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Tryptophan

LNAA. 5-HT1 A. 5-HT1 A. TPH. AADC. 5-HIAA. MAO. 5-HT. 5HT. 5-HT1 B. SERT. 5-HT2 C. 5-HT2 A. 5-HT1 B. Tryptophan. Presynaptic. Tryptophan. 5-HTP. 5-HT. 5-HT. 5-HT. Postsynaptic. ”Criteria for Assessing Neurotoxicity: Is 2’-NH 2 -MPTP a Serotonergic Neurotoxin?".

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Tryptophan

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  1. LNAA 5-HT1A 5-HT1A TPH AADC 5-HIAA MAO 5-HT 5HT 5-HT1B SERT 5-HT2C 5-HT2A 5-HT1B Tryptophan Presynaptic Tryptophan 5-HTP 5-HT 5-HT 5-HT Postsynaptic

  2. ”Criteria for Assessing Neurotoxicity:Is 2’-NH2-MPTP aSerotonergic Neurotoxin?"

  3. 2’-NH2-MPTP is Unique Among Ortho-substituted Analogs of MPTP

  4. NH2 CH3 NH2 NHCH3 Cl PCA CH3 CH3 Methamphetamine Amphetamine NHCH2CH3 CH3 CF3 NH2 NHCH3 O O Fenfluramine CH3 CH3 O O MDMA MDA “Ecstasy” Substituted Amphetamines

  5. PSYCHOPHYSIOLOGICAL FUNCTIONS INFLUENCED BY SEROTONIN • Affect & Anxiety Emesis • Aggression/Impulse Control Endocrine Regulation • Appetite/Satiety GI Function • Cardiovascular Function Motor Activity • Circadian Rhythms/Sleep Pain • Cognitive Function Sexual Activity

  6. NEUROPSYCHIATRIC DISORDERS IN WHICH SEROTONERGIC DYSFUNCTION IS IMPLICATEDUnipolar Affective DisorderSimple PhobiasSocial PhobiaGeneralized Anxiety DisorderPanic Disorder/AgoraphobiaObsessive-Compulsive DisorderTrichotillomaniaAddiction Anorexia NervosaAutism BulimiaAlcoholism ObesityMigrainePremenstrual SyndromeAggression Epilepsy

  7. NEUROCHEMICAL TECHNIQUESBrain neurotransmitter levelsIn vivo MicrodialysisIn vivo VoltammetryBiosensors: 5-HT, O2-Brain Imaging: AutoradiographyImmunohistochemistryPositron Emission TomographyProteomicsGENETIC ALTERATIONS NEUROTOXINSTransgenic mice2’-NH2-MPTPKnock-out mice MDMAInducible knock-outs FenfluramineROLE OF 5-HT IN NORMAL/ALTERED FUNCTION

  8. Criteria for Assessing Drug-induced Degeneration of Serotonergic Neurons • Decreased regional 5-HT & 5-HIAA levels • Decreases in TPH activity • Decreases in [3H]5-HT uptake • Demonstration of swollen immunoreactive axons and subsequent decrease in fiber density • Decreases in the density of radiolabeled SERT • GFAP • Cuprous silver degeneration stain • Functional changes • TIME-RELATED DIMENSION Serotonin: From Cell Biology to Pharmacology & Therapeutics, Battaglia, G. (1990)

  9. Degenerated Neurons in the Dorsal Raphe Nucleus48 Hours After 2’-NH2-MPTP

  10. Criteria for Assessing Drug-induced Degeneration of Serotonergic Neurons • Decreased regional 5-HT & 5-HIAA levels • Decreases in TPH activity • Decreases in [3H]5-HT uptake • Demonstration of swollen immunoreactive axons and subsequent decrease in fiber density • Decreases in the density of radiolabeled SERT • GFAP • Cuprous silver degeneration stain • Functional changes • TIME-RELATED DIMENSION Serotonin: From Cell Biology to Pharmacology & Therapeutics, Battaglia, G. (1990)

  11. CONTRIBUTORS • Dennis Murphy (NIMH) • David Jacobowicz (NIMH) • Jean Lud Cadet (NIDA) • Bruce Ladenheim (NIDA) • Douglas Sheridan (PSU) • Erica Unger (PSU) • Francesca Coppelli (PSU)

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