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LNAA
Presynaptic
Tryptophan
Tryptophan
5-HT1A
TPH
5-HTP
AADC
5-HT
5-HIAA
MAO
5HT
5-HT
5-HT
5-HT1B
5-HT
SERT
5-HT2A
5-HT1A
5-HT2C
Postsynaptic
5-HT1B
”Criteria for Assessing Neurotoxicity:
Is 2’-NH2-MPTP a
Serotonergic Neurotoxin?"
2’-NH2-MPTP is Unique Among Ortho-substituted
Analogs of MPTP
CH3
CH3
N
N
NH 2
2'-NH 2 -MPTP
X
2'-substituted-MPTP's
(X = -CH3 , -CH 3 CH 2 , -Cl,
-OCH3 , -CH 2 F, -F, -CF3 )
Substituted Amphetamines
NH2
CH3
Cl
NHCH3
NH2
PCA
CH3
CH3
Methamphetamine
Amphetamine
NHCH2CH3
CH3
CF3
Fenfluramine
NH2
O
CH3
O
MDA
NHCH3
O
O
CH3
MDMA
“Ecstasy”
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
NEUROPSYCHIATRIC DISORDERS IN WHICH
SEROTONERGIC DYSFUNCTION IS IMPLICATED
Unipolar Affective Disorder
Simple Phobias
Social Phobia
Generalized Anxiety Disorder
Panic Disorder/Agoraphobia
Obsessive-Compulsive Disorder
Trichotillomania
Addiction
Anorexia Nervosa
Autism
Bulimia
Alcoholism
Obesity
Migraine
Premenstrual Syndrome
Aggression
Epilepsy
NEUROCHEMICAL TECHNIQUES
Brain neurotransmitter levels
In vivo Microdialysis
In vivo Voltammetry
Biosensors: 5-HT, O2Brain Imaging:
Autoradiography
Immunohistochemistry
Positron Emission Tomography
Proteomics
GENETIC ALTERATIONS
Transgenic mice
Knock-out mice
Inducible knock-outs
NEUROTOXINS
2’-NH2-MPTP
MDMA
Fenfluramine
ROLE OF 5-HT IN NORMAL/ALTERED FUNCTION
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,
Degenerated Neurons in the Dorsal Raphe Nucleus
48 Hours After 2’-NH2-MPTP
non-Tg
Heterozygous-Tg
Homozygous-Tg
120
100
a
a
** *
% Control
80
** *
60
** *
** *
40
** *
20
0
Frontal Cortex
Hippocampus
Striatum
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,
CONTRIBUTORS
•
•
•
•
•
•
•
Dennis Murphy (NIMH)
David Jacobowicz (NIMH)
Jean Lud Cadet (NIDA)
Bruce Ladenheim (NIDA)
Douglas Sheridan (PSU)
Erica Unger (PSU)
Francesca Coppelli (PSU)