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

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.

Molecular Mechanisms of Action of Novel Psychoactive Substances (NPS). A New Threat for Young Drug Users with Forensic-Toxicological Implications

“…Drug-induced dopaminergic activity parallels the locomotor stimulation and rewarding effect [ 118 , 143 , 144 ]. Methylone is a nonspecific substrate [ 118 ], producing an inward current at SERT but not at DAT, similarly to MDMA [ 145 ], and oxidative stress, which is responsible for the neurotoxicity of methylone and, to a greater extent, MDPV [ 146 ]. 4-MEC, 4-MePP, and α-PVP also mainly block DAT, with greater abuse potential compared to other stimulants [ 147 , 148 ].…”

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

“…Selection of a mouse strain was based on published data indicating low basal immobility of DBA/2J mice in forced swim and tail suspension tests, allowing for more sensitive detection of potential depressive effects, and its sensitivity to acute desipramine and fluoxetine as well as chronic lithium treatment (Can et al 2011;Lucki et al 2001). Moreover, the behavioral characteristics of DBA/2J mice differ markedly from previously used C57BL/6J (Võikar et al 2005;Wojcieszak et al 2020). Therefore, it was used to confirm whether previous findings regarding the effects of 4-CMC and 4-MeO-PVP are independent of genetic background.…”

“…The acute effects of 4-CMC and 4-MeO-PVP on the spontaneous activity of mice were first assessed to select the drug doses to be used in later studies requiring multiple treatments. Spontaneous locomotor activity was measured according to Wojcieszak et al ( 2020 ) with minor modifications, using Opto-Varimex Auto-Track (model 0271-002M, Columbus Instruments, Columbus, OH, USA) open field chambers (20.3 × 20.3 × 20.3 cm; 4 units) equipped with 16 infrared beams and corresponding photodetectors, spaced by 1.3 cm; these were located on the X and Y horizontal axes, on two planes, to detect both horizontal and vertical movements.…”

“…Motor coordination was measured in order to detect behavioral signs of a possible dopaminergic toxicity after prolonged treatment with drugs stimulating DA circuitry in the brain. The procedure was conducted as previously described (Wojcieszak et al 2020 ) on four consecutive days (testing days 1–4), always as the last behavioral test during the day, and after a minimum of 1 h rest from the previous tests. The test was conducted by placing mice on a rotating horizontal rod (3 cm in diameter, 5.5 cm in width; Rotarod, model RTD-4, Ataner, Lublin, Poland) made of non-slippery, sandy polyvinyl chloride that could not be gripped by the animals.…”

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

“…Studies reported by [31,32] have demonstrated that para-halogenated αpyrrolidinophenones act as potent DA uptake inhibitors. Regarding the in vivo effects, the authors of [33] recently demonstrated that 4-F-α-PVP administration induces a dosedependent increase in horizontal locomotor activity in mice. Additionally, 3-F-α-PVP and 3-Br-α-PVP are also available through the internet, and some samples have been identified in non-governmental organizations' (NGOs') drug testing laboratories (i.e., www.drugsdata.org; www.ecstasydata.org, accessed on 20 December 2021); although, to our knowledge, there is no information regarding the pharmacology of these metahalogenated derivatives.…”