Synaptotagmin I and IV are differentially regulated in the brain by the recreational drug 3,4-methylenedioxymethamphetamine (MDMA).

3,4-Methylenedioxymethamphetamine (MDMA or Ecstasy) is a widely abused drug. In brains of mice exposed to MDMA, we recently detected altered expression of several cDNAs and genes by using the differential display polymerase chain reaction (PCR) method. Expression of one such cDNA, which exhibited 98% sequence homology with the synaptic vesicle protein synaptotagmin IV, decreased 2 h after MDMA treatment. Herein, the effect of MDMA on expression of both synaptotagmin I and IV was studied in detail, since the two proteins are functionally interrelated. PCR analyses (semi-quantitative and real-time) confirmed that upon treatment with MDMA, expression of synaptotagmin IV decreased both in the midbrain and frontal cortex of mice. Decreases in the protein levels of synaptotagmin IV were confirmed by Western immunoblotting with anti-synaptotagmin IV antibodies. In contrast, the same exposure to MDMA increased expression of synaptotagmin I in the midbrain, a region rich in serotonergic neurons, but not in the frontal cortex. This differential expression was confirmed at the protein level with anti-synaptotagmin I antibodies. MDMA did not induce down- or up-regulation of synaptotagmin IV and I, respectively, in serotonin transporter knockout mice (-/-) that are not sensitive to MDMA. Therefore, psychoactive drugs, such as MDMA, appear to modulate expression of synaptic vesicle proteins, and possibly vesicle trafficking, in the brain.