Post on 18-Jan-2016
transcript
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
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a
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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)