Behavioral and neurochemical consequences of multiple MDMA administrations in the rat: role of individual differences in anxiety-related behavior.

Using the elevated plus-maze (EPM), Wistar rats can be distinguished into high (HA) or low anxiety (LA) subjects. These differences seem to reflect traits, since HA and LA rats vary also in other anxiety-dependent tasks, neurochemical mechanisms, and psychopharmacological reactivity, including lasting consequences after single treatment with 3,4-methylenedioxymethamphetamine (MDMA). Here, we tested whether multiple MDMA treatments also have subject-dependent effects. Based on routine EPM screening, male Wistar rats were divided into HA and LA sub-groups, which received five (i.e. multiple) daily injections of MDMA (5 mg/kg) or saline, followed by a test battery, including a challenge test with MDMA, a retest in the EPM, a novel-object test, and a final neurochemical analysis. Acutely, MDMA led to comparable hyperactivity in HA and LA rats. After multiple MDMA, behavioral sensitization was observed, especially in LA rats. Open arm time during the EPM retest (min 0-5) correlated with that of the initial one only in those rats, which had received a single injection of MDMA. Rats with multiple MDMA, especially LA-rats, showed more open-arm time and locomotion during the subsequent 5-10 min of the retest. In a novel-object test, rats with multiple MDMA, again especially LA subjects, showed more exploratory bouts towards the novel object. Neurochemically, multiple MDMA led to moderately lower serotonin in the ventral striatum, and higher dopamine levels in the frontal cortex as compared to single MDMA; these effects were also moderated by subject-dependent factors. Our data show that low-dosed multiple MDMA can lead to behavioral sensitization and outlasting consequences, which affect behavior in the EPM and a novel object task. Detecting such sequels partly requires consideration of individual differences.