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A strategy to prioritize emerging drugs of abuse for analysis: Abuse liability testing using intracranial self-stimulation (ICSS) in rats and validation with α-pyrrolidinohexanophenone (α-PHP)

NCJ Number
Date Published
8 pages

The goal of the reported study was to illustrate the potential of intracranial self-stimulation (ICSS) for assessing novel psychoactive substances (NPS) by testing the synthetic cathinone α-pyrrolidinohexanophenone (α-PHP) and comparing it to a well-known abused stimulant, cocaine.


NPS threaten public health and safety, so their composition, the nature of their effects, and the prevalence of their use must be determined, which strains the limited resources of forensic laboratories. In order to efficiently use the forensic laboratory resources available, the current project tested a new strategy for prioritizing NPS with abuse liability testing that used a preclinical behavioral procedure in rats known as intracranial self-stimulation (ICSS). In validating this assay, the recently scheduled synthetic cathinone α-PHP was compared to cocaine, a mechanistically similar drug of abuse, as a positive control and saline as a negative control. Six male Sprague-Dawley rats were implanted with electrodes that targeted the medial forebrain bundle. The rats were trained to respond by lever-press for electrical brain stimulation. The rats were tested with doses of 0.32, 1.0, and 3.2 mg/kg α-PHP as well as 10 mg/kg of cocaine and saline administered by intraperitoneal injection. Neither saline nor 0.32 mg/kg α-PHP altered ICSS response rates compared to baseline levels of responding; however, doses of 1.0 and 3.2 mg/kg α-PHP and 10 mg/kg cocaine facilitated ICSS responding. This ICSS profile suggests that α-PHP has high abuse potential, with a rapid onset of effects and a long duration of action, supporting the decision to schedule this compound. This study thus demonstrates the ability of ICSS to distinguish between compounds of low and high potential for abuse and threat to the abuser. A strategy is proposed for screening NPS by using ICSS and classifying emerging drugs into four priority categories for further analysis. 5 figures and 55 references

Date Published: January 1, 2021