by Nicholas Saunders
[ Appendix 4 sec. 1 ] [ Index ] [ Appendix 4 sec. 3 ]
Appendix 4: Bibliography Biochemistry
- Elayan, I., Gibb, J.W., Hanson, G.R., Lim, H.K., Foltz, R.L. and Johnson,
M. , Short-term Effects of 2,4,5-Trihydroxyamphetamine,
2,4,5-Trihydroxymethamphetamine and 3,4-Dihydroxymethamphetamine on Central
Tryptophan Hydroxylase Acticity. J. Pharm. Exptl. Therap. 262 813-8
(1993).
- The short term effects of the three title metabolites of MDMA (THA, THM and
DHM) on tryptophan hydroxylase are reported. The first two metabolites
were quite effective, but the third (DHM) had no effect. In vitro studies
were unsuccessful in reversing these changes.
- Gibb, J.W., Hanson, G.R. and Johnson, M. Effects of
(+)-3,4-Methylenedioxymethamphetamine [(+)MDMA] and
(-)-3,4-Methylenedioxymethamphetamine [(-)MDMA] on Brain Dopamine, Serotonin, and
their Biosynthetic Enzymes. Soc. Neurosciences Abstrts. 12 169.2 (1986).
- The optical isomers of MDMA were studied in rats, as to the extent of
serotonin and dopamine depletion, and the changes in their respective
biosynthetic enzymes TPH (tryptophane hydroxylase) and TH (tyrosine
hydroxylase). The (+) was the more effective in reducing serotonin levels
at several sites in the brain, and was the more effective in reducing the
TPH levels at all sites. Striatal TH was not effected by either isomer.
- Hanson, G.R., Hanson, G.R. and Johnson, M. Effects of
(+)-3,4-Methylenedioxymethamphetamine [(+)MDMA] and
(-)-3,4-Methylenedioxymethamphetamine [(-)MDMA] on Brain Dopamine,
Serotonin, and their Biosynthetic Enzymes. Soc. Neurosciences Abstrts. 12
169.2 (1986).
- The optical isomers of MDMA were studied in rats, as to the extent of
serotonin and dopamine depletion, and the changes in their respective
biosynthetic enzymes TPH (tryptophane hydroxylase) and TH (tyrosine
hydroxylase). The (+) isomer was the more effective in reducing serotonin
levels at several sites in the brain, and was the more effective in
reducing the TPH levels at all sites. Striatal TH was not effected by
either isomer.
- Hanson, G.R., Merchant, K.M., Johnson, M., Letter, A.A., Bush, L. and Gibb,
J.W. Effect of MDMA-like Drugs on CNS Neuropeptide Systems. The Clinical,
Pharmacological and Neurotoxicological Effects of the Drug MDMA. Kluwer,
New York. (1990) Ed: S.J. Peroutka.
- An increase in both neurotensin and dynorphin in selected areas of rat
brain following single administrations of MDMA has been observed. The
ramifications of these changes are discussed.
- Johnson, M., Bush, L.G., Stone, D.M., Hanson, G.R. and Gibb, J.W. Effects
of Adrenalectomy on the 3,4-Methylenedioxymethamphetamine (MDMA)-induced
Decrease of Tryptophan Hydroxylase Activity in the Frontal Cortex and
Hippocampus. Soc. Neurosci. Abstr. 13, 464.6 (1987).
- The tryptophan hydroxylase (TPH) activity of rat frontal cortex and
hippocampus was found to decrease seven days following an acute large
dosage of MDMA. The latter area was spared enzyme loss with adrenalectomy.
- Johnson, M., Hanson, G.R. and Gibb, J.W. Effect of MK-801 on the Decrease
in Tryptophan Hydroxylase Induced by Methamphetamine and its Methylenedioxy
Analog. Europ. J. Pharmacol. 165 315-318 (1989).
- Repeated injections of methamphetamine or MDMA in rats reduced neostriatal
TPH activity. If MK-801 is administered concurrently the methamphetamine
depletion of enzyme is attenuated, but the MDMA induced depletion is not.
There may be some involvement of NMDA receptors.
- Johnson, M., Mitros, K., Stone, D.M., Zobrist, R., Hanson, G.R. and Gibb,
J.W. Effect of Flunarizine and Nimodipine on the Decrease in Tryptophan
Hydroxylase Activity Induced by Methamphetamine and
3,4-Methylenedioxymethamphetamine. J. Pharm. Exptl. Therap. 261 586-591
(1992).
- The effects of calcium channel blockers on the decrease of central
tryptophan hydroxylase activity and serotonin concentration induced by
repeated large doses of methamphetamine and MDMA were evaluated. The
results suggest that calcium influx may participate in these responses.
- Kumagai, Y., Lin, L.Y., Schmitz, D.A. and Cho, A.K. Hydroxyl Radical
Mediated Demethylenation of (Methylenedioxy)phenyl Compounds. Chem. Res.
Toxicol. 4 330-334 (1991).
- The oxidative demethylation of methylenedioxybenzene, MDA and MDMA was
achieved with two hydroxy iron-containing radical systems, one with
ascorbate and one with xanthine oxidase. Hydrogen peroxide alone was not
effective in producing the metabolite catechols.
- Kumagai, Y., Wickham, K.A., Schmitz, D.A. and Cho, A.K. Metabolism of
Methylenedioxyphenyl Compounds by Rabbit Liver Preparations. Biochem.
Pharmacol. 42 1061-1067 (1991).
- The demethyleneation of methylenedioxbenzene, MDA and MDMA is a major
metabolic pathway, and is achieved in the microcome fraction by the action
of P-450. Studies involving inducers and suppressors indicate that several
isozymes are involved in the formation of the product catechols.
- Letter, A.A., Merchant, K., Gibb, J.W. and Hanson, G.R. Roles of D2 and
5-HT2 Receptors in Mediating the Effects of Methamphetamine,
3,4-Methylenedioxymethamphetamine, and 3,4-Methylenedioxyamphetamine on
Striato-Nigral Neurotensin Systems. Soc. Neurosciences Abstrts. 12 1005 (#
277.7) 1986.
- The chronic treatment of rats with methamphetamine, MDA or MDMA leads to a
2-3x increase of the neurotensin-like immunoreactivity in the
striato-nigral areas of the brain. Efforts to assign neurotransmitter roles
led to the simultaneous administration of serotonin and dopamine
antagonists. These interrelationships are discussed.
- Merchant, K., Letter, A.A., Stone, D.M., Gibb, J.W. and Hanson, G.R.
Responses of Brain Neurotensin-like Immunoreactivity to
3,4-Methylene-dioxymethamphetamine (MDMA) and 3,4-Methylenedioxyamphetamine
(MDA). Fed. Proc. 45 1060 (# 5268) (1986).
- The administration of MDA and MDMA profoundly alters the levels of
neurotensin-like immunoreactivity (NTLI) concentrations in various portions
of the brain of the rat. Increases of up to a factor of 3x are observed in
some regions of the brain.
- Nash, J.F. and Meltzer, H.Y. Neuroendocrinological Effects of MDMA in the
Rat. The Clinical, Pharmacological and Neurotoxicological Effects of the
Drug MDMA. Kluwer, New York. (1990) Ed: S.J. Peroutka.
- MDMA has been observed to increase plasma ACTH and corticosterone
concentrations in a dose-dependent manner. A series of pharmacological
challenges suggests that serotonin release may be a responsible factor.
- Poland, R.E. Diminished Corticotropin and Enhanced Prolactin Responses to
8-Hydroxy-2-(di-n-propylamino)tetralin in Methylenedioxymethamphetamine
Pretreated Rats. Neuropharmacology 29 1099-1101 (1990).
- Pretreatment of rats with a single, modest dose of MDMA followed by a
challenge with the serotonin agonist 8-OH DPAT led to a decrease
corticotropin and an enhanced prolactin response. This suggests that MDMA
produces abnormal serotonin receptor-coupled neuroendocrine responses.
- Schmidt, C.J. and Taylor, V.L. Acute Effects of
Methylenedioxymethamphetamine (MDMA) on 5-HT Synthesis in the Rat Brain.
Pharmacologist 29 ABS-224 (1987). See also: Biochemical Pharmacology 36
4095-4102 (1987).
- Acute exposure of MDMA dropped the tryptophane hydroxylase activity of
rats, and this persisted for several days. Subsequent administration of
Fluoxetine recovered this activity, but reserpine or alpha-methyl-tyrosine
did not.
- Stone, D.M., Hanson, G.R. and Gibb, J.W. GABA-Transaminase Inhibitor
Protects Against Methylenedioxy-methamphetamine (MDMA)-induced
Neurotoxicity. Soc. Neurosci. Abstr. Vol. 13, Part 3 (1987). # 251.3.
- The neurotoxicity of MDMA (in the rat) was protected against by
GABA-transaminase inhibitors.
- Stone, D.M., Johnson, M., Hanson, G.R. and Gibb, J.W. A Comparison of the
Neurotoxic Potential of Methylenedioxyamphetamine (MDA) and its
N-methylated and N-ethylated Derivatives. Eur. J. Pharmacol. 134 245-248
(1987).
- Multiple doses of MDA and MDMA decreases the level of brain tryptophan
hydroxylase (TPH). The N-ethyl homologue was without effect. It is argued
that although the studies here were well above human exposures, the
cumulative effects of repeated exposures, the differences between rat and
human metabolism, and increased human sensitivity to this drug, could
present a serious threat to human abusers of this drug.
- Stone, D.M., Johnson, M., Hanson, G.R. and Gibb, J.W. Acute Inactivation of
Tryptophan Hydroxylase by Amphetamine Analogs Involves the Oxidation of
Sulfhydryl Sites. Europ. J. Pharmacol. 172 93-97 (1989).
- MDMA, Fenfluramine and methamphetamine, separately, reduced the tryptophan
hydroxylase activity in rat brain. The enzyme activity could be restored,
in the cases of the latter two drugs, by treatment that suggested that some
reversible oxidation of sulfhydryl groups was involved. With MDMA, the
changes were irreversible, and serotonergic toxicity is suggested.
- Stone, D.M., Stahl, D.C., Hanson, G.R. and Gibb, J.W. Effects of
3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphet-amine
(MDMA) on Tyrosine Hydroxylase and Tryptophane Hydroxylase Activity in the
Rat Brain. Fed. Proc. 45 1060 (# 5267) April 13-18, 1986.
- The effects of rats treated chronically with either MDA or MDMA on the
enzymes involved with neurotransmitter synthesis is reported. The levels of
tryptophane hydroxylase (TPH, involved with serotonin synthesis) were
markedly reduced, differently in different areas of the brain. The tyrosine
hydroxylase (TH, involved with dopamine synthesis) remains unchanged. This
is in contrast to the documented reduction of TH that follows high dosages
of methamphetamine.
- Wilkerson, G. and London, E.D. Effects of Methylenedioxymethamphetamine on
Local Cerebral Glucose Utilization in the Rat. Neuropharmacology 28
1129-1138 (1989).
- MDMA was found to influence glucose utilization at some 60 different areas in the rat brain, as determined by the employment of radioactive 2-deoxyglucose. A thorough tally has been made of these areas, and the changes that follow four different dose levels of exposure.