NEUROTOXIC EFFECTS OF DRUGS ON SEROTONERGIC NEURONS

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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.