The objective of this proposal, which extends our ongoing studies, is to characterize the neurotoxicity of psychotropic drugs upon serotonergic neurons. These studies will employ primarily anatomic methods to characterize the response of neurons to drug-induced injury, to identify the neuronal compartment that is damaged, and to correlate anatomic and biochemical parameters of toxicity. These experiments should identify the sites at which mood-altering drugs act, clarify the mechanisms of drug toxicity, and evaluate criteria to study the neurotoxic effects of drugs. A central issue is to evaluate structural evidence for neurotoxic drug effects in order to provide definitive evidence for neuronal injury and to determine the extent of damage.
The aims are: I. Further characterize the structural damage to serotonergic neurons produced by 3,4-methylenedioxy- amphetamine (MDA) and related amphetamine derivatives: A. identify the intact proximal segment of raphe axons and test the hypothesis that degeneration is restricted to axon terminals using anterograde axonal transport; B. determine the response of raphe cell bodies to injury using high resolution light and electron microscopy; C. analyze 5-HT reinnervation after MDA treatment and determine the properties of sprouting 5-HT axons. R. Characterize the binding of neurotoxic drugs to the 5-HT uptake carrier, and determine whether different uptake sites are associated with two classes of 5-HT axons that are differentially vulnerable to these drugs. III. Analyze the correlation between anatomic and biochemical parameters of neurotoxicity in the same animals. IV. The effects of drugs on 5-HT neurons in the myenteric plexus will be studied to determine whether they show toxic effects similar to those in the brain. V. Prenatal administration of amphetamine derivatives and enkephalins will be employed to study their effects on serotonin neuron development and possible secondary effects on forebrain development in the perinatal period. The proposed studies should provide new information regarding the mechanisms of drug-induced neurotoxicity, the potential for regeneration, and drug effects during pregnancy. These studies should also provide new tools, applicable to man and other primates, for assessing the neurotoxicity of drugs of abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Johns Hopkins University
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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
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
Wilson, M A; Molliver, M E (1991) The organization of serotonergic projections to cerebral cortex in primates: regional distribution of axon terminals. Neuroscience 44:537-53

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