Comparison of locomotor stimulant and drug discrimination effects of four synthetic cathinones to commonly abused psychostimulants

Background: The underground market is constantly flooded with newer synthetic as alternatives to the older cathinones. Drug Enforcement Administration (DEA) has identified four cathinone compounds of particular concern: 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (3,4-MD-α-PHP), 4-chloro-α-pyrrolidinopropiophenone (4-Cl-α-PPP), alpha-pyrrolidinoisohexiophenone (α-PiHP) and 4-chloro-pentedrone (4-Cl-pentedrone). Aims: The current study aimed to evaluate the behavioral pharmacology of four synthetic cathinones Methods: 3,4-MD-α-PHP, 4-Cl-α-PPP, α-PiHP, and 4-CPD were tested for locomotor activity in mice and in a drug discrimination assay with rats trained to discriminate either methamphetamine or cocaine. Results: Locomotor stimulant effects of 3,4-MD-α-PHP ((effective dose) ED₅₀ = 1.98 mg/kg), α-PiHP (ED₅₀ = 2.46 mg/kg), and 4-Cl-α-PPP (ED₅₀ = 7.18 mg/kg) were observed within 10 min following injection and lasted from 2 to 3.5 h. The stimulant action of 4-CPD (ED₅₀ = 17.24 mg/kg) was delayed, occurring 40–70 min following injection. The maximal motor stimulant actions of 3,4-MD-α-PHP and α-PiHP 1 were equivalent to that of cocaine and methamphetamine, whereas 4-CPD (50% of cocaine) and 4-Cl-α-PPP (73% of cocaine) were less efficacious. All of the test compounds fully substituted for the discriminative stimulus effects of cocaine, 3,4-MD-α-PHP (ED₅₀ = 2.28 mg/kg), α-PiHP (ED₅₀ = 3.84 mg/kg), and 4-Cl-α-PPP (ED₅₀ = 15.56 mg/kg). Only 3,4-MD-α-PHP (ED₅₀ = 1.65 mg/kg), α-PiHP (ED₅₀ = 1.87 mg/kg), and 4-Cl-α-PPP (ED₅₀ = 9.79 mg/kg) fully substituted for the discriminative stimulus effects of methamphetamine. 4-Cl-pentedrone caused 55–70% methamphetamine-appropriate responding at doses that also suppressed responding and produced convulsions. Conclusions: These data indicate that 3,4-MD-α-PHP, α-PiHP, and 4-Cl-α-PPP have a potential for abuse similar to that of methamphetamine and cocaine. In contrast, 4-Cl-pentedrone may not be popular for recreational use due to its convulsant effects.