Tryptophan

5-HTP

5-HT

5-HT5-HT

SERT

5HT5HT

5-HT15-HT1BB5-HT25-HT2CC

PostsynapticPostsynaptic

5-HT25-HT2AA

Tryptophan

MAOMAO

5-HIAA

5-HT15-HT1AA

5-HT15-HT1BB

5-HT15-HT1AA

5-HT5-HT

5-HT5-HT

TPHTPH

AADCAADC

PresynapticPresynapticLNAALNAA

””Criteria for Assessing Criteria for Assessing Neurotoxicity:Neurotoxicity:

Is 2’-NHIs 2’-NH22-MPTP a-MPTP aSerotonergic Neurotoxin?"Serotonergic Neurotoxin?"

2’-NH2’-NH22-MPTP is Unique Among Ortho--MPTP is Unique Among Ortho-substituted Analogs of MPTPsubstituted Analogs of MPTP

2'-substituted-MPTP's (X = -CH3, -CH3CH2, -Cl, -OCH3, -CH2F, -F, -CF3)

N

CH3

X

2'-NH2-MPTP

N

CH3

NH2

Substituted Amphetamines

NH2

CH3

Amphetamine

NHCH3

CH3

Methamphetamine

O

O

NH2

CH3

MDA

O

O CH3

NHCH3

MDMA“Ecstasy”

Cl

NH2

CH3

PCA

CF3

NHCH2CH3

CH3

Fenfluramine

PSYCHOPHYSIOLOGICAL FUNCTIONS PSYCHOPHYSIOLOGICAL FUNCTIONS INFLUENCED BY SEROTONININFLUENCED 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

NEUROPSYCHIATRIC DISORDERS IN WHICH NEUROPSYCHIATRIC DISORDERS IN WHICH SEROTONERGIC DYSFUNCTION IS IMPLICATEDSEROTONERGIC DYSFUNCTION IS IMPLICATED

Unipolar Affective Disorder

Simple PhobiasSocial Phobia

Generalized Anxiety DisorderPanic Disorder/Agoraphobia

Obsessive-Compulsive DisorderTrichotillomania

Addiction Anorexia NervosaAutism BulimiaAlcoholism Obesity

MigrainePremenstrual Syndrome

Aggression Epilepsy

NEUROCHEMICAL TECHNIQUESNEUROCHEMICAL TECHNIQUESBrain neurotransmitter levels

In vivo MicrodialysisIn vivo VoltammetryBiosensors: 5-HT, O2

-

Brain Imaging: AutoradiographyImmunohistochemistry

Positron Emission TomographyProteomics

GENETIC ALTERATIONSGENETIC ALTERATIONS NEUROTOXINSNEUROTOXINSTransgenic mice 2’-NH2-MPTP

Knock-out mice MDMAInducible knock-outs Fenfluramine

ROLE OF 5-HT IN NORMAL/ALTERED FUNCTIONROLE OF 5-HT IN NORMAL/ALTERED FUNCTION

Serotonin: From Cell Biology to Pharmacology & Therapeutics, Battaglia, G. (1990)

Criteria for Assessing Drug-induced Criteria for Assessing Drug-induced Degeneration of Serotonergic Degeneration of Serotonergic

NeuronsNeurons

• Decreased regional 5-HT & 5-HIAA levelsDecreased regional 5-HT & 5-HIAA levels

• Decreases in TPH activityDecreases in TPH activity

• Decreases in [Decreases in [33H]5-HT uptakeH]5-HT uptake

• Demonstration of swollen immunoreactive axons and Demonstration of swollen immunoreactive axons and subsequent decrease in fiber densitysubsequent decrease in fiber density

• Decreases in the density of radiolabeled SERTDecreases in the density of radiolabeled SERT

• GFAPGFAP

• Cuprous silver degeneration stainCuprous silver degeneration stain

• Functional changesFunctional changes

• TIME-RELATED DIMENSIONTIME-RELATED DIMENSION

Degenerated Neurons in the Dorsal Raphe Degenerated Neurons in the Dorsal Raphe NucleusNucleus

48 Hours After 2’-NH48 Hours After 2’-NH22-MPTP-MPTP

Frontal Cortex Hippocampus Striatum0

20

40

60

80

100

120 non-TgHeterozygous-TgHomozygous-Tg

% Control

***

***

a

***

***

a***

Serotonin: From Cell Biology to Pharmacology & Therapeutics, Battaglia, G. (1990)

Criteria for Assessing Drug-induced Criteria for Assessing Drug-induced Degeneration of Serotonergic Degeneration of Serotonergic

NeuronsNeurons

• Decreased regional 5-HT & 5-HIAA levelsDecreased regional 5-HT & 5-HIAA levels

• Decreases in TPH activityDecreases in TPH activity

• Decreases in [Decreases in [33H]5-HT uptakeH]5-HT uptake

• Demonstration of swollen immunoreactive axons and Demonstration of swollen immunoreactive axons and subsequent decrease in fiber densitysubsequent decrease in fiber density

• Decreases in the density of radiolabeled SERTDecreases in the density of radiolabeled SERT

• GFAPGFAP

• Cuprous silver degeneration stainCuprous silver degeneration stain

• Functional changesFunctional changes

• TIME-RELATED DIMENSIONTIME-RELATED DIMENSION

CONTRIBUTORSCONTRIBUTORS

• Dennis Murphy (NIMH)Dennis Murphy (NIMH)

• David Jacobowicz (NIMH)David Jacobowicz (NIMH)

• Jean Lud Cadet (NIDA)Jean Lud Cadet (NIDA)

• Bruce Ladenheim (NIDA)Bruce Ladenheim (NIDA)

• Douglas Sheridan (PSU)Douglas Sheridan (PSU)

• Erica Unger (PSU)Erica Unger (PSU)

• Francesca Coppelli (PSU)Francesca Coppelli (PSU)