Dissecting the Abuse Liability of Cathinone and Amphetamine Stimulants

The abuse of psychomotor stimulants, including cocaine and methamphetamine, as well as the synthetic cathinone drugs (“bathsalts”), continues to wreak havoc worldwide and in the United States of America, with most individuals that suffer with stimulant use disorders going untreated. The more established stimulants such as cocaine and methamphetamine are highly addictive, can be acutely lethal and can result in long-term brain alterations with many implications for health and well-being. Recent studies show that synthetic cathinone psychoactive drugs 3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP) and associated close analogs are a highly potent and efficacious reinforcers in animal models. These compounds tend to be used as cheaper or more available substitutes in lower socioeconomic populations, by incarcerated individuals, etc. Efforts to develop small molecule or vaccine therapies for psychomotor stimulant dependence have not, as yet, succeeded. It continues to be critical to better understand how stimulant dependence is established and maintained so as to better prevent stimulant addiction before it is established. This project will investigate the situational and behavioral contributors to escalating stimulant drug taking in rat models of intravenous self-administration, consistent with the goals of NOSI NOT-DA-21-028. Studies proposed under Aim I will determine if binge-like acquisition of psychostimulant self-administration alters the propensity for escalated intake under extended access conditions. The goal is to understand the consequences of initial uncontrolled consumption and whether that has lasting consequences for dependence. Studies under Aim II will determine if the intra-cranial self-stimulation (ICSS) reward threshold indexes the escalation in self-administration under extended access conditions, in a novel test of a longstanding negative-reinforcement framework for understanding escalating stimulant use. Finally, investigations under Aim III will determine if alternating cathinone and methamphetamine use alters the escalation of self-administration. These novel poly-drug models will address an understudied phenomenon whereby some human stimulant users substitute drugs depending on cost and availability. In total, these proposed studies will advance our understanding of the development of dependence on psychomotor stimulant drugs.