The Effects of Exposure to Mephedrone During Adolescence on Brain Neurotransmission and Neurotoxicity in Adult Rats

Abstract

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.

Keywords: Adolescence; Mephedrone; Microdialysis; Neurotoxicity; Neurotransmitters.

Scheme 1

A schematic presentation of chronic mephedrone (8 × 5 mg/kg) administration during adolescence. Gray bars indicate days of administration; PND postnatal day

Fig. 1

The effect of repeated administration of mephedrone (MEPH, 8 × 5 mg/kg) during adolescence on extracellular level of DA, 5-HT, and glutamate (GLU) measured in adulthood (90 PNDs) in the rat striatum. a–c The time course. Values are the mean ± SEM (n = 4–6 animals per group). Time of drug injection is indicated with an arrow. *P < 0.001, vs. saline/saline group (repeated measures ANOVA and Tukey’s post hoc test)

Fig. 2

The effect of repeated administration of mephedrone (MEPH, 8 × 5 mg/kg) during adolescence on extracellular level of DA, 5-HT, and glutamate (GLU) measured in adulthood (90 PNDs) in the rat nucleus accumbens. a–c The time course. Values are the mean ± SEM (n = 4–6 animals per group). Time of drug injection is indicated with an arrow. *P < 0.001, vs. saline/saline group; ^P < 0.001, vs. saline/MEPH group (repeated measures ANOVA and Tukey’s post hoc test)

Fig. 3

The effect of repeated administration of mephedrone (MEPH, 8 × 5 mg/kg) during adolescence on extracellular level of DA, 5-HT, and glutamate (GLU) measured in adulthood (90 PNDs) in the rat frontal cortex. a–c The time course. Values are the mean ± SEM (n = 4–6 animals per group). Time of drug injection is indicated with an arrow. *P < 0.001, vs. saline/saline group; ^P < 0.001, vs. saline/MEPH group (repeated measures ANOVA and Tukey’s post hoc test)

Fig. 4

The effect of repeated mephedrone (MEPH, 8 × 5 mg/kg) administration during adolescence on DA turnover rate measured in adulthood (90 PNDs) in the rat striatum (STR), nucleus accumbens (NAS), and frontal cortex (FCX). Data are shown as the mean ± SEM (n = 5 animals per group). a Percent change in comparison to saline-treated rats and calculated from the absolute numbers given in nanograms/milligram of tissue content presented in supplementary material. b (DOPAC + HVA)/DA ratio

Fig. 5

The effect of repeated mephedrone (MEPH, 8 × 5 mg/kg) administration during adolescence on 5-HT turnover rate measured in adulthood (90 PNDs) in the rat striatum (STR), nucleus accumbens (NAS), and frontal cortex (FCX). Data are shown as the mean ± SEM (n = 5 animals per group). a Percent change in comparison to saline-treated rats and calculated from the absolute numbers given in nanograms/milligram of tissue content presented in supplementary material. b 5-HIAA/5-HT ratio

Fig. 6

The effect of a single (5 mg/kg) and repeated (8 × 5 mg/kg) administration of mephedrone (MEPH) during adolescence on the oxidative damage of DNA in the nuclei from the rat cortex measured in adulthood (90 PNDs). Data are the mean ± SEM (n = 6 animals per group) and represent an olive tail moment shown as the product of the tail length and the fraction of total DNA in the tail. *P < 0.01, in comparison to the control group; ^P < 0.01, chronic vs. single administration (one-way ANOVA and Tukey’s post hoc test)