Stereoselective neurochemical, behavioral, and cardiovascular effects of α‐pyrrolidinovalerophenone enantiomers in male rats

Abstract

The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. Racemic α-PVP blocked the uptake of both dopamine and norepinephrine ex vivo, but did not block the uptake of serotonin (5-HT), at their respective transporters. S-α-PVP was slightly more potent than racemic α-PVP, while R-α-PVP was 10 to 20 times less potent at blocking dopamine and norepinephrine uptake. In microdialysis studies, racemic and S-α-PVP increased extracellular dopamine levels in the nucleus accumbens, but not levels of 5-HT. Racemic and S-α-PVP also increased locomotor activity. When tested at the same doses, S-α-PVP produced larger effects than racemic α-PVP. R-α-PVP also increased extracellular dopamine levels and locomotor activity, but only at 30 times higher doses than S-α-PVP. Racemic and S-α-PVP were self-administered by rats at 0.03 mg/kg/ injection, whereas R-α-PVP was self-administered at a 10 times higher dose. Doseeffect determinations following acquisition suggested that R-α-PVP was at least 30 times less potent than S-α-PVP. Finally, racemic and S-α-PVP increased blood pressure and heart rate at doses approximately 30 times less than was required for R-α-PVP to produce similar effects. These results show that the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP most likely reflect the actions of S isomer.

Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

“…DAT/SERT selectivity ratio, is regularly used as a predictive indicator of drug addictive properties (12,16). In agreement with previous studies (18), we found that S-αPVP has a high DAT/SERT selectivity ratio when compared to both cocaine and R-αPVP, which suggests a higher abuse-liability. However, despite the fact that DAT/SERT selectivity has been proven to be an important indicator for the screening of drugs, several high a nity and DAT-selective inhibitors such as benztropines, rimcazole, GBR12909 and related analogs, do not induce the same reinforcing and stimulatory effects induced by cocaine (15,54).…”

“…A prolonged NET inhibition could indeed dramatically impact the cardiovascular system due to the role of norepinephrine in the regulation of blood pressure and heart rate (71). In agreement, administration of αPVP-enantiomers in rats shows an extended increase in blood-pressure (18). However, it is important to consider that DAT, in addition to its important role in the brain, is also widely expressed peripherally (72).…”

“…In this study we have focused on the pharmacology of αPVP enantiomers at DAT because of its well-established role of DAT in psychomotor functions (4). However, considering the role of norepinephrine and NET in the regulation of blood pressure and heart rate (71), the structural similarities between DAT and NET (1), and the high a nity that αPVP has for NET as well (18), we surmise that a slow dissociation rate at NET might underly the peripheral side effects commonly observed in αPVP users. A prolonged NET inhibition could indeed dramatically impact the cardiovascular system due to the role of norepinephrine in the regulation of blood pressure and heart rate (71).…”

Flakka: New Dangerous Synthetic Cathinone on the Drug Scene

“…Similarly, Schindler et al [54] investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. The results showed that S-α-PVP is slightly more potent than racemic α-PVP, while R-α PVP is 10 to 20 times less effective in blocking dopamine and norepinephrine uptake.…”

Distinguishing the behavioral potencies of α-pyrrolidino-phenone cathinone stimulants

“…This class of pyrrolidino-phenone cathinone compounds are dopamine transporter (DAT) and norepinephrine transporter (NET) selective (over the serotonin transporter; SERT) inhibitors which do not serve as substrates/releasers (Eshleman et al, 2017) as do commonly recognized amphetamineclass stimulants such as methamphetamine and 3,4methylenedioxy-methamphetamine and even some of the cathinones such as mephedrone or methylone (Simmler et al, 2013;Simmler et al, 2014). Cocaine is a classic non-substrate monoamine transporter inhibitor psychomotor stimulant, thus it is unsurprisingly that MDPV (Aarde et al, 2013;Aarde et al, 2015b;Gannon et al, 2017b;Watterson et al, 2014) and α-PVP (Aarde et al, 2015a;Gannon et al, 2017a;Gannon et al, 2017b;Huskinson et al, 2017;Javadi-Paydar et al, 2018a;Schindler et al, 2019) are highly effective reinforcers in animal models. MDPV and a-PVP appear to have similar potency as reinforcers (Aarde et al, 2015a), consistent with similar potencies as DAT inhibitors in vivo (Gannon et al, 2018).…”