Neurochemical and Cardiovascular Effects of 4-Chloro Ring-Substituted Synthetic Cathinones in Rats

Synthetic cathinones are a class of new psychoactive substances that display psychomotor stimulant properties, and novel cathi-none analogs continue to emerge in illicit drug markets worldwide. The aim of the present study was to characterize the pharmacol-ogy of 4-chloro ring-substituted cathinones that are appearing in illicit drug markets compared with the effects of 4-methylmethca-thinone (mephedrone). Synaptosomes were prepared from rat caudate for dopamine transporter (DAT) assays or from whole brain minus caudate and cerebellum for norepinephrine trans-porter (NET) and serotonin transporter (SERT) assays. Findings from transporter uptake inhibition and release assays showed that mephedrone and 4-chloromethcathinone (4-CMC) function as substrates at DAT, NET, and SERT, with similar potency at all three transporters. In contrast, 4-chloro-a-pyrrolidinopropiophe-none (4-CaPPP) was an uptake inhibitor at DAT and NET, with similar potency at each site, but had little activity at SERT. 4-Chloroethcathinone (4-CEC) was a low-potency uptake inhibitor at DAT and NET but a substrate at SERT. In rats implanted with telemetry transmitters, mephedrone and 4-CMC increased blood pressure, heart rate, and locomotor activity to a similar extent. 4-CEC and 4-CaPPP were less potent at increasing blood pres-sure and had modest stimulatory effects on heart rate and activity. 4-CMC also transiently decreased temperature at the highest dose tested. All three 4-chloro ring-substituted cathinones are biologically active, but only 4-CMC has potency comparable to mephedrone. Collectively, our findings suggest that 4-CMC and other 4-chloro cathinones may have abuse potential and adverse effects in humans that are analogous to those associated with mephedrone.

Automated summary

Synthetic cathinones, including 4-CMC and other 4-chloro analogs, are new psychoactive substances with stimulant properties and potential for abuse. These substances act on dopamine, norepinephrine, and serotonin transporters, similar to mephedrone. However, each 4-chloro analog has slightly different pharmacological effects. Mephedrone and 4-CMC are more potent in increasing blood pressure and locomotor activity compared to 4-CEC and 4-CaPPP.