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Behavioral Screening and Chiral Bioanalysis of Emerging Stimulant-Type Drugs in Rats

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This dissertation proposes a strategy to use intracranial self-stimulation (ICSS) as a behavioral screening tool to assess emerging drugs of abuse for their abuse potential to generate a proactive threat assessment.



A series of stimulant-type drugs including methcathinone, α-pyrrolidinohexanophenone (α-PHP), cocaine, and the phenyltropane analogs of cocaine WIN35428 and RTI-31 were evaluated using ICSS, and a bioanalytical method was developed to detect methcathinone and its metabolites in blood. ICSS predicted high abuse potential for methcathinone, novel methcathinone analogs, α-PHP, cocaine, and phenyltropane analogs of cocaine. The ICSS procedure was modified to account for pharmacokinetic differences resulting in different rates of drug onset and had sufficient resolution to distinguish between the rate of onset of cocaine, WIN-35428, and RTI-31. A preliminary chiral bioanalytical method was developed to quantify methcathinone and cathinone enantiomers in blood, and to qualitatively detect ephedrine, pseudoephedrine, norpseudoephedrine, phenylpropanolamine, and 4-hydroxyephedrine. Methcathinone and cathinone were detected in the blood, with a time course that correlated with the behavioral effects observed in ICSS testing and formed a counterclockwise hysteresis loop. ICSS appears to be an effective tool for an in vivo bioassay to screen emerging drugs of abuse for abuse potential, and appropriate bioanalytical methods should be developed to monitor the effectiveness of interventions. (Published abstract provided)


Date Published: January 1, 2022