The abuse-related effects of pyrrolidine-containing cathinones are related to their potency and selectivity to inhibit the dopamine transporter

Abstract

Synthetic cathinones are common constituents of abused "bath salts" preparations and represent a large family of structurally related compounds that function as cocaine-like inhibitors or amphetamine-like substrates of dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters. Preclinical evidence suggests that some cathinones (e.g., MDPV and α-PVP) are more effective reinforcers than prototypical stimulant drugs of abuse, such as cocaine or methamphetamine. Although the reinforcing potency of these cathinones is related to their potency to inhibit DAT, less is known about the pharmacological determinants of their unusually high reinforcing effectiveness. To this end, we tested the hypothesis that reinforcing effectiveness of cathinone stimulants is positively correlated with their selectivity for DAT relative to SERT. Uptake inhibition assays in rat brain synaptosomes were used to directly compare the potency of MDPV, MDPBP, MDPPP, α-PVP, α-PPP, and cocaine at DAT, NET, and SERT, whereas intravenous self-administration in rats was used to quantify relative reinforcing effectiveness of the drugs using progressive ratio (PR) and behavioral economic procedures. All cathinones were more potent at DAT than NET or SERT, with a rank order for selectivity at DAT over SERT of α-PVP > α-PPP > MDPV > MDPBP > MDPPP > cocaine. These synthetic cathinones were more effective reinforcers than cocaine, and the measures of reinforcing effectiveness determined by PR and demand curve analyses were highly correlated with selectivity for DAT over SERT. Together, these studies provide strong and convergent evidence that the abuse potential of stimulant drugs is mediated by uptake inhibition at DAT, with activity at SERT serving as a negative modulator of reinforcing effectiveness.

The synthetic cathinone psychostimulant α‐PPP antagonizes serotonin 5‐HT2A receptors: In vitro and in vivo evidence

“…Moreover, this effect is blocked by pre‐treatment with the 5‐HT 1A R antagonist WAY‐100653, but not by naloxone . Most germane to our studies, the K i of α‐PPP at DAT is ~1.3 μM, an affinity that is only about two‐fold higher than its affinity at 5‐HT 2A R, and the IC 50 of α‐PPP to inhibit DAT is ~332 nM, which is only about three‐fold higher than its potency to antagonize 5‐HT 2A R signaling, according to our observations. Still, until now, most effects produced by α‐PPP have been attributed to its actions at DAT.…”

“…These observations suggest that acute NET inhibition does not inhibit the DOI‐elicited HTR, which argues that the effects of α‐PPP in this assay were not mediated this pharmacological property. Likewise, it is unlikely the effect was mediated by DAT inhibition, as MDPPP has a measurably higher potency to inhibit DAT than α‐PPP . Finally, none of the animals treated with DOI and α‐PPP behaved grossly differently from animals treated with DOI alone, DOI and MDPPP, or DOI and 3‐BMC.…”

“…Recent, preclinical work shows that the reinforcing effectiveness of SCs is positively correlated with their selectivity for DAT over SERT . Relatedly, psychoactive drugs that block SERT tend to have reduced stimulant qualities .…”

“…MDPV is >20‐fold and > 50‐fold more potent than amphetamine and cocaine, respectively, at blocking uptake at the dopamine transporter (DAT) . Similarly, α‐PVP is 15‐fold more potent than cocaine at inhibiting DAT . MDPVs and α‐PVPs high potencies at DAT probably account for most of their perilous effects.…”

“…Moreover, it remains unscheduled by the Drug Enforcement Agency (DEA) of the United States, and in the last two years, it is one of the less common SCs identified in seizures by the DEA (DEA Emerging Threat Reports, 2016–2018). α‐PPPs unpopularity is peculiar, as it has similar potency to cocaine as a DAT inhibitor, and it has high selectivity for DAT, relative to the serotonin transporter (SERT), which together, would seemingly make it a pervasive drug of abuse. We contend that the 5‐HT 2A R antagonist activity of α‐PPP may mitigate its effects at DAT.…”