Morris Water Maze Learning in Two Rat Strains Increases the Expression of the Polysialylated Form of the Neural Cell Adhesion Molecule in the Dentate Gyrus But Has No Effect on Hippocampal Neurogenesis

In the current study, the authors investigated whether Morris water maze learning induces alterations in hippocampal neurogenesis or neural cell adhesion molecule (NCAM) polysialylation in the dentate gyrus. Two frequently used rat strains, Wistar and Sprague–Dawley, were trained in the spatial or the nonspatial version of the water maze. Both training paradigms did not have an effect on survival of newly formed cells that were labeled 7–9 days prior to the training or on progenitor proliferation in the subgranular zone. However, the granule cell layer of the spatially trained rats contained significantly more positive cells of the polysialylated form of the NCAM. These data demonstrate that Morris water maze learning causes plastic change in the dentate gyrus without affecting hippocampal neurogenesis.

Gender differences in hyperthermia and regional 5-HT and 5-HIAA depletion in the brain following MDMA administration in rats

In the present research the role of gender in MDMA-induced hyperthermia and serotonin depletion is studied by injecting male and female male rats with MDMA or saline 3 times (i.p.) with 3 h interval at dosages of 0.3, 1, 3 or 9 mg/kg at an ambient temperature of 25 °C. The acute hyperthermia following the higher dosages was much stronger in males than in females. After the highest dose, body temperature was even raised for several days. This effect was particularly present in males where nocturnal hyperthermia persisted the whole 4-week period of sampling. Despite the differences in the acute hyperthermic response, no significant gender differences were found in 5-HT depletion 4 weeks after MDMA (9 mg/kg) administration. A striking difference was present, however, in the concentration of the 5-HT metabolite 5-HIAA after MDMA administration. In males 5-HIAA levels decreased, whereas in females this metabolite was hardly affected, suggesting a lasting increase in 5-HT turnover in females following drug administration. When genders were matched for their acute physiological hyperthermic response by repeated injection of 9 mg/kg in female rats and 6 mg/kg in male rats, 5-HT depletion was only present in females. In this experiment with matched acute physiological responses 5-HIAA levels also decreased much stronger in males, suggesting an increased 5-HT turnover in females 4 weeks after MDMA administration. In conclusion, although male rats are clearly more susceptible for the acute as well as the lasting hyperthermic effects of MDMA than females, this is not reflected in levels of 5-HT depletion following administration of similar dosages of the drug. This may indicate that, in case of a similar thermogenic response, females have a higher 5-HT neurotoxicity following MDMA than males.

Long-term neurobiological consequences of ecstasy: A role for pre-existing trait-like differences in brain monoaminergic functioning?

This study investigated whether trait-like differences in brain monoaminergic functioning relate to differential vulnerability for the long-term neurochemical depletion effects of MDMA. Genetically selected aggressive (SAL) and non-aggressive (LAL) house-mice differing in baseline serotonergic and dopaminergic neurotransmission were administered MDMA. An acute binge-like MDMA injection protocol (three times, using either of the dosages of 0, 5, 10 and 20 mg/kg i.p. with 3 h interval) was employed. Three and 28 days after treatment with MDMA induced a dose-dependent depletion of striatal dopamine and its metabolites that did not differ between SAL and LAL mice. Similarly, the dose-dependent MDMA-induced serotonergic depletion did not differ between lines 3 days after treatment. Interestingly, 28 days after MDMA in LAL mice, 5-HT and 5-HIAA levels were still significantly depleted after treatment with 3×10 mg/kg, while in SAL mice 5-HT depletion was only seen after the highest dosage. Surprisingly, LAL mice did not show any long-term 5-HT depletion after treatment with the highest dose. In conclusion, only LAL mice are able to restore initial severe loss of MDMA-evoked 5-HT and 5-HIAA levels. SAL and LAL mice are differentially susceptible for the long-term but not short-term MDMA-induced serotonergic depletion in the striatum. The differentiation between both lines in the long-term striatal serotonergic response to MDMA seems to depend on the capacity of the brain to adapt to the short-term depletion of monoaminergic levels and may somehow be related to individual, trait-like characteristics of brain monoaminergic systems.

MDMA-induced serotonergic neurotoxicity enhances aggressiveness in low- but not high-aggressive rats

Ecstasy or 3,4-methylenedioxymethamphetamine (MDMA) is a frequently (ab)used recreational drug for its acute euphoric effects but on the long-term may cause neurotoxic damage to serotonin (5-hydroxytryptamine; 5-HT) nerve endings in the brain. Since decreased brain 5-HT function has been strongly associated with several impulse control disorders like hostility and violent aggression, ecstasy users might be at risk developing this form of psychopathology. The present study examined the ability of a MDMA administration protocol (3×6 mg/kg, with 3 h intervals at 25 ºC ambient temperature), that previously was shown to partially deplete brain serotonin levels, to increase offensive aggressive behavior in male Wild-type Groningen (WTG) rats. This rat strain is known for its broad individual variation in offensive aggression. Resident-intruder aggression was assessed 5 days before and 23 days after MDMA administration. On day 28, MDMA neurotoxicity to 5-HT nerve terminals was assessed by quantification of serotonin reuptake transporter (SERT) immuno-positive axons in defined brain regions. Based on their expressed aggression level in the initial aggression test, rats were divided into low (<10% aggression), high (>50% aggression) or medium aggressive (10–50%) groups. The study demonstrated that MDMA treatment increased aggressiveness in only low aggressive rats and not in medium and high aggressive animals. Irrespective of their initial aggressiveness, MDMA significantly reduced the number of SERT-positive axons in all animals. In conclusion, vulnerability for increased aggression long after a single MDMA treatment is dependent on the individual's trait aggressiveness but not on the degree of MDMA-induced serotonergic neurotoxicity.

Social stress during adolescence in Wistar rats induces social anxiety in adulthood without affecting brain monoaminergic content and activity

Adolescence has been described as an important period to acquire social competences required for adult life. It has been suggested that early stress experiences could affect the development of the brain at different levels. These changes in the brain during adolescence may be related with the development of psychopathologies such as depression and social anxiety in adulthood. In the first experiment, we examined long-term effects of repeated social stress during adolescence on adult social approach–avoidance behavior. For that purpose, adolescent male Wistar rats were exposed twice at postnatal day (Pnd) 45 and Pnd48 to the resident–intruder paradigm followed by three times psychosocial threat with the same resident. Three weeks after the last psychosocial threat experience the animals were behaviorally tested in a social approach–avoidance test. Socially stressed animals spent less time in the interaction zone with an unfamiliar male adult rat. These data suggest that animals exposed to social stress during adolescence show a higher level of social anxiety in adulthood. In the second experiment, we investigated whether these long-term effects of social stress during adolescence on behavior draw a parallel with changes in brain monoamine content, biosynthesis and turnover. Using the same experimental design as in the first experiment, HPLC analysis of various brain regions showed that there were no differences in monoamine content, monoamine biosynthesis and monoamines activity in the prefrontal cortex, hippocampus, hypothalamus and striatum in adulthood. These results indicate that long-lasting changes in social behavior following social stress during adolescence are not accompanied by changes in brain monoamine content, biosynthesis and turnover.