The distribution of 3,4-methylenedioxymethamphetamine "Ecstasy"-induced c-fos expression in rat brain

Rats were injected with 3,4-methylenedioxymethamphetamine ("Ecstasy") and a ssessed for changes in locomotor activity and for the expression of the imm ediate early gene c-fos throughout the brain. A dose-dependent increase in locomotor activity was seen with 3,4-methylenedioxymethamphetamine (0, 5 an d 20 mg/kg) that continued for at least 2 h following administration. Dose- dependent increases in c-fos expression were seen in much of the cortex, fo rebrain, brainstem and cerebellum in rats given 3,4-methylenedioxymethamphe tamine. Expression was pronounced in 5-hydroxytryptamine terminal regions i ncluding the medial prefrontal cortex, caudate-putamen, nucleus accumbens, olfactory tubercle, islands of Calleja, lateral septum, paraventricular hyp othalamus and paraventricular thalamus. High levels of c-fos expression wer e also seen in the supraoptic and median preoptic nuclei, regions involved in the control of fluid balance and body temperature, respectively. This is potentially important since deaths in 3,4-methylenedioxymethamphetamine us ers have been linked to hyperthermia and hyponatremia. In the brainstem, tw o regions of high c-fos expression were Barrington's nucleus, which is invo lved in micturition, and the pontine reticular nucleus oralis, a region inv olved in motor control of mastication. Activation of this latter structure may partly explain the bruxism (grinding of the jaw) reported by human 3,4- methylenedioxymethamphetamine users. Robust c-fos expression was seen in th e cerebellum, particularly in the flocculus, and this may explain the repor ted deleterious effects of 3,4-methylenedioxymethamphetamine on balance and co-ordination. Significant c-fos expression was also seen in the ventral t egmental area, amidst the cell bodies of mesolimbic and mesocortical dopami ne neurons, and in the median and dorsal raphe, where the serotonergic inne rvation of the forebrain originates. Double-labelling of fos-positive neuro ns with 5-hydroxytryptamine showed that only a small number of serotonergic neurons in the raphe expressed c-fos following 3,4-methylenedioxymethamphe tamine. The widespread distribution of 3,4-methylenedioxymethamphetamine-induced c- fos expression seen in this study can be linked to the profound alterations in physiological function, mood and behaviour produced by this drug. (C) 1 999 IBRO. Published by Elsevier Science Ltd.