Biochemistry and Biological Psychiatry Biochemistry and by lgq95870


									 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

    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,
    biological hypotheses of mental disorders
     (schizophrenia, affective disorders)
    Biological Psychiatry: Web Pages
1. Educational portal of our faculty:

    (section Psychiatry, Psychology, Sexuology)

2. Direct links:

    (presentation of lectures from psychiatry)
    (teaching material from biological psychiatry)

   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
   Neurons
   Action potentials
   Synapses
   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
   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 mediates the
    signal transmission from
    one neuron to another.
   Neurons communicate with one
    another by
    • direct electrical coupling
    • secretion of neurotransmitters

   Synapses are specialized structures
    for signal transduction from one
    neuron to other. Chemical synapses
    are studied in the biological
Morphology of Chemical Synapse
 Synapse -
Model of Plasma Membrane
      Intercellular and Intracellular
   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
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                  Transmitter
Cholinergic             acetylcholine
Aminoacidergic          GABA, aspartic acid, glutamic
                        acid, glycine, homocysteine
 • Catecholamines       dopamine, norepinephrine,
 • Indolamines          tryptamine, serotonin
 • Others, related to   histamine, taurine
Purinergic              adenosine, ADP, AMP, ATP
                        nitric oxide
Catecholamine Biosynthesis
Serotonin Biosynthesis
     Reuptake and Metabolism of
     Monoamine Neurotransmitters
   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
galanin, neuromedin K, neuropeptideY (NPY),
peptide YY (PYY),
cortikotropin releasing hormone (CRH)
growth hormone releasing hormone (GHRH),                  hypothalamic
gonadotropin releasing hormone (GnRH),                    releasing factors
somatostatin, thyrotropin releasing hormone (TRH)
adrenocorticotropic hormone (ACTH)
growth hormone (GH), prolactin (PRL), lutenizing          pituitary hormones
hormone (LH), thyrotropin (TSH)
oxytocin, vasopressin                                     neurohypophyseal
atrial natriuretic peptide (ANF), vasoactive intestinal   neuronal and
peptide (VIP)                                             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      FGF-1
    factors            FGF-2
Transforming growth    Transforming growth factors  (TGF)
   factor             Bone morphogenetic factors (BMPs)
   superfamily         Glial-derived neurotrophic factor (GDNF)
Epidermal growth       Epidermal growth factor (EGF)
   factor              Transforming growth factor  (TGF)
   superfamily         Neuregilins
Other growth factors   Platelet-derived growth factor (PDGF)
                       Insulin-like growth factor I (IGF-I)
        Membrane Receptors
   Receptor is macromolecule
    specialized on transmission of

   Receptor complex includes:
    1. Specific binding site
    2. Internal ion channel or transduction
    3. Effector system (ion channels or
       system of 2nd messengers)
   Regulation of receptors
1. Density of receptors (down-regulation,
2. Properties of receptors
   (desensitisation, hypersensitivity)
     Receptor Classification

1. Receptor coupled directly to the ion
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

Nicotinic acetylcholine
receptor is made of 5
subunits, 2 of which
(shown in orange) bind
acetylcholine (red).

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
             Adenylyl           Phosphoinositide Arachidonic acid
             cyclase system     system           system
NEURO-      NE, 5-HT, DA,
                                NE, 5-HT, DA, Ach   Histamine
                                                    Unknown G-
TRANSDUCER Gs, Gi               Gp
             Adenylyl cyclase   Phospholipase C     Phospholipase A
             cAMP               IP3, DAG, Ca++      Arachidonic acid
                               •Calcium and
                               calmoduline          •5-Lipoxygenase
             •Protein kinase A dependent protein    •12-Lipoxygenase
                               kinases              •Cycloxygenase
                               •Protein kinase C
         Types of Receptors
     System                            Type
acetylcholinergic   acetylcholine nicotinic receptors
                    acetylcholine muscarinic receptors
monoaminergic 1-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        Subtype           Transducer   Structure
1-adrenoceptors   1A       Gq/11     IP3/DAG   466/7
                   1B       Gq/11     IP3/DAG   519/7
                   1D       Gq/11     IP3/DAG   572/7
2-adrenoceptors   2A       Gi/o      cAMP       450/7
                   2B       Gi/o      cAMP       450/7
                   2C       Gi/o      cAMP       461/7
                   2D       Gi/o      cAMP       450/7
-adrenoceptors    1        Gs        cAMP      477/7
                   2        Gs        cAMP      413/7
                   3        Gs, Gi/o cAMP       408/7
Subtypes of Dopamine Receptors

RECEPTORS   Subtype           Transducer       Structure
dopamine    D1        Gs      cAMP            446/7
            D2        Gi      cAMP             443/7
                      Gq/11   IP3/DAG, K+,
            D3        Gi      cAMP             400/7
            D4        Gi      cAMP, K+        386/7
            D5        Gs      cAMP            477/7
 Subtypes of Serotonin Receptors
   RECEPTORS            Subtype           Transducer       Structure
5-HT                    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        cAMP          387/7
                        5-ht5A    ?                        357/7
                        5-ht6     Gs        cAMP          440/7
                        5-HT7     Gs        cAMP          445/7
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     positive    psychostimulant drugs
                 negative    hypnotic drugs

affectivity      positive    antidepressants

                 negative    dysphoric drugs
psychic          positive    neuroleptics, atypical
integrations                   antipsychotics
                 negative    hallucinogenic agents
memory           positive    nootropics
                 negative    amnestic drugs
        Main Psychotropic Drugs

   Antipsychotics
   Antidepressants
   Anxiolytics
   Hypnotics
   Cognitives
   Psychostimulants
   Hallucinogens
  Potential Action of Psychotropics
1. Synthesis and storage of
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
  Classification of Antipsychotics
          Group                        Examples
                           chlorpromazine, chlorprotixene,
                           clopenthixole, levopromazine,
                           periciazine, thioridazine
Conventional               droperidole, flupentixol,
antipsychotics             fluphenazine, fluspirilene,
(classical neuroleptics)   haloperidol, melperone,
                           oxyprothepine, penfluridol,
                           perphenazine, pimozide,
                           prochlorperazine, trifluoperazine
Atypical antipsychotics    amisulpiride, clozapine,
                           olanzapine, quetiapine,
(antipsychotics of 2nd     risperidone, sertindole, sulpiride,
generation)                aripiprazole
        Mechanisms of Action of
Conventional  D2 receptor blockade of postsynaptic in
antipsychotics the mesolimbic pathway

                D2 receptor blockade of postsynaptic in the
                 mesolimbic pathway to reduce positive
                enhanced dopamine release and 5-HT2A
Atypical         receptor blockade in the mesocortical
antipsychotics   pathway to reduce negative symptoms;
                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
sertindole   D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1
ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-
             HT7, D3, 1, NRI, SRI
loxapine     D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1,
             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, 5-
             HT6, 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)
                  • serotonin reuptake inhibitors (SRI)
                  • norepinephrine reuptake inhibitors (NRI)
                  • selective SRI (SSRI)
Reuptake          • selective NRI (SNRI)
inhibitors        • serotonin/norepinephrine inhibitors (SNRI)
                  • norepinephrine and dopamine reuptake
                    inhibitors (NDRI)
                  • 5-HT2A antagonist/reuptake inhibitors (SARI)
Agonists of       • 5-HT1A
Antagonists of    • 2-AR
receptors         • 5-HT2
Inhibitors or stimulators of other components of signal transduction
Action of
    Biological Hypotheses of Mental

   Schizophrenia
   Affective disorders

Biological models of schizophrenia
  can be divided into four related
 Environmental models

 Genetic models

 Neurodevelopmental models

 Dopamine hypothesis
Schizophrenia - Genetic Models
Multifactorial-polygenic threshold
 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
1.   Dopamine-releasing drugs (amphetamine,
     mescaline, LSD) can induce state closely
     resembling paranoid schizophrenia.
2.   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.
3.   Antipsychotics raise dopamine turnover.
Classical Dopamine Hypothesis of

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
                    stress                  increased sensitivity
                    chronobiology           desynchronisation of
                                            biological rhythms
NEUROCHEMISTRY neurotransmitters availability, metabolism
                    receptors               number, affinity, sensitivity
                    postreceptor            G proteins, 2nd messengers,
                    processes               phosphorylation,
IMMUNONEURO-        HPA    (hypothalamic-   increased activity during
ENDOCRINOLOGY       pituitary-              depression
                    immune function         different changes during
    Data for Neurotransmitter
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
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 down-
  regulation or up-regulation of
  postsynaptic or presynaptic receptors.
 The delay of clinical response
  corresponds with these receptor
       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
 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                                   Norepinephrine
           Motivation          Alertness
           Pleasure Attention    Energy
           Reward     Interest




                    Serotonin                    Nutt 2008
      Postreceptor Hypotheses
Neurotrophic hypothesis (molecular and
  cellular theory) of depression:
 Transcription factor, cAMP response element-
  binding 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
                                      Duman et al. 1997
Neurotrophic Effects of Antidepressants

                               Nestler et al. 2002
Antidepressant Treatments
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