in cerebral spinal fluid and whole rat brain homogenate. The apoptotic, pro-inflammatory, and oxidative stress markers were measured in rat blood plasma samples and brain homogenate. According to the findings of this study, AMG decreases ERK-1/2 levels and modulates neurochemical alterations in rat brains, minimising MeHg+ -induced neurotoxicity.

Dataset Information

Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats.

Publications

Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats.

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