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Neurotoxicity: Neuronal injury & microglia; Neuronal mechanisms of substance abuse and addiction; Serotonin & dopamine neurons: role of monoamine transporters

      This laboratory studies mechanisms of neuronal injury in two experimental models; axon terminals degenerate in one and neuronal cell bodies in the other. Histochemical methods are used to investigate serotonin (5-HT) and dopamine (DA) neuronal systems, which are of special interest due to their role in drug addiction and affective state control. Brainstem 5-HT neurons project to all parts of the forebrain and mediate the effects of stimulant & hallucinogenic drugs. We have identified two types of 5-HT neuronal projections that have distinct chemical, pharmacologic and morphologic features, and are differentially vulnerable to stimulant drugs. Hallucinogenic amphetamines that are drugs of abuse (e.g., methamphetamine, MDMA, "Ecstacy") release 5-HT from axon terminals that express the 5-HT transporter and these axons degenerate after drug treatment. The other 5-HT axon type lacks the 5-HT transporter, projects mainly to limbic system and is especially prominent in the nucleus accumbens, a region of the striatum that is involved in reward and addiction. We are presently analyzing the mechanisms of amphetamine toxicity, interactions between 5-HT and DA systems, and their role in addiction.

Injury to neuronal cell bodies and activation of glial cells are being studied with other drugs. Neurotoxic hallucinogens such as ibogaine and harmaline are useful tools for analyzing mechanisms of neuronal injury. Ibogaine, an indole alkaloid being evaluated for treatment of drug addiction, causes hallucinations and tremor, followed by excitotoxic degeneration of Purkinje cells in the cerebellum. Ibogaine produces excitation of neurons in the inferior olive; sustained bursting of olivary neurons leads to release of glutamate from climbing fiber terminals that synapse repeatedly over the surface of Purkinje cells, and leads to excitotoxic damage. We are using ibogaine as a model system to analyze mechanisms of excitotoxic injury and to develop strategies that protect against glutamate toxicity.