Comparative neuropharmacological studies on three pyrrolidine-containing synthetic cathinones

Abstract

Purpose 3,4-Methylenedioxypyrovalerone (3,4-MDPV) is a prevalent member of α-pyrrolidinophenones, a group of new psychoactive substances, known for its strong psychostimulant effect resulting from potent stimulation of dopamine (DA) circuitry in the brain. As 3,4-MDPV and its derivatives are successively being scheduled, each year novel analogs appear on the market. This study aimed at examination and direct comparison of psychostimulant properties of structural isomer of 3,4-MDPV, namely 2,3-MDPV along with a model α-pyrrolidinophenone, pyrovalerone. Methods Open field spontaneous locomotor activity of mice was assessed as a measure of psychostimulant potency. To evaluate the in vivo pharmacological properties of the drugs, extracellular levels of DA and serotonin (5-HT) in the mouse striatum were measured using an in vivo microdialysis technique followed by high-performance liquid chromatography with electrochemical detection. Involvement of dopaminergic system in the behavioral effects of the tested α-pyrrolidinophenones was examined by pre-treatment with a selective D 1-DA receptor antagonist, SCH 23390, before measurement of locomotor activity in response to the drugs. Results 3,4-MDPV, 2,3-MDPV and pyrovalerone produced time-and dose-dependent stimulation of locomotor activity, with 3,4-MDPV being more potent than the other two compounds. Observed locomotor stimulation was mediated by elevated DA-ergic neurotransmission, as all compounds caused a significant increase of extracellular DA levels in the striatum, with 3,4-MDPV being the most potent, and psychostimulant effects were abolished by SCH 23390. Interestingly, the tested pyrovalerones caused in vivo elevation of extracellular 5-HT levels, which contrasted with their in vitro pharmacologic properties. Conclusions Pyrovalerone, 2,3-MDPV and 3,4-MDPV produced psychostimulant effects mediated by stimulation of dopaminergic neurotransmission. Additionally, all tested compounds elevated extracellular levels of 5-HT in vivo.

Citrus limon L. (lemon) seed extract shows neuro-modulatory activity in an in vivo thiopental-sodium sleep model by reducing the sleep onset and enhancing the sleep duration

“…Animal head-dipping behavior remains closely correlated with their psychological response. Gamma amino-butyric acid (GABA) can modulate the central nervous system through the voltage-gated Ca 2+ channel or chlorine conductance [40][41][42][43][44][45][46][47][48][49][50]. It was revealed that the animals' head-dipping behavior is clearly relevant to their mental state, and this test is used to investigate anxiety-related activities.…”

Pharmacotherapy of Patients Taking New Psychoactive Substances: A Systematic Review and Analysis of Case Reports

“…In the United States, for example, there have been a particularly high number of deaths due to opioid overdoses in recent years (91). These substances cause a euphoric effect as they bind to the presynaptic µ-opioid receptors (83). One of the main symptoms in the case reports studied was impaired thinking and a decreased level of consciousness.…”

“…The obtained results indicate a greater influence of synthetic cathinone intake on the occurrence of aggression in comparison to cannabinoids. The presence of a pyrrolidine ring and a quaternary amine moiety increases the lipophilicity and potency of these compounds (83). An example of this is MDPV, the consumption of which has been reported to cause fatalities as well as extremely aggressive behavior (84).…”

A narrative review of the neuropharmacology of synthetic cathinones—Popular alternatives to classical drugs of abuse

“…In vitro affinity studies indicate that pyrovalerones should not interact with SERT and should not cause 5‐HT release, therefore the observed elevated 5‐HT concentration can presumably be explained by the functional coupling of dopaminergic and serotonergic systems. In the case of high extracellular DA concentrations, the phenomenon of its uptake by SERT is observed, accompanied by a concomitant SERT‐mediated release of 5‐HT (Larsen et al., 2011; Simmler, 2018; Wojcieszak Andrzejczak et al., 2020; Wojcieszak et al., 2018). Interestingly, recent studies in mice have shown that SCs possessing a pyrrolidine ring, unlike SCs of the second methamphetamine‐like group, cause, in addition to horizontal, also vertical increased dose‐dependent locomotor activity.…”

“…Interestingly, recent studies in mice have shown that SCs possessing a pyrrolidine ring, unlike SCs of the second methamphetamine‐like group, cause, in addition to horizontal, also vertical increased dose‐dependent locomotor activity. The increased vertical locomotor activity is presumably indicative of particularly potent and selective dopaminergic stimulation and anxiety reduction in contrast to derivatives such as those of the second methamphetamine‐like group (Wojcieszak, Andrzejczak, et al., 2020; Wojcieszak et al., 2018, 2019; Wojcieszak, Kuczyńska, & Zawilska, 2020). Popular compounds in this group include, among others, PV8 (1‐Phenyl‐2‐pyrrolidin‐1‐ylheptan‐1‐one), MDPV, and α‐PVP (1‐phenyl‐2‐[1‐pyrrolidinyl]‐1‐pentanone) (Simmler, 2018; Simmler et al., 2013).…”