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

• Published in: Neuroscience Vol. 92; no. 3; pp. 1011 - 1023
• Main Authors: Stephenson, C.P., Hunt, G.E., Topple, A.N., McGregor, I.S.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-01-1999; Elsevier
• Subjects: 5-HT; Animals; Biological and medical sciences; Brain - drug effects; Brain - metabolism; c-fos; c-fos gene; dopamine; Drug addictions; Ecstasy; Immunohistochemistry; Male; MDMA; Medical sciences; Motor Activity - drug effects; N-Methyl-3,4-methylenedioxyamphetamine - pharmacology; Proto-Oncogene Proteins c-fos - metabolism; rat; Rats; Rats, Wistar; Serotonin - metabolism; Serotonin Agents - pharmacology; Tissue Distribution - physiology; Toxicology; Ecstasy; PVN, paraventricular nucleus of the hypothalamus; SON, supraoptic nucleus; PNO, pontine reticular nucleus oralis; rat; NAS, nucleus accumbens septi; c-fos; PCA, p-chloroamphetamine; MDMA; ADH, antidiuretic hormone; PB, phosphate buffer; PBS, phosphate-buffered saline; MPO, median preoptic nucleus; CEA, central nucleus of the amygdala; BNST, bed nucleus of the stria terminalis; 5-HT; 5-HT, 5-hydroxytryptamine; MPC, medial prefrontal cortex; dopamine; MDMA, 3,4-methylenedioxymethamphetamine, “Ecstasy”; PBH, phosphate-buffered horse serum; Amphetamine derivatives; Dopamine; Rat; Serotonin; Rodentia; Central nervous system; Gene expression; Locomotion; Vertebrata; Mammalia; Animal; Distribution; Drug of abuse; Protooncogene; Brain (vertebrata); Immediate early gene
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(99)00049-4

Rats were injected with 3,4-methylenedioxymethamphetamine (“Ecstasy”) and assessed for changes in locomotor activity and for the expression of the immediate early gene
c-fos throughout the brain. A dose-dependent increase in locomotor activity was seen with 3,4-methylenedioxymethamphetamine (0, 5 and 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, forebrain, brainstem and cerebellum in rats given 3,4-methylenedioxymethamphetamine. Expression was pronounced in 5-hydroxytryptamine terminal regions including the medial prefrontal cortex, caudate–putamen, nucleus accumbens, olfactory tubercle, islands of Calleja, lateral septum, paraventricular hypothalamus and paraventricular thalamus. High levels of
c-fos expression were 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 users have been linked to hyperthermia and hyponatremia. In the brainstem, two regions of high
c-fos expression were Barrington's nucleus, which is involved in micturition, and the pontine reticular nucleus oralis, a region involved 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 the cerebellum, particularly in the flocculus, and this may explain the reported deleterious effects of 3,4-methylenedioxymethamphetamine on balance and co-ordination. Significant
c-fos expression was also seen in the ventral tegmental area, amidst the cell bodies of mesolimbic and mesocortical dopamine neurons, and in the median and dorsal raphe, where the serotonergic innervation of the forebrain originates. Double-labelling of fos-positive neurons with 5-hydroxytryptamine showed that only a small number of serotonergic neurons in the raphe expressed
c-fos following 3,4-methylenedioxymethamphetamine.
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.