Dissecting the Abuse Liability of Cathinone Derivative Psychomotor Stimulants in Female Rats

Rationale Use of a diversity of synthetic psychoactive cathinone drugs (“bathsalts”) continues to expand worldwide despite legal control. The pyrrolidinophenones, 3,4‐methylenedioxypyrovalerone (MDPV) and α‐pyrrolidinopentiophenone (α‐PVP), cause violent and/or bizarre public behavior in some users and are potent reinforcers in rodent intravenous self‐administration (IVSA) models. Other cathinones with entactogen‐like pharmacology appear to be more efficacious reinforcers than the class‐defining 3,4‐methylenedioxymethamphetamine (MDMA). Objectives To determine how modification of the aromatic ring and extension of the alpha carbon alkyl chain modifies the reinforcing properties of cathinone derivatives. Methods Female Wistar rats were trained in IVSA of α‐PVP (0.05 mg/kg/inf; 1 h sessions), MDMA (0.5 mg/kg/inf; 6 h) or Pentylone (0.5 mg/kg/inf; 6 h). Following acquisition, the groups were subjected to dose‐substitution under FR and PR response contingencies. Experiments evaluated: α‐PVP, α‐pyrrolidinohexiophenone, pentylone, methylone, pentedrone, 4‐methylpentedrone, MDMA and an MDMA analog. Results Extension of the carbon chain decreased potency, but increased efficacy, of MDMA and methylone. Removal of the pyrrolidino group decreased potency of α‐PVP or MDPV. Effects of 4‐methyl vs 3,4‐methylenedioxy substitution were not consistent across core structures. Conclusions Recreational use of a wide variety of closely‐related cathinone derivatives drives structure‐activity inferences about abuse liability. IVSA studies in rats, however, show that predictions based on structure are often incomplete or in error. In vivo studies of abuse liability are therefore necessary to understand health risks of novel cathinone derivatives. Support or Funding Information These studies supported by USPHS Grant: R01 DA042211