Abuse-related effects of MDPV, α-PVP, and related synthetic cathinones: structural determinants of reinforcing potency and effectiveness

<p>Background: The abuse of New Psychoactive Substances (NPSs), such as synthetic cathinones, has increased around the world. Although international regulations have made some synthetic cathinones illegal (e.g., MDPV and α-PVP) the subsequent introduction of structurally-related analogues results in an ever-evolving threat to public health worldwide. The current study aimed to directly compare the pharmacologic properties and abuse potential of six structurally-related synthetic cathinones (MDPV, MDPBP, MDPPP, α-PVP and α-PPP). </p><p>Methods: Synaptosomes prepared from rat brains were used to assess the capacity of each of the cathinones (and cocaine) to inhibit monoamine uptake DAT, NET and SERT. Male Sprague Dawley rats (n=12 per drug) were trained to self-administer MDPV, MDPBP, MDPPP, α-PVP, α-PPP, or cocaine. Measures of reinforcing potency and effectiveness were obtained from dose-response curves generated under a progressive ratio (PR) schedule of reinforcement; demand curve analyses of fixed ratio (FR) responding were also used to obtain measures of drug value. </p><p>Results: Like cocaine, each of the cathinones inhibited uptake at DAT, NET, and SERT. The rank order for selectivity at DAT relative to SERT was α-PVP > α-PPP > MDPV > MDPBP > MDPPP > cocaine. Similarly, all compounds also maintained robust self-administration. The rank order for reinforcing potency was MDPV > α-PVP > MDPBP > α-PPP > MDPPP = cocaine, whereas the rank order for reinforcing effectiveness (PR and demand) was α-PVP > MDPV = α-PPP > MDPBP = MDPPP > cocaine. </p><p>Conclusions: These studies suggest that MDPV, α-PVP, and their structural analogues are all more effective reinforcers than cocaine. The reinforcing potency of these cathinones was highly correlated with their potency to inhibit DAT, and inversely related to the length of the α-alkyl side chain (e.g., MDPV > MDPPP). The relative reinforcing effectiveness of these cathinones was highly correlated with their selectivity for DAT over SERT, which was reduced by the presence of a methylenedioxy moiety (e.g., α-PVP > MDPV), and related to the length of the α-alkyl side chain (e.g., MDPV > MDPPP). Together, these studies provide insight into the structure activity relationships of synthetic cathinones and suggest that MDPV-like cathinones have high potential for abuse.</p>