THC Prevents MDMA Neurotoxicity in Mice

The main psychoactive compound in cannabis, THC, can protect against brain damage caused by MDMA (ecstasy) in mice, primarily by preventing the dangerous rise in body temperature that MDMA induces. MDMA caused hyperthermia, glial activation, and loss of dopamine terminals in the striatum, especially at a warm ambient temperature of 26 degrees Celsius. THC prevented MDMA-induced hyperthermia and glial activation at both room and warm temperatures, and reversed dopamine terminal loss at the warm temperature. These protective effects were blocked by the CB1 receptor antagonist AM251 and in CB1 knockout mice, but only partially blocked by CB2 receptor antagonism or knockout, indicating that THC's neuroprotection is primarily mediated by CB1 receptor activation reducing hyperthermia, with CB2 receptors contributing to reduced neuroinflammation.

Study at a glance

Abstract

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4) were pretreated with THC (3 mg/kg x 4) at room (21 degrees C) and at warm (26 degrees C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1) receptor antagonist AM251 and the CB(2) receptor antagonist AM630, as well as in CB(1), CB(2) and CB(1)/CB(2) deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1) receptor antagonist AM251, neither in CB(1) and CB(1)/CB(2) knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2) cannabinoid antagonist and in CB(2) knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1) receptor, although CB(2) receptors may also contribute to attenuate neuroinflammation in this process.