Fig. 5

A Schematic Representation of MDMA’s Sites of Action in Hippocampus. This figure summarizes the effects of a single-dose (15 mg/kg, intraperitoneal) of 3,4-methylenedioxymethamphetamine (MDMA) 3 weeks earlier on hippocampal neurons in Dark Agouti rats. White circles represent molecular events explained in this legend. Based on current knowledge, neuronal long-term potentiation (LTP) would be initiated by glutamate release from synaptic vesicles (1) and their binding to NMDA-type glutamate receptors, which after activated, let Ca2+ flow into the cells (2). The elevated intracellular Ca-levels, on one hand, cause endocannabinoid synthesis acting as a negative feedback mechanism via cannabinoid 1 (CB1) receptors (3), while on the other hand, activate calcium/calmodulin dependent kinase II (CaMK II) and induce autoactivation of the enzyme (4). The active CaMK II molecules phosphorylate intracellular targets, thereby activating Rho GTPases (5) to induce changes in synaptic membrane morphology (6) and, thereby, let AMPA glutamate receptors be expressed in postsynaptic membranes (7). The newly recruited AMPA receptors may react to presynaptic glutamate release causing elevated excitability upon repeated stimuli and a strengthening of synaptic transmission. Downregulations caused by the single-dose administration are marked by blue numbers and show that besides of decreased mRNA levels found in our study in the subunits of the LTP-members (which was supported by downregulations in regulation of synaptic plasticity, cognition and memory gene sets), the drug also induced downregulation in Eph receptors, which may be responsible for direct cell-cell contacts in synapses. These changes indicate that the connectivity and thus, hippocampal neuronal network functions might be damaged as a consequence of the administration of the drug. Please, note, changes represent mRNA level up/downregulations, no protein levels were measured. See text for further details