Basics of Behavioral Neurochemistrykelvin/ismrm2002/neurobehav.pdf · Basics of Behavioral...
Transcript of Basics of Behavioral Neurochemistrykelvin/ismrm2002/neurobehav.pdf · Basics of Behavioral...
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Basics of BehavioralNeurochemistry
Kelvin O. Lim, M.D.Drs. T.J. and Ella M. Arneson Endowed Chair Professor
University of MinnesotaDepartment of Psychiatry
Center for Magnetic Resonance Research
ISMRM Weekend Educational Course on Basics of Brain FunctionMay 18, 2002, Honolulu, Hawaii
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SLIDES
http://cmrr.umn.edu/~kelvin/ismrm2002
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Neurochemistry
Behavior
?
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GOAL
Provide a framework for thinking
about behavior and neurochemistry
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BEHAVIOR
Broad definition• motor• cognition• affect• disease
How does neurochemistry relate to thesebehaviors?
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OBJECTIVES
• Name 5 neurotransmitter systems and abehavior associated with each one
• Identify drugs which act on each of the 5neurotransmitter systems
• Be aware of how MR is being used in thestudy of neurotransmitters
• Finish in time for lunch!
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PRETEST:Match the NT to the behavior
1. Dopamine
2. Serotonin
3. Acetylcholine
4. GABA
5. Glutamate
A. Alzheimer’s disease
B. epilepsy
C. depression
D. Schizophrenia
E. Parkinson’s disease
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PRETEST:Match the NT to a drug
1. Dopamine
2. Serotonin
3. Acetylcholine
4. GABA
5. Glutamate
A. diazepam (Valium)
B. donepezil (Aricept)
C. Phencylidine
D. fluoxetine (Prozac)
E. Cocaine
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PRETEST:Match the NT to the MR method
1. Dopamine
2. Serotonin
3. Acetylcholine
4. GABA
5. Glutamate
A. BOLD
B. Spectroscopy
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Tools
• Behavior
• Pharmacology - drug effects– Increase - agonists
– Decrease - antagonists
• Receptor location
• Anatomical connections
• Molecular characterization
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Synapse - sites of action
Siegel et al,Basic NeurochemistrySixth edition
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Fast Receptor
Kandel et al, Principles ofNeural Science
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Slow Receptor
Kandel et al, Principles ofNeural Science, 3rd edition
Influences activityon scale of minutesto days
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Brain Anatomy and Function• frontal cortex - higher cognition,planning• brainstem - basic physiologicalfunctions• striatum - motor• limbic system - memory, emotion• amygdala - fear• nucleus acumbens - reward• ventral tegmental area - reward
Kandel et al, Principles ofNeural Science, 3rd edition
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Receptors
Classified through:• drug related characteristics• intracellular signal-transduction mechanisms• amino acid sequence of receptor protein
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Dopamine receptors
D1 D2 D3 D4 D5
AA 446 415 400 387 477
Chro 5 11 3 11 4
mRNA CP hippo CP hypoth frontal
NA hypoth NA NA medulla
OT OT OT midbrain
effector cAMP cAMP cAMP cAMP cAMP
K,Ca K
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DOPAMINE (DA)
• ventral tegmentum, nucleus acumbens• frontal cortex• mesolimbic• striatum
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COMT - effects of polymorphism
• COMTmetabolizesDA
• LESS DA,poorerprefrontalperformance
• Met allele isLESS activethan val allele,MORE DA Egan et al, PNAS, 2001
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Parkinson’s Disease
• Progressive neurodegenerative disorder
• DA containing neurons in substantia nigra
• Motor symptoms-incapacitating
• Cognitive and emotional symptoms
• Incidence - 0.5%
• Palli ative treatment– drugs
– surgery, DBS , fetal tissue, stem cell
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Michael J. Fox
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Schizophrenia
• Illness which affects reality testing,motivation, social interaction
• Onset in early adulthood, lifetime ill ness
• Incidence 1% of population
• Genetics– Monozygotic twins, 50% concordance
– First degree relatives, 12%
• Some symptoms reduced by medication
• No cure
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Schizophrenia
• Dopamine hypothesis
• Other NT systems are important
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John Forbes Nash, Jr.
Nobel Laureate, Economics, 1993
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DA Pharmacology
• Increase activity– L-dopa - increase
amount of DA
– cocaine - release
– amphetamine - reduceuptake
• Decrease activity– haloperidol - block
receptor
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SEROTONIN (5-HT)
5-HT neurons along midline in brainstemProjections to all areas of brainModulatory role?
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Serotonin Receptors in CNS
5-HT1[A,D,E,F]
5-HT2[A,B,C]
5-HT3
5-HT4
5-HT5[A,B]
5-ht6
5-HT7
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5-HT1
5-HT1A limbic system modulation of emotion
neocortex cognition
5-HT1D basal ganglia Parkinson’s disease
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5-HT2
Lack of selective agonists and antagonists hampers determiningfunctional role
5-HT2A frontal cortex
basal ganglia
olfactory nuclei
5-HT2C limbic system
neocortex
basal ganglia
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5-HT3
5-HT3 medulla pain
neocortex
limbic system
area postrema chemoreceptor trigger zone
facili tate release of substance P
modulate DA release in VTA
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Serotonin Effects
• Appetitive
• Emotional
• Motor
• Cognition
• Autonomic
• Endocrine
• Circadian
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Depression
• Selective serotonin reuptake inhibitors
• fluoxetine (Prozac)
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Appetitive
• D-fenfluramine
• promotes release of 5-HT
• reuptake inhibitor
• reduces meal size, rate of eating and eatingbetween meals
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Synapse - sites of action
Siegel et al,Basic Neurochemistry
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Acetylcholine (ACh)
• ACh found in bacteria, fungi and protozoa and plants• Have biosynthetic and degradative capacities• ACh is distributed outside of the nervous system:
• cornea• cili ated epithelia• placenta
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Acetylcholine Receptor
NICOTINIC Neuromuscular
MUSCARINIC
M1 hippocampus
cerebral cortex
M2 cerebellum
brainstem
M4 striatum
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ACh - Neuromuscular
• Botulinum is aneurotoxin producedby the gram positivebacterium Clostridiumbotulinum
• Interferes with pre-synaptic ACh release
• Denervates muscle
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Myasthenia Gravis
• abnormal muscle fatigabil tiy
• muscle shows evidence ofinflammation
• autoimmune process - AChreceptor
Brain’ s Clinical NeurologyFifth edition
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Acetylcholinesterase
• Acetylcholine is broken down by acetylcholinesterases(AChE)
• AChE inhibitors interfere with AChE, prolonging the action ofACh
• Reversible AChE have been used clinically
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Myasthenia Gravis
Brain’ s Clinical NeurologyFifth edition
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Alzheimer’s Disease
• Cholinergic neurons observed to die out
• Cholinergic antagonists observed to impairmemory
• Pharmacological strategy to prolong actionof acetylcholine
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AD treatment - donepezil
Rogers et al, Arch Int Med, 1998.
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Acetylcholinesterase
• build-up of ACh at cholinergic synapses canbe toxic
• Organophosphorus or nerve gases, formincredibly stable phosphorus bonds withAChE.
• Irreversible AChE inhibitors are highly toxic.
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Tabun
Used by Iraq in 1980 war with IranExposure to 1 mg• felt first in the eyes (as a persistent contraction of the pupil ) • chest (as a tightness or asthma-like constriction)• running nose, sweating• involuntary urination and defaecation• vomiting, twitching• convulsions, paralysis and unconsciousness
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Sarin - 20March1995
• Sarin released inTokyo subway duringrush hour
• 12 fatalities, 5500injured
• Police are paramedics
• Large stocks ofantidote
• Poison not vaporized
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GABA (gamma-aminobutyricacid)
• major inhibitor neurotransmitter inmammalian CNS• ubiquitous in the brain• found in milli molar quantities (unlike DAmicromolar)
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GABA Receptors
• GABAA
– Cl- channel
– membrane hyperpolarization
– many different isoforms
• GABAB
– K+ channels
– decrease Ca2++ conductance
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GABA pharmacology
• Barbiturates
• Benzodiazepine
• Ethanol
• Steroid
Siegel et al,Basic NeurochemistrySixth edition
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GABA disease
• epilepsy
• alcoholism
• Huntington’s disease
• tardive dyskinesia
• schizophrenia
• sleep disorders
• Parkinson’s disease
• mental retardation
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Glutamate
• Major excitatory neurotransmitter
• A neurotoxin when energy metabolism iscompromised
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Glutamate receptors
• Ionotropic (ion channels)– NMDA
– AMPA
– Kainate
• Metabotropic (second messenger systems)– Class I
– Class II
– Class III
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Cascade
Siegel et al,Basic NeurochemistrySixth edition
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Paths to Neuronal Injury
• Clinical trials have been disappointing
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NMDA
• Phencyclidine
• Developed after WWI as surgical anesthetic - not safe
• 1957 - Sernyl, Parke-Davis tests as anesthetic, side effectsof hallucinations, deli rium
• 1965 - Sernylan - marketed as an animal tranquili zer
• Appeared on street, produces syndrome similar toschizophrenia
• PCP binds to the NMDA receptor
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Neurolathyrism• lower limb weakness
• epidemics withdroughts
• India, sub Sahara
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Grasspea (Lathyrus sativus)
• Hippocrates describeda paralysis associatedwith eating peas
• Plant resistant todrought, used to feedanimals
• produces a legumesimilar to mung bean
• OK to eat in smallquantities
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Neurolathyrism
• Get weakness in 2-3 weeks
• Paralysis in 3-6 months
• Mental retardation and death in children
• Men > Women
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ß-ODAP
3-(N-oxalyl)-L-2,3-diaminopropionic acid (ß-ODAP)(Spencer et al., 1986 and Roy and Spencer, 1989)
Active at AMPA receptors
Damages motor neurons in specif ic region of spinal cordcontrolling the leg musculature
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Grasspea (Lathyrus sativus)
• Outlawed in somecountries butcontinues to be grown
• New strains producedthrough cross breedingwhich reducesneurotoxin from 1.2%to .02%
• Implications for otherdegenerative disorders
International Center for AgriculturalResearch in the Dry Areas (ICARDA)
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Top Drug Categories by Sales(2000)
• 1 Cholesterol reducers statins
• 2 SSRI
• 3 Proton pump inhibitors
• 4 Cytostatics
• 5 Calcium blockers
• 6 Antipsychotics
• 7 Erythropoetins
• 8 COX-2 inhibitors
• 9 Anti seizure
• 10 ACE inhibitorsPharmacy Times
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Top Drug Categories by Scripts(2000)
• 1 Codeine 103M
• 2 Aminopenicilli ns 53M
• 3 SSRI/SNRI 42M
• …
• 7 Benzodiazepines 39M
• ...
• 14 Anti seizure 26M
Pharmacy Times
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MR Techniques
Direct measurement
Indirect measurement
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GABA Measurement
Rothman et al, PNAS, 1993
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Anticonvulsant comparison
• Drugs have different mechanisms– topiramate - potentiates GABA action
– gabapentin - structurally like GABA but not an agonist, noinhibition of degradation
– lamotrigine - inhibit Na+, modulate excitatory NT release
• Use MRS to examine acute and chronic effects on healthysubjects
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Anticonvulsant comparison
• Healthy subjects given drug and followed both acutely andchronically (4 weeks) with MRS at 4.1T
ACUTE CHRONIC
Topiramate 70% 46%
Gabapentin 48% 25%
Lamotrigine 0% 25%
Kuzniecky et al., Neurology, 2002
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Glu, Gln at 4.0T
Glu
Gln
STEAM acquisition, 8cc anterior cingulate, CMRR, University of Minnesota
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Glutamate/Glutamine
• Glutamate/glutaminecycling
• Can use C-13 MRS tomonitor and quantitate fluxrates.
Siegel et al,Basic NeurochemistrySixth edition
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Indirect Measurement
• Parkinson’s disease - fetal cell transplant
• PET - typically used for DA receptor
• PET - radiation complicates longitudinal studies
• Use MR to assess blood flow response to drug challenge
• Generalized or specific response?
• Role for MR?
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phMRI
Chen et al, Neuroreport, 1999
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Fetal cell transplant monitoring
Chen et al, Neuroreport, 1999
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POST TEST:Match the NT to the behavior
1. Dopamine
2. Serotonin
3. Acetylcholine
4. GABA
5. Glutamate
A. Alzheimer’s disease
B. epilepsy
C. depression
D. Schizophrenia
E. Parkinson’s disease
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POST TEST:Match the NT to a drug
1. Dopamine
2. Serotonin
3. Acetylcholine
4. GABA
5. Glutamate
A. diazepam (Valium)
B. donepezil (Aricept)
C. Phencylidine
D. fluoxetine (Prozac)
E. Cocaine
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POST TEST:Match the NT to the MR method
1. Dopamine
2. Serotonin
3. Acetylcholine
4. GABA
5. Glutamate
A. BOLD
B. Spectroscopy