New designer phenethylamines 2C-C and 2C-P have abuse potential and induce neurotoxicity in rodents.

The drugs 2C-C and 2C-P, members of the 2C family of phenethylamines, show abuse potential and neurotoxic effects at high doses in animal models. In mice, both drugs produced conditioned place preference in a dose-dependent manner and increased self-administration in rats, indicating abuse potential. High doses decreased locomotor activity, rota-rod performance, and scores on memory tests (Y-maze, novel object recognition, passive avoidance). The drugs altered expression of D1 and D2 dopamine receptors, the dopamine transporter, and its phosphorylated form in the nucleus accumbens and medial prefrontal cortex, and increased c-Fos-positive cells in the nucleus accumbens. High doses also activated microglia, suggesting neuroinflammation in the striatum.

Study at a glance

Abstract

2C (2C-x) is the general name for the family of phenethylamines containing two methoxy groups at the 2 and 5 positions of the benzene ring. The abuse of 2C family drugs has grown rapidly, although the abuse potential and neurotoxic properties of 2C drugs have not yet been fully investigated. In this study, we investigated the abuse potential and neurotoxicity of 4-chloro-2,5-dimethoxyphenethylamine (2C-C) and 2,5-dimethoxy-4-propylphenethylamine (2C-P). We found that 2C-C and 2C-P produced conditioned place preference in a dose-dependent manner in mice, and increased self-administration in rats, suggesting that 2C-C and 2C-P have abuse potential. To investigate the neurotoxicity of 2C-C and 2C-P, we examined motor performance and memory impairment after high doses of 2C-C and 2C-P. High doses of 2C-C and 2C-P decreased locomotor activity, rota-rod performance, and lower Y-maze test, novel objective recognition test, and passive avoidance test scores. We also observed that 2C-C and 2C-P affected expression levels of the D1 dopamine receptor, D2 dopamine receptor, dopamine transporter, and phospho-dopamine transporter in the nucleus accumbens and the medial prefrontal cortex, and increased c-Fos immuno-positive cells in the nucleus accumbens. Moreover, high doses of 2C-C and 2C-P induced microglial activation, which is involved in the inflammatory reaction in the striatum. These results suggest that 2C-C and 2C-P have abuse potential by affecting dopaminergic signaling and induce neurotoxicity via initiating neuroinflammation at high doses.