The goals of this project are to characterize the neurotoxic effects of substituted amphetamines (MDA and MDMA) upon CNS monoaminergic neurons. The hypothesis will be tested that the toxic effects of these drugs are due to the formation of a hepatic metabolite. The potential for regenerative sprouting and recovery of damaged serotonin axons will be determined. A method will be developed to test the toxicity of metabolites derived from hepatic microsomal incubations. 1) To characterize the neurotoxic effects, immunocytochemistry will be used to visualize degenerating and spared monoamine axons; changes in neurotransmitter levels will be determined by HPLC. Different doses will be studied to determine the dose-response curve and to identify the specific neuronal compartment damaged. Regional effects will be studied in forebrain, brainstem and spinal cord to determine the specificity of the toxic effect on serotonin axons and to identify raphe cell groups and axon types that may be spared. The cells of origin of damaged versus spared serotonin axons will be identified by axonal transport methods. The results obtained from the rat will be used to guide similar studies of neurotoxicity in primates. 2) It is essential to resolve whether the neurotoxic effects of systemic MDA are due to a metabolite or may be secondary to hyperthermia or cardiovascular changes. To show that the parent compound is not directly neurotoxic, sustained intracerebral doses of the drugs will be administered by a chronic implanted cannula and minipump. 3) To study the potential for sprouting and recovery of damaged axons, immunocytochemistry and HPLC will be done following long survivals; axon transport methods will be used to determine which cell groups give rise to regenerating axons. 4) Identification of the toxic class of metabolites will be attempted by intracerebral microinjection of extracts from hepatic microsomal incubations of the drugs. These studies should characterize the mechanism, conditions, and specificity of neurotoxicity caused by substituted amphetamines that have become widely used as drugs of abuse. Moreover, if safe conditions and doses can be identified, these drugs may be useful in psychotherapy. Because of widespread abuse among college and professional groups, these drugs constitute a major and serious health hazard to young Americans; their dramatic neurotoxicity needs to be established definitively and publicized educationally.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA004431-01
Application #
3210055
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1987-07-01
Project End
1990-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Brown, P; Molliver, M E (2000) Dual serotonin (5-HT) projections to the nucleus accumbens core and shell: relation of the 5-HT transporter to amphetamine-induced neurotoxicity. J Neurosci 20:1952-63
Schell, M J; Brady Jr, R O; Molliver, M E et al. (1997) D-serine as a neuromodulator: regional and developmental localizations in rat brain glia resemble NMDA receptors. J Neurosci 17:1604-15
Ruat, M; Molliver, M E; Snowman, A M et al. (1995) Calcium sensing receptor: molecular cloning in rat and localization to nerve terminals. Proc Natl Acad Sci U S A 92:3161-5
Wilson, M A; Molliver, M E (1994) Microglial response to degeneration of serotonergic axon terminals. Glia 11:18-34
Wilson, M A; Mamounas, L A; Fasman, K H et al. (1993) Reactions of 5-HT neurons to drugs of abuse: neurotoxicity and plasticity. NIDA Res Monogr 136:155-78;discussion 178-87
Axt, K J; Mullen, C A; Molliver, M E (1992) Cytopathologic features indicative of 5-hydroxytryptamine axon degeneration are observed in rat brain after administration of d- and l-methylenedioxyamphetamine. Ann N Y Acad Sci 648:244-7
Berger, U V; Grzanna, R; Molliver, M E (1992) The neurotoxic effects of p-chloroamphetamine in rat brain are blocked by prior depletion of serotonin. Brain Res 578:177-85
Ricaurte, G A; Molliver, M E; Martello, M B et al. (1991) Dexfenfluramine neurotoxicity in brains of non-human primates. Lancet 338:1487-88
Mamounas, L A; Mullen, C A; O'Hearn, E et al. (1991) Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5-HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives. J Comp Neurol 314:558-86
Axt, K J; Molliver, M E (1991) Immunocytochemical evidence for methamphetamine-induced serotonergic axon loss in the rat brain. Synapse 9:302-13

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