Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine stimulant
drug of abuse with close structural and mechanistic similarities to
methamphetamine. One of the most powerful actions associated with
mephedrone is the ability to stimulate
dopamine (DA) release and block its re-uptake through its interaction with the
dopamine transporter (DAT). Although
mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against
methamphetamine-induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with
mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of
methamphetamine (four
injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and
tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of
methamphetamine was not prevented by any dose of
mephedrone but was, in fact, significantly enhanced. The
hyperthermia caused by combined treatment with
mephedrone and
methamphetamine was the same as seen after either
drug alone.
Mephedrone also enhanced the neurotoxic effects of
amphetamine and 3,4-methylenedioxymethamphetamine on DA nerve endings. In contrast,
nomifensine protected against
methamphetamine-induced neurotoxicity. As
mephedrone increases
methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of
mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co-abused with it, leading to heightened neurotoxicity.