Locomotor activity and discriminative stimulus effects of a novel series of synthetic cathinone analogs in mice and rats

Abstract

Rationale Recent years have seen an increase in the recreational use of novel, synthetic psychoactive substances. There are little or no data on the abuse liability of many of the newer compounds. Objectives The current study investigated the discriminative stimulus and locomotor effects of a series of synthetic analogues of cathinone: alpha-PPP, alpha-PHP, alpha-PVT, 3,4-methylenedioxy-PBP (MDPBP), and ethylone. Methods Locomotor activity was assessed in an open-field assay using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine or methamphetamine from vehicle. Results Each of the compounds produced an inverted-U dose-effect on locomotor activity. Maximal effects were similar among the test compounds, but potencies varied with relative potencies of MDPBP>α-PPP=α-PHP>ethylone>α-PVT. Each of the test compounds substituted fully for the discriminative stimulus effects of methamphetamine. α-PPP, α-PHP, and ethylone fully substituted for cocaine. α-PVT produced a maximum of 50% cocaine-appropriate responding and MDPBP produced an inverted U-shaped dose-effect curve with maximum effects of 67%. Conclusions These data provide initial evidence that these structurally-similar, emerging novel psychoactive substances demonstrate potential for abuse and may be utilized for their stimulant-like effects, given their ability to stimulate locomotor activity and their substitution for the discriminative stimulus effects of the classical psychostimulants cocaine and/or methamphetamine.

Differential effects of synthetic psychoactive cathinones and amphetamine stimulants on the gut microbiome in mice

“…The structural similarity shared by these drugs translates into an extensive overlap in their pharmacological, neurochemical and behavioral effects. The SPCs and amphetamines share the ability to interact with monoamine transporters to cause the release of dopamine (DA), serotonin (5HT) or norepinephrine (NE) [6][7][8], alter thermoregulation [6,9,10], increase locomotor activity [6,9,11] and serve as discriminative stimuli [9,12,13]. The abuse potential of these drugs has also been affirmed in animal models of addiction [14][15][16].…”

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

“…[2][3][4][5][6][7]), a growing number of synthetic cathinones have been reported to increase locomotor activity, produce cocaine-, methamphetamine-, or 3,4-methylenedioxymethamphetaminelike discriminative stimulus effects, and maintain intravenous self-administration (e.g., refs. [10][11][12][13][14][15][16][17][18][19]). For instance, we have recently shown that rats will acquire self-administration of the pyrrolidine-containing cathinones MDPV, MDPBP, MDPPP, α-PVP, and α-PPP at rates comparable to those observed with cocaine and that the potencies of these drugs to maintain responding under a fixed ratio (FR) 5 schedule of reinforcement are highly correlated with their potencies to inhibit uptake at DAT and NET but not SERT [13,16].…”

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

“…Preclinical studies that have examined α‐PPPs psychostimulant properties, mediated by dopaminergic signaling, employed doses similar to or higher than doses needed to abolish the DOI‐elicited HTR. For example, α‐PPP increases locomotor activity in mice with peak effects at 25 mg/kg . In rats, 30 mg/kg α‐PPP produced significant increases in locomotor activity for 60 minutes (the entire test session), while a dose of 10 mg/kg only produced significant increases for the first 50 minutes of the session .…”

“…For example, α-PPP increases locomotor activity in mice with peak effects at 25 mg/kg. 55 In rats, 30 mg/kg α-PPP produced significant increases in locomotor activity for 60 minutes (the entire test session), while a dose of 10 mg/kg only produced significant increases for the first 50 minutes of the session. 56 In another study examining the effects of pyrrolidine SCs on locomotor activity in mice, it was found that 10 mg/kg of the much more potent DAT inhibitor, α-PVP, produced significant increases in locomotor activity that lasted for 120 minutes, whereas 3 mg/kg effects lasted for 80 min.…”