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.2020 Aug;38(2):536-551.
doi: 10.1007/s12640-020-00227-8. Epub 2020 Jun 6.

Four Synthetic Cathinones: 3-Chloromethcathinone, 4-Chloromethcathinone, 4-Fluoro-α-Pyrrolidinopentiophenone, and 4-Methoxy-α-Pyrrolidinopentiophenone Produce Changes in the Spontaneous Locomotor Activity and Motor Performance in Mice with Varied Profiles

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Four Synthetic Cathinones: 3-Chloromethcathinone, 4-Chloromethcathinone, 4-Fluoro-α-Pyrrolidinopentiophenone, and 4-Methoxy-α-Pyrrolidinopentiophenone Produce Changes in the Spontaneous Locomotor Activity and Motor Performance in Mice with Varied Profiles

Jakub Wojcieszak et al. Neurotox Res.2020 Aug.

Abstract

Two chloromethcathinones, 3-chloromethcathinone (3-CMC) and 4-chloromethcathinone (4-CMC), and two para-substituted α-pyrrolidinophenones, 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-PVP) and 4-fluoro-α-pyrrolidinopentiophenone (4-F-PVP), represent synthetic cathinones, the second most frequently abused group of new psychoactive substances (NPSs), which has aroused a worldwide health concern in the last decade. Synthetic cathinones act as psychostimulants by elevating extracellular levels of monoaminergic neurotransmitters. This study investigates effects of 3-CMC, 4-CMC, 4-MeO-PVP, and 4-F-PVP on the spontaneous locomotor activity and motor performance of mice. Additionally, neurotoxicity of substituted methcathinones against SH-SY5Y neuroblastoma cells was evaluated. All test cathinones stimulate in a dose-dependent manner horizontal locomotor activity of mice. Consistently to our prior findings, pyrrovalerones, but not methcathinone derivatives, produce dose-dependent elevation of vertical locomotor activity (rearing behavior). None of the tested compounds decreases the time spent on the accelerating rotarod, pointing to the lack of considerable motor disability in mice after acute exposition. Only 4-MeO-PVP at the high tested dose (20 mg/kg) increases motor performance of mice. Considering that α-pyrrolidinophenones are highly potent and selective DA uptake inhibitors, while chloromethcathinones enhance non-selective DA/5-HT release, we suggest that the increase of vertical locomotor activity and performance on rotarod in mice may serve as a behavioral indicator of the monoaminergic profile of synthetic cathinones. Finally, this study gives first insights into cytotoxicity of both 3-CMC and 4-CMC displayed against SH-SY5Y cells, which emerges and intensifies after prolonged incubation, suggesting the indirect mechanism of action, unrelated to interactions with monoamine transporters.

Keywords: 3-CMC; 4-CMC; 4-F-PVP; 4-MeO-PVP; Rotarod; Spontaneous locomotor activity.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Effects of 3-CMC (5, 10, 20 mg/kg) on the spontaneous locomotor activity of mice. Average horizontal (a–c) and vertical (e–g) activities in 10-min bins. Total distance traveled during 120 min (d). Total rearing counts during 120 min (h). Data presented as mean ± standard error of the mean (SEM) (n = 8). ***p < 0.001; **p < 0.01; *p < 0.05 vs. control group
Fig. 2
Fig. 2
Effects of 4-CMC (5, 10, 20 mg/kg) on the spontaneous locomotor activity of mice. Average horizontal (a–c) and vertical (e–g) activities in 10-min bins. Total distance traveled during 120 min (d). Total rearing counts during 120 min (h). Data presented as mean ± standard error of the mean (SEM) (n = 8). ***p < 0.001; **p < 0.01; *p < 0.05 vs. control group; ##p < 0.01 vs. 4-CMC 20 mg/kg group
Fig. 3
Fig. 3
Effects of 4-F-PVP (5, 10, 20 mg/kg) on the spontaneous locomotor activity of mice. Average horizontal (a–c) and vertical (e–g) activities in 10-min bins. Total distance traveled during 120 min (d). Total rearing counts during 120 min (h). Data presented as mean ± standard error of the mean (SEM) (n = 8). ***p < 0.001; **p < 0.01; *p < 0.05 vs. control group; ###p < 0.001; ##p < 0.01; #p < 0.05 vs. 4-F-PVP 20 mg/kg group
Fig. 4
Fig. 4
Effects of 4-MeO-PVP (5, 10, 20 mg/kg) on the spontaneous locomotor activity of mice. Average horizontal (a–c) and vertical (e–g) activities in 10-min bins. Total distance traveled during 120 min (d). Total rearing counts during 120 min (h). Data presented as mean ± standard error of the mean (SEM) (n = 8). ***p < 0.001; **p < 0.01; *p < 0.05 vs. control group; ###p < 0.001; ##p < 0.01; #p < 0.05 vs. 4-MeO-PVP 20 mg/kg group
Fig. 5
Fig. 5
Effects ofa 3-CMC (10, 20 mg/kg),b 4-CMC (10, 20 mg/kg),c 4-F-PVP (10, 20 mg/kg), andd 4-MeO-PVP (10, 20 mg/kg) on the performance of mice on the rotarod. Data presented as mean ± standard error of the mean (SEM) (n = 12—drug-treated groups or 14—control group). *p < 0.05 vs. control group
Fig. 6
Fig. 6
Cytotoxic effects of 3-CMC and 4-CMC against human SH-SY5Y neuroblastoma cells. Effects ofa,b 3-CMC (10–300 μM) andd,e 4-CMC (10–300 μM) on the mitochondrial activity measured after 24-h or 72-h incubation with MTT test. Data presented as mean ± standard error of the mean (SEM) from at least 3 independent experiments and expressed as a percentage of control group considered 100% viable. Effects ofc 3-CMC (100–300 μM) andf 4-CMC (100–300 μM) on the integrity of cell membranes after 48-h incubation measured with LDH test. Data presented as mean ± standard error of the mean (SEM) from at least 3 independent experiments and expressed as a percentage of positive control group considered 100% cytotoxicity. ***p < 0.001; **p < 0.01; *p < 0.05 vs. control group
Fig. 7
Fig. 7
Comparison of the potency of 3-CMC, 4-CMC, 4-F-PVP, and 4-MeO-PVP to stimulate the spontaneous horizontal activity of mice at 10 mg/kg (a) and 20 mg/kg (b) and the spontaneous vertical locomotor activity of mice at 10 mg/kg (c) and 20 mg/kg (d). Figure constructed with data presented in Figs. 1, 2, 3, and 4. Data presented as mean ± standard error of the mean (SEM) (n = 8). ***p < 0.001; **p < 0.01; *p < 0.05 vs. 4-MeO-PVP group; ###p < 0.001 vs. 4-F-PVP group
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