MDMA 'ecstasy' increases cerebral cortical perfusion determined by bolus-tracking arterial spin labelling (btASL) MRI.

BACKGROUND AND PURPOSE: The purpose of this study was to assess cerebral perfusion changes following systemic administration of the recreational drug 3,4-methylendioxymethamphetamine (MDMA 'ecstasy') to rats. EXPERIMENTAL APPROACH: Cerebral perfusion was quantified using bolus-tracking arterial spin labelling (btASL) MRI. Rats received MDMA (20 mg·kg(-1); i.p.) and were assessed 1, 3 or 24 h later. Rats received MDMA (5 or 20 mg·kg(-1); i.p.) and were assessed 3 h later. In addition, rats received MDMA (5 or 10 mg·kg(-1); i.p.) or saline four times daily over 2 consecutive days and were assessed 8 weeks later. Perfusion-weighted images were generated in a 7 tesla (7T) MRI scanner and experimental data was fitted to a quantitative model of cerebral perfusion to generate mean transit time (MTT), capillary transit time (CTT) and signal amplitude. KEY RESULTS: MDMA reduces MTT and CTT and increases amplitude in somatosensory and motor cortex 1 and 3 h following administration, indicative of an increase in perfusion. Prior exposure to MDMA provoked a long-term reduction in cortical 5-HT concentration, but did not produce a sustained effect on cerebral cortical perfusion. The response to acute MDMA challenge (20 mg·kg(-1); i.p.) was attenuated in these animals indicating adaptation in response to prior MDMA exposure. CONCLUSIONS AND IMPLICATIONS: MDMA provokes changes in cortical perfusion, which are quantifiable by btASL MRI, a neuroimaging tool with translational potential. Future studies are directed towards elucidation of the mechanisms involved and correlating changes in cerebrovascular function with potential behavioural deficits associated with drug use.

Combining exercise and cyclooxygenase-2 inhibition does not ameliorate learning deficits after brain insult, despite an increase in BDNF levels.

Neurodegeneration can produce behavioral impairments. Previously, we have found that inhibition of cyclooxygenase-2 activity or physical activity was neuroprotective during kainic-acid-induced neural loss. Here, we investigated the combined effect of exercise pre-insult and cyclooxygenase inhibitor treatment post-kainate-induced brain damage. However, in spite of an increase in BDNF levels, the combination did not improve behavioral performance in Morris watermaze and object exploration tasks.

Exercise, but not environmental enrichment, improves learning after kainic acid-induced hippocampal neurodegeneration in association with an increase in brain-derived neurotrophic factor.

Previous studies have suggested that exercise in a running wheel can be neuroprotective, perhaps due to, among others, gene-expression changes after exercise, increases in trophic proteins and/or enhanced cardiovascular responsivity. Here we ask whether physical exercise or environmental enrichment provide protection after brain damage, especially in terms of recovery of cognitive function. To evaluate the neuroprotective effect of these conditions, we used the kainic acid (KA) model of neuronal injury. Systemically-administered KA induces excitotoxicity by overstimulation of glutamate receptors, resulting in neuronal death by necrosis and apoptosis. Our results show that exercise, but not enriched environment, prior to KA-induced brain damage, improved behavioural performance in both Morris watermaze and object exploration tasks. However, prior exercise did not decrease to control levels the hyperactivity normally seen in KA-treated animals, as measured by ambulation in the open field. Furthermore, both exercise and enriched environment did not protect against neuron loss in CA1, CA2 and CA3 areas of the hippocampus, despite a substantial increase in brain-derived neutrophic factor (BDNF) levels in dentate gyrus of the exercise and KA-treated animals.

Impact of enriched-environment housing on brain-derived neurotrophic factor and on cognitive performance after a transient global ischemia.

Environmental enrichment promotes structural and functional changes in the brain, including enhanced learning and memory performance in rodents. Transient global cerebral ischemia (15 min) causes specific damage to dorsal hippocampal area CA1 pyramidal cells of the rat concomitantly with cognitive deficits. Thus, we investigated if environmental enrichment can protect rats against the cognitive and neurological consequences of transient ischemia. We evaluated the impairment of learning and memory with three tasks: odour discrimination, object exploration and spatial learning. Contrary to expectation, we found that the enriched environment improved performances for both ischemic and sham rats in odour discrimination and object exploration tasks compared with standard condition housed rats. After exposure to an enriched environment, ischemic rats performed better in the water maze than those in the standard housing conditions. However, exposure to an enriched environment does not protect against actual loss of CA1 pyramidal cells. Brain-derived neurotrophic factor (BDNF) levels were increased in environmental enrichment animals compared to those housed in standard conditions. We conclude that environmental enrichment has positive effects that are independent of the effects of ischemic brain lesions.

Post-treatment, but not pre-treatment, with the selective cyclooxygenase-2 inhibitor celecoxib markedly enhances functional recovery from kainic acid-induced neurodegeneration.

We have investigated the role of inflammation in the excitotoxicity induced by overstimulation of glutamate receptors using kainic acid, an important tool for studying functions related to excitatory amino acid transmission and for producing neuronal death, especially in areas CA1 and CA3 of the hippocampus. We hypothesised that by inhibiting one of the major components of the neuroinflammation response, after kainic acid injection, that there would be less inflammation and therefore a reduction in cell loss, an enhancement of cognitive function (using spatial learning and object exploration tasks) or both. We examined brain-derived neurotrophic factor levels, expecting that there would be a correlation between its level and subsequent recovery. Our results confirmed our hypothesis: the kainic acid injected-rats treated with celecoxib (after kainic injection) performed better in the spatial and non-spatial tasks than the kainic acid-treated group. However, there was not any improvement if celecoxib was given before kainic acid treatment, underlining also the importance of the production of prostaglandin at the beginning of inflammation.