Sustained MDMA-induced inhibition of tryptophan hydroxylase activity leads to the long term cerebral 5-HT loss   1V. Sanchez, 1E. O'Shea, 1I. Escobedo, 1J. Camarero, 1L. Orio, 2A.R. Green & 1M.I. Colado. 1Dept. Farmacol., F. Medicina, Univ. Complutense, 28040 Madrid, Spain & 2School of Pharmacy, De Montfort Univ., Leicester, LE1 9BH.

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Administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') to rats produces an acute hyperthermic response and a long-term degeneration of 5-HT nerve endings reflected in a loss of several brain 5-HT markers (Green et al., 1995). Hyperthermia appears to play a key role in the reduction of 5-HT nerve endings since its prevention attenuates or abolishes the decrease in indole content and 5-HT transporter (5-HTT) density (Colado et al., 1998). Nevertheless, the relationship between the hyperthermic response and the long-lasting reduction in tryptophan hydroxylase (TPH) activity induced by MDMA is unknown. We have now examined the effect of MDMA on brain TPH activity of rats maintained at 22ºC and 4ºC during the time of drug administration. The content of 5-HT and the density of 5-HTT were also determined in order to evaluate whether changes induced by MDMA at the two room temperatures occur in a parallel way.

Male Dark Agouti rats (175-200g) housed at a room temperature of 22ºC or 4ºC received MDMA (12.5 mg kg^-1, i.p.) or saline. Rats were housed in these conditions 4 h before injecting MDMA and maintained in them for 6 h after treatment. Rectal temperature was measured throughout. Animals were sacrificed 7 days later. The concentration of 5-HT in cortex, hippocampus and striatum and the density of 5-HTT in cortex were determined by h.p.l.c and [³H]paroxetine binding, respectively. TPH activity was measured as the accumulation of 5-hydroxytryptophan (5-HTP) in the brain after inhibition of aromatic L-amino acid decarboxylase by NSD 1015 (100 mg kg^-1, i.p.) given 30 min before killing (Kokoshka et al., 2000). 5-HTP levels were determined by h.p.l.c.

Rats maintained at 22ºC showed a hyperthermic response immediately after MDMA administration, in contrast to those kept at 4ºC where hyperthermia was totally abolished, and a transitoryhypothermia produced. Administration of MDMA at 22ºC and 4ºC induced a significant decrease in TPH activity and 5-HT concentration, the effect being significantly less in the cortex (Table 1) and hippocampus but not in striatum of animals maintained at 4ºC. In contrast, the density of 5-HTT although decreased in the cortex of rats maintained at 22ºC, was not altered in those kept at 4ºC.

These findings indicate that a reduction in the ambient temperature produces a parallel attenuation of the MDMA-induced decrease in cortical 5-HT concentration and TPH activity but completely prevents the reduction in 5-HT uptake sites produced by the drug. Therefore, this suggests that the long-term depletion in 5-HT content induced by MDMA may be a consequence of a persistent decrease of 5-HT synthesis due to a reduction in TPH activity and not necessarily to a loss of 5-HT terminals, 7 days after administration.

Table 1. Changes (%) in cortical tryptophan hydroxylase (TPH) activity, 5-HT levels and 5-HT transporter (5-HTT) density induced by MDMA 7 days after administration. Results shown as mean ± s.e.mean, n= 6-7. Different from the corresponding saline-treated group: ^aP<0.05, ^bP<0.01,^cP<0.001. Different from MDMA given at 22ºC: *P<0.05.

Colado, M.I. et al., (1998) Br. J. Pharmacol. 124: 479-484.
Green, A.R. et al., (1995) Psychopharmacology 119, 246-260.
Kokoshka, J.M. et al., (2000) J. Neurochem. 75, 2095-2102.

M.I.C. thanks MCYT (SAF2001-1437) and FIS.