Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats

Abstract

Background: Synthetic cathinone derivatives are used as alternatives both for stimulant drugs such as cocaine and methamphetamine and for club drugs such as 3,4-methylenedioxymethamphetamine (MDMA), but little is known about their MDMA-like subjective effects. Methods In order to determine their similarity to MDMA, the discriminative stimulus effects of 10 pyrrolidinyl cathinones (α-pyrrolidinopropiophenone, 4′-methyl-α-pyrrolidinopropiophenone (4′-MePPP), α-pyrrolidinobutiophenone, 3′,4′-methylenedioxy-α-pyrrolidinobutyrophenone (MD-PBP), α-pyrrolidinovalerophenone, 3,4-methylenedioxy-pyrovalerone (MDPV), α-pyrrolidinopentiothiophenone, napthylpyrovalerone (naphyrone), α-pyrrolidinohexiophenone, and 4′-methyl-α-pyrrolidinohexiophenone (4′-MePHP)) were assessed in Sprague–Dawley rats trained to discriminate 1.5 mg/kg racemic ±-MDMA from vehicle. Results: Compounds with no substitutions on the phenyl ring and the thiophene produced 44–67% MDMA-appropriate responding. In contrast, the substituted pyrrolidinyl cathinones produced a range of MDMA-appropriate responding dependent upon the length of the alpha side chain. 4′-MePPP, with a single carbon on the alpha position, produced 99.8% MDMA-appropriate responding, MD-PBP (two carbons) produced 83%, naphyrone (three carbons) produced 71%, MDPV (three carbons) produced, 66%, and 4′-MePHP (four carbons) produced 47%. Conclusions: Many cathinone compounds have discriminative stimulus effects similar to those of MDMA. However, the pyrrolidine substitution appears to reduce serotonergic effects, with a commensurate decrease in MDMA-like effects. Substitutions on the phenyl ring appear to be able to restore MDMA-like responding, but only in compounds with short alpha side chains. These findings agree with earlier findings of increasing dopaminergic effects and stronger reinforcing effects with increasing side chain. Assessment of more compounds is necessary to establish the replicability/robustness of this phenomenon. These findings may be of use in predicting which compounds will have MDMA/club drug-like effects versus psychostimulant-like effects.

Behavioral effects of four novel synthetic cathinone analogs in rodents

“…Many cathinones fully substitute for the discriminative stimulus effects of MDMA; however, several do not. [45][46][47][48] Recently, it has been reported that chemical structure plays a role, such that compounds with no substitutions on the phenyl ring, pyrrolidinyl cathinones, and compounds with long alpha side chains produce less MDMA-appropriate responding, 13,49 which is in agreement with other studies indicating that the alpha side chain length 38 and 4-substitutions 37,49 predict activity of cathinones.…”

“…However, all the low efficacy compounds have a single carbon appended to the alpha position, whereas MPHP has a 4‐carbon side chain. Earlier work has reported that the 4‐position phenyl substitutions increase SERT activity 36,37 and MDMA‐like discriminative stimulus effects, 13 whereas lengthening the alpha side chain increases DAT selectivity 38 and decreases MDMA‐like discriminative stimulus effects 13 …”

“…Earlier work has reported that the 4-position phenyl substitutions increase SERT activity 36,37 and MDMA-like discriminative stimulus effects, 13 whereas lengthening the alpha side chain increases DAT selectivity 38 and decreases MDMA-like discriminative stimulus effects. 13 All four of the synthetic cathinones tested in the current study (MPHP, N-ethylhexedrone, dipentylone, and 4-CEC) produced discriminative stimulus effects similar to those of methamphetamine and cocaine, although 4-CEC only substituted for methamphetamine and cocaine at doses that decreased rates of responding. This suggests that 4-CEC has fairly weak psychostimulant-like discriminative stimulus effects and may be used less on the street as a substitute for cocaine or methamphetamine, particularly because doses of 4-CEC high enough to produce stimulant effects may also produce unpleasant adverse effects.…”

Reinforcing Effects of the Synthetic Cathinone α-Pyrrolidinopropiophenone (α-PPP) in a Repeated Extended Access Binge Paradigm

“…However, the potency of α-PPP as a DAT inhibitor is approximately 70 times less than that of MDPV ( 25 ), which is likely reflected in the higher doses of α-PPP required to support self-administration, as observed in the present and previous studies ( 15 ). Interestingly, however, α-PPP does not show significant affinity for presynaptic serotonin transporters, but recent studies have revealed some MDMA-like discriminative stimulus effects of this cathinone derivative ( 12 ).…”

“…Studies in rodents support the notion that synthetic cathinones possess a high potential for abuse and dependence. For example, in line with their pharmacological actions, MDPV and a-PPP induce discriminative stimulus effects similar to those of cocaine and methylenedioxymethamphetamine (MDMA) (9)(10)(11)(12) and are intravenously self-administered under conditions of limited drug access (13)(14)(15). However, detailed case reports have revealed that users of synthetic cathinones often engage in bingelike intake patterns that last 3-5 consecutive days or longer (16,17).…”