Download Biochemistry and Biological Psychiatry

Biochemistry and
Biological Psychiatry
ass. prof. Zdeněk Fišar, CSc.
Department of Psychiatry
1st Faculty of Medicine
Charles University, Prague
Head: prof. MUDr. Jiří Raboch, DrSc.
Biochemistry and Biological Psychiatry
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cellular neurochemistry (neurons, action
potentials, synapses)
intercellular signalling (neurotransmitters,
receptors, growth factors)
intracellular signalling (G proteins,
effectors, 2nd messengers, proteinkinases,
transcription factors)
psychotropic drugs (antipsychotics,
antidepressants)
biological hypotheses of mental disorders
(schizophrenia, affective disorders)
Biological Psychiatry: Web Pages
1. Educational portal of our faculty:
 http://connect.lf1.cuni.cz
 http://portal.lf1.cuni.cz/
(section Psychiatry, Psychology, Sexuology)
2. Direct links:
 http://www.lf1.cuni.cz/zfisar/psychiatry/
(presentation of lectures from psychiatry)

http://psych.lf1.cuni.cz/bpen/default.htm
(teaching material from biological psychiatry)
Introduction
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Biological psychiatry studies disorders
in human mind from the
neurochemical, neuroendocrine and
genetic point of view mainly.
It is postulated that changes in brain
signal transmission (at the level of
chemical synapse) are essential in the
development of mental disorders.
Cellular Neurochemistry
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Neurons
Action potentials
Synapses
Neuron
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The neurons are the
brain cells that are
responsible for
intracellular and
intercellular signalling.
Action potential is
large and rapidly
reversible fluctuation in
the membrane potential,
that propagate along the
axon.
At the end of axon there
are many nerve
endings (synaptic
terminals, presynaptic
parts, synaptic buttons,
knobs). Nerve ending
form an integral parts of
synapse.
Synapse mediates the
signal transmission from
one neuron to another.
Synapse
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Neurons communicate with one
another by
• direct electrical coupling
• secretion of neurotransmitters
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Synapses are specialized structures
for signal transduction from one
neuron to other. Chemical synapses
are studied in the biological
psychiatry.
Morphology of Chemical Synapse
Chemical
Synapse Signal
Transduction
Model of Plasma Membrane
Membrane
Transporters
Intercellular and Intracellular
Signalling
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Neurotransmitters
Growth factors
Receptors
G proteins
Effector systems (2nd messengers,
proteinkinases, transcription factors)
Criteria to Identify Neurotransmitters
1. Presence in presynaptic nerve terminal
2. Synthesis by presynaptic neuron
3. Releasing on stimulation (membrane
depolarisation)
4. Producing rapid-onset and rapidly
reversible responses in the target cell
5. Existence of specific receptor
There are two main groups of neurotransmitters:
• classical neurotransmitters
• neuropeptides
Selected Classical Neurotransmitters
System
Cholinergic
Transmitter
acetylcholine
Aminoacidergic
GABA, aspartic acid, glutamic
acid, glycine, homocysteine
Monoaminergic
• Catecholamines
• Indolamines
• Others, related to
aa
Purinergic
dopamine, norepinephrine,
epinephrine
tryptamine, serotonin
histamine, taurine
adenosine, ADP, AMP, ATP
nitric oxide
Catecholamine Biosynthesis
Serotonin Biosynthesis
Reuptake and Metabolism of
Monoamine Neurotransmitters
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Reuptake
Monoamine oxidase (MAO)
Catechol-O-methyltransferase (COMT)
Selected Bioactive Peptides
Peptide
Group
substance P, substance K (tachykinins), neurotensin, brain and
cholecystokinin (CCK), gastrin, bombesin
gastrointestinal
peptides
galanin, neuromedin K, neuropeptideY (NPY),
peptide YY (PYY),
neuronal
cortikotropin releasing hormone (CRH)
growth hormone releasing hormone (GHRH),
gonadotropin releasing hormone (GnRH),
somatostatin, thyrotropin releasing hormone (TRH)
hypothalamic
releasing factors
adrenocorticotropic hormone (ACTH)
growth hormone (GH), prolactin (PRL), lutenizing
hormone (LH), thyrotropin (TSH)
pituitary hormones
oxytocin, vasopressin
neurohypophyseal
peptides
atrial natriuretic peptide (ANF), vasoactive intestinal
peptide (VIP)
neuronal and
endocrine
enkephalines (met-, leu-), dynorphin, -endorphin
opiate peptides
Growth Factors in the Nervous System
Neurotrophins
Nerve growth factor (NGF)
Brain-derived neurotrophic factor (BDNF)
Neurotrophin 3 (NT3)
Neurotrophin 4/5 (NT4/5)
Neurokines
Ciliary neurotrophic factor (CNTF)
Leukemia inhibitory factor (LIF)
Interleukin 6 (IL-6)
Cardiotrophin 1 (CT-1)
Fibroblast growth
factors
FGF-1
FGF-2
Transforming growth
factor 
superfamily
Transforming growth factors  (TGF)
Bone morphogenetic factors (BMPs)
Glial-derived neurotrophic factor (GDNF)
Neurturin
Epidermal growth
factor
superfamily
Epidermal growth factor (EGF)
Transforming growth factor  (TGF)
Neuregilins
Other growth factors
Platelet-derived growth factor (PDGF)
Insulin-like growth factor I (IGF-I)
Membrane Receptors
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Receptor is macromolecule
specialized on transmission of
information.
Receptor complex includes:
1. Specific binding site
2. Internal ion channel or transduction
element
3. Effector system (ion channels or
system of 2nd messengers)
Regulation of receptors
1. Density of receptors (down-regulation,
up-regulation)
2. Properties of receptors
(desensitisation, hypersensitivity)
Receptor Classification
1. Receptor coupled directly to the ion
channel
2. Receptor associated with G proteins
3. Receptor with intrinsic guanylyl
cyclase activity
4. Receptor with intrinsic tyrosine
kinase activity
1. Receptors with Internal Ion Channel
1. Receptors with
Internal Ion Channel
acetylcholine
Nicotinic acetylcholine
receptor is made of 5
subunits, 2 of which
(shown in orange) bind
acetylcholine (red).
membrane
receptor
acetylcholine
1. Receptors with internal ion channel
GABAA receptor, nicotonic acetylcholine
receptors, ionotropic glutamate receptors, etc.
2. Receptors
Associated with
G Proteins
1. adenylyl cyclase system
2. phosphoinositide system
3. arachidonic acid system
Receptors Associated with G Proteins
SYSTEM
Adenylyl
cyclase system
Phosphoinositide Arachidonic acid
system
system
NEURONE, 5-HT, DA,
TRANSMITTER Ach
NE, 5-HT, DA, Ach
Histamine
TRANSDUCER Gs, Gi
Gp
Unknown Gprotein
PRIMARY
EFFECTOR
Adenylyl cyclase
Phospholipase C
Phospholipase A
SECONDARY
MESSENGER
cAMP
IP3, DAG, Ca++
Arachidonic acid
SECONDARY
EFFECTOR
•Calcium and
calmoduline
•Protein kinase A dependent protein
kinases
•Protein kinase C
•5-Lipoxygenase
•12-Lipoxygenase
•Cycloxygenase
Types of Receptors
System
acetylcholinergic
Type
acetylcholine nicotinic receptors
acetylcholine muscarinic receptors
monoaminergic 1-adrenoceptors
2-adrenoceptors
-adrenoceptors
dopamine receptors
serotonin receptor
aminoacidergic
GABA receptors
glutamate ionotropic receptors
glutamate metabotropic receptors
glycine receptors
histamine receptors
peptidergic
opioid receptors
other peptide receptors
purinergic
adenosine receptors (P1 purinoceptors)
P2 purinoceptors
Subtypes of Norepinephrine
Receptors
RECEPTORS
1-adrenoceptors
2-adrenoceptors
-adrenoceptors
Subtype
Transducer
Structure
(aa/TM)
1A
Gq/11
IP3/DAG
466/7
1B
Gq/11
IP3/DAG
519/7
1D
Gq/11
IP3/DAG
572/7
2A
Gi/o
cAMP
450/7
2B
Gi/o
cAMP
450/7
2C
Gi/o
cAMP
461/7
2D
Gi/o
cAMP
450/7
1
Gs
cAMP
477/7
2
Gs
cAMP
413/7
3
Gs, Gi/o cAMP
408/7
Subtypes of Dopamine Receptors
RECEPTORS
dopamine
Subtype
Transducer
Structure
(aa/TM)
D1
Gs
cAMP
446/7
D2
Gi
Gq/11
cAMP
IP3/DAG, K+,
Ca2+
443/7
D3
Gi
cAMP
400/7
D4
Gi
cAMP, K+
386/7
D5
Gs
cAMP
477/7
Subtypes of Serotonin Receptors
RECEPTORS
5-HT
(5-hydroxytryptamine)
Subtype
Transducer
Structure
5-HT1A
Gi/o
cAMP
421/7
5-HT1B
Gi/o
cAMP
390/7
5-HT1D
Gi/o
cAMP
377/7
5-ht1E
Gi/o
cAMP
365/7
5-ht1F
Gi/o
cAMP
366/7
5-HT2A
Gq/11
IP3/DAG
471/7
5-HT2B
Gq/11
IP3/DAG
481/7
5-HT2C
Gq/11
IP3/DAG
458/7
5-HT3
internal cationic channel 478
5-HT4
Gs
5-ht5A
?
5-ht6
Gs
cAMP
440/7
5-HT7
Gs
cAMP
445/7
cAMP
387/7
357/7
Feedback to Transmitter-Releasing
Crossconnection of Transducing
Systems on Postreceptor Level
AR – adrenoceptor
G – G protein
PI-PLC – phosphoinositide
specific phospholipase C
IP3 – inositoltriphosphate
DG – diacylglycerol
CaM – calmodulin
AC – adenylyl cyclase
PKC – protein kinase C
Psychotropic Drugs
Biochemical hypotheses of mental disorders
are based on the study of mechanisms of
action of psychotropic drugs at the level of:
• chemical synapse
• intracellular processes connected with
signal transduction
Classification of Psychotropics
parameter
effect
group
watchfulness
(vigility)
positive
psychostimulant drugs
negative
hypnotic drugs
affectivity
positive
antidepressants
anxiolytics
psychic
integrations
memory
negative
dysphoric drugs
positive
neuroleptics, atypical
antipsychotics
negative
hallucinogenic agents
positive
nootropics
negative
amnestic drugs
Main Psychotropic Drugs
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Antipsychotics
Antidepressants
Anxiolytics
Hypnotics
Cognitives
Psychostimulants
Hallucinogens
Potential Action of Psychotropics
1. Synthesis and storage of
neurotransmitters
2. Releasing of neurotransmitters
3. Receptor-neurotransmitter
interactions (agonists, antagonists)
4. Catabolism of neurotransmitters
5. Reuptake of neurotransmitters
6. Transduction element (G protein)
7. Effector's system
8. Transcription factor activity and gene
expression
Classification of Antipsychotics
Group
Conventional
antipsychotics
(classical neuroleptics)
Atypical antipsychotics
(antipsychotics of 2nd
generation)
Examples
chlorpromazine, chlorprotixene,
clopenthixole, levopromazine,
periciazine, thioridazine
droperidole, flupentixol,
fluphenazine, fluspirilene,
haloperidol, melperone,
oxyprothepine, penfluridol,
perphenazine, pimozide,
prochlorperazine, trifluoperazine
amisulpiride, clozapine,
olanzapine, quetiapine,
risperidone, sertindole, sulpiride,
aripiprazole
Mechanisms of Action of
Antipsychotics
Conventional  D2 receptor blockade of postsynaptic in
the mesolimbic pathway
antipsychotics
 D2 receptor blockade of postsynaptic in the
mesolimbic pathway to reduce positive
symptoms;
 enhanced dopamine release and 5-HT2A
Atypical
receptor blockade in the mesocortical
pathway to reduce negative symptoms;
antipsychotics
 other receptor-binding properties may
contribute to efficacy in treating cognitive
symptoms, aggressive symptoms and
depression in schizophrenia
Receptor Systems Affected by Atypical Antipsychotics
risperidone D2, 5-HT2A, 5-HT7, 1, 2
D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1
sertindole
ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5HT7, D3, 1, NRI, SRI
D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1,
loxapine
M1, H1, NRI
zotepine
D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1,
D3, D4, 1, H1, NRI
clozapine
D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1
olanzapine D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1,
D3, D4, D5, 1, M1-5, H1
quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1
aripiprazole D2, 5-HT2A, 5-HT1A, 1, 2, H1
Classification of Antidepressants
(based on acute pharmacological actions)
Inhibitors of
neurotransmitter • monoamine oxidase inhibitors (IMAO)
catabolism
Reuptake
inhibitors
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•
•
•
•
•
serotonin reuptake inhibitors (SRI)
norepinephrine reuptake inhibitors (NRI)
selective SRI (SSRI)
selective NRI (SNRI)
serotonin/norepinephrine inhibitors (SNRI)
norepinephrine and dopamine reuptake
inhibitors (NDRI)
• 5-HT2A antagonist/reuptake inhibitors (SARI)
Agonists of
receptors
• 5-HT1A
Antagonists of
receptors
• 2-AR
• 5-HT2
Inhibitors or stimulators of other components of signal transduction
Action of
SSRI
Biological Hypotheses of Mental
Disorders
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Schizophrenia
Affective disorders
Schizophrenia
Biological models of schizophrenia
can be divided into four related
classes:
 Environmental models
 Genetic models
 Neurodevelopmental models
 Dopamine hypothesis
Schizophrenia - Genetic Models
Multifactorial-polygenic threshold
model:
 Schizophrenia is the result of a combined
effect of multiple genes interacting with
variety of environmental factors.
 The liability to schizophrenia is linked to
one end of the distribution of a continuous
trait, and there may be a threshold for the
clinical expression of the disease.
Schizophrenia Neurodevelopmental Models
A substantial group of patients, who
receive diagnosis of schizophrenia in
adult life, have experienced a
disturbance of the orderly development
of the brain decades before the
symptomatic phase of the illness.
Basis of Classical Dopamine
Hypothesis of Schizophrenia
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2.
3.
Dopamine-releasing drugs (amphetamine,
mescaline, LSD) can induce state closely
resembling paranoid schizophrenia.
Antipsychotics, that are effective in the
treatment of schizophrenia, have in
common the ability to inhibit the
dopaminergic system by blocking action of
dopamine in the brain.
Antipsychotics raise dopamine turnover.
Classical Dopamine Hypothesis of
Schizophrenia
Psychotic symptoms are related to
dopaminergic hyperactivity in the
brain. Hyperactivity of dopaminergic
systems during schizophrenia is result
of increased sensitivity and density of
dopamine D2 receptors. This increased
activity can be localized in specific
brain regions.
Biological Psychiatry and
Affective Disorders
BIOLOGY
genetics
vulnerability to mental
disorders
stress
increased sensitivity
chronobiology
desynchronisation of
biological rhythms
NEUROCHEMISTRY neurotransmitters availability, metabolism
IMMUNONEUROENDOCRINOLOGY
receptors
number, affinity, sensitivity
postreceptor
processes
G proteins, 2nd messengers,
phosphorylation,
transcription
HPA
increased activity during
depression
(hypothalamicpituitaryadrenocortical)
system
immune function
different changes during
depression
Data for Neurotransmitter
Hypothesis
1. Tricyclic antidepressants through
blockade of neurotransmitter reuptake
increase neurotransmission at
noradrenergic and serotonergic synapses
2. MAOIs increase availability of monoamine
neurotransmitters in synaptic cleft
3. Depressive symptoms are observed after
treatment by reserpine, which depletes
biogenic amines in synapse
Monoamine Hypothesis
Depression was due to a deficiency of
monoamine neurotransmitters,
norepinephrine and serotonin.
Advanced monoamine theory: serotonin or
norepinephrine levels in the brain are
regulated by MAO-A activity mainly. However,
specific symptoms of depression or mania are
related to changes in the activity of
monoamine transporters in specific brain
regions. So, both MAO-A activity and density
of transporters are included in the
pathophysiology of affective disorders.
Permissive Biogenic Amine
Hypothesis
A deficit in central serotonergic transmission
permits affective disorder, but is insufficient
for its cause; changes in central
catecholaminergic transmission, when they
occur in the context of a deficit in
serotonergic transmission, act as a
proximate cause for affective disorders and
determine their quality (catecholaminergic
transmission being elevated in mania and
diminished in depression).
Receptor Hypotheses
The common final result of chronic
treatment by majority of
antidepressants is the downregulation or up-regulation of
postsynaptic or presynaptic receptors.
 The delay of clinical response
corresponds with these receptor
alterations.
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Receptor Hypotheses
Receptor catecholamine hypothesis:
 Supersensitivity of catecholamine receptors
in the presence of low levels of serotonin is
the biochemical basis of depression.
Classical norepinephrine receptor
hypothesis:
 There is increased density of postsynaptic
-AR in depression. Long-term
antidepressant treatment causes down
regulation of 1-AR. Transient increase of
neurotransmitter availability can cause fault
to mania.
Neurotransmitter Regulation of
Mood and Behavior
Dopamine
Motivation
Alertness
Pleasure Attention
Energy
Interest
Reward
Norepinephrine
Mood
Anxiety
Obsession
Compulsion
Serotonin
Nutt 2008
Postreceptor Hypotheses
Neurotrophic hypothesis (molecular and
cellular theory) of depression:
 Transcription factor, cAMP response elementbinding protein (CREB), is one intracellular
target of long-term antidepressant treatment and
brain-derived neurotrophic factor (BDNF) is
one target gene of CREB. Chronic stress leads to
decrease in expression of BDNF in hippocampus.
Long-term increase in levels of glucocorticoids,
ischemia, neurotoxins, hypoglycaemia etc.
decreases neuron survival. Long-term
antidepressant treatment leads to increase in
expression of BDNF and his receptor trkB through
elevated function of serotonin and norepinephrine
systems.
Duman et al. 1997
Neurotrophic Effects of Antidepressants
Nestler et al. 2002
Antidepressant Treatments
Thank you for your attention
Web pages:
http://connect.lf1.cuni.cz
http://portal.lf1.cuni.cz