02042012 Fritschy Neuropharmacology FS2012

8/13/2019 02042012 Fritschy Neuropharmacology FS2012

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A paradigm shift: role of dopamine in behavior

Effect of L-DOPA in

dopamine-depleted rabbits

A. Carlsson (1960)


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Emotional responses activate the same brain

regions as actual sensory stimuli


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Contents

Basic principles of neuropharmacology and

classification of brain diseases Monamines: properties and relevance for neuro- and

psychopharmacology

Antipsychotic drugs Experimental approaches to study brain diseases:

Molecular basis of the sedative and anxiolytic action of

benzodiazepines

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Basic principles of neuropharmacology

CNS diseases affect a large fraction of the general

population and have a very high social cost The pathophysiological mechanisms underlying most

brain disorders are poorly understood

Many CNS disorders have a genetic basis. The

elucidation of mutations in familial forms of thesediseases contributes markedly to our understanding oftheir pathophysiology

Pharmacological treatments are mainly symptomatic

and the mechanism of drug action is often unknown Neuropsychiatric disorders are difficult to reproduce inanimal models


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Experimental approaches to study brain diseases

Genetic screening of familial forms of disease to

identify genes contributing to the pathophysiology

Large scale genetic screening for identifying disease-

susceptibility genes

Molecular and cell biological studies in vitro to

understand the function of implicated genes In vivo animal models (lesion, pharmacological

treatment, targeted gene mutations)


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Classification of brain diseases (1)

1. Psychiatric diseases

Neurodevelopmental disorders (autism, Rettsyndrome, X-linked mental retardation, attention-

deficit disorders)

Anxiety (panic, generalized anxiety, phobia, post-

traumatic stress disorder)

Mood disorders (depression, bipolar disorder)

Schizophrenia, Tourettes disease

Drug dependence


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2. Neurological diseases

Stroke and ischemia Brain lesions (trauma, tumors, infections)

Epilepsy

Chronic pain Sleep disorders

Movement disorders (dystonia; tremor)

3. Autoimmune diseases Multiple Sclerosis (MS)

Myasthenia gravis


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4. Neurodegenerative diseases

Alzheimer Parkinson

Huntington

Fronto-temporal lobe dementia (FTLD) Amyotrophic lateral sclerosis (ALS)

Prion diseases (Creutzfeld-Jacob)

The cause of neurodegeneration is not established but is oftenlinked to the production of protein aggregates (e.g. -amyloids),

due to abnormal proteolytic processing or to mutations (e.g.,

trinucleotide repeats)


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Examples of diseases caused by trinucleotide repeats

Disease Repeat

Fragile X syndrome (CGG)n in FMR1 gene

Myotonic dystrophy (CTG)n in myotonin-protein

kinase gene

Spinobulbar muscle

dystrophy

(CAG)n in androgen-receptor

gene

Huntington (CAG)n in Huntingtin gene


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Huntingtons disease

Autosomal dominant disorder causes by mutation in

the huntingtin gene (short arm of chromosome 4)

Onset in middle adulthood (minor motor coordination

problems, involuntary jerking progressing towards

major deterioration)

Cognitive alterations and changes in personality(impulsivity, depression, psychotic symptoms)

Molecular basis: presence of tri-nucleotide repeats

(37 86) coding for glutamine (CAG). Longer repeats

lead to early onset and more severe symptoms

Physiological role of huntingtin is unknown


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Pathophysiology of Huntingtons disease

Progredient loss of

GABAergic

neurons inputamen and

caudate nucleus

Upregulation ofGABAA receptors

in target regions

(globus pallidus)

Selectivity ofdegeneration is not

explained


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Lessons from Huntingtons disease

Power of reverse genetics: the affected gene could

be identified without knowledge about ist function The pathophysiology of the disease is not due to anobvious dysfunction in the striatum

The selectivity of neurodegeneration remainsunexplained

The path to therapy is very long and no goal is insight

In the case of complex genetic diseases, such aspsychiatric diseases, the development of novel

therapies based on genetic information might beeven more difficult


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Monoamines: relevance to psycho- and

neuropharmacology


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Monoamines

Catecholamines (dopamine, noradrenaline, and

adrenaline) are derived from tyrosine Serotonin (an indolamine) is derived from tryptophan

They are the neurotransmitter of small groups ofneurons in the brainstem that innervate most of the

brain Monoaminergic neurons regulate brain state and

function (neuroendocrine systems, sleep-wake cycle,motor functions, sensory perception, emotions,

attention, memory)


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Catecholamine synthesis

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Common principles of monoaminergic transmission

Local synthesis and storage in vesicles

Ca++-dependent release

Termination of synaptic transmission by re-uptake.

The transporter proteins are a major drug target

Action on a multitude of receptors (mainly 7 TM

domain receptors coupled to G-proteins)

Presence of pre- and postsynaptic receptors

Complex metabolism, in neurons, glial cells, and

other tissues (Monoamine oxidase A and B);metabolites can be toxic

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Significance of monoaminergic transmission in

neuro- and psychopharmacology

Monoaminergic transmission is the target of many

psychoactive drugs (antidepressants, antipsychotic

drugs, some psychostimulant and psychotropicdrugs, and anti-parkinson drugs)

Many unwanted side effects of psychopharma-

cological treatment arise from interactions withmonoaminergic transmission

Dysfunction of dopaminergic systems underlie

multiple neurological and psychiatric disorders, as

well as drug addiction


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Complex pharmacology of monoaminergic systems

Direct drug effects by receptor activation/inhibition(agonist, antagonist)

Indirect effects by enhancing effects of endogenoustransmitter (increased release (e.g., amphetamin,inhibition of re-uptake (e.g. cocain), inhibition ofcatabolism)

Complex interactions with precursor (e.g., L-Dopa) orpseudo-transmitters (e.g., -Methyl-Tyrosin)

Inhibition of catabolism can affect pseudo-transmitterspresent in food

Complex regulation of receptors (super-sensitivity,desensitization, opposite action of pre- and post-synaptic receptors

Importance of target selectivity


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A dopaminergic synapse

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Dopamine receptors

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Dopamine

Major dopaminergic projections

Mesostriatal projection Mesolimbic projection


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Thalamus

Ca

Pu

GPe

GPi

ic

STN

SNr

SNc

Hypoth

Hip

Insula

cc


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DA receptor agonist-induced rotation in lesioned

animals


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Opposite rotation effects caused by amphetamine


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Serotonin (5-Hydroxytryptamine)

Source:Enterochromaffin cells, thrombocytes,

neurotransmitter in centralneurons (raphe nuclei)

EffectsPeriphery: complex actions on thecardiovascular system, increasedmotility of the gastrointestinal tract,vasoconstriction

CNS: Regulation of blood pressure,

temperature, appetite, sleep-weakcycle, motor activity, pain perception,emotional behavior (serotoninreuptake inhibitors areantidepressants)


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Serotonergic neurons


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Functional and pharmacological relevance of

the serotonergic system

Serotonin exerts multiple, complex actions by

activating pre- and postsynaptic receptors coupled to

various signal transduction pathways

Serotonin regulates mood, attention, sleep-wake

cycle, descending pain control, motor systems,

autonomic functions, neuroendocrine systems Selective 5-HT reuptake inhibitors (SSRI) are widely

used antidepressants

Psychostimulants, recreational drugs, and

hallucinogens have mixed actions of theserotonergic, noradrenergic, and dopaminergic

system.

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Noradrenergic neurons: Locus coeruleus

Immunhistochemistry of dopamine--hydroxylase Nissl staining


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Noradrenergic projections from the locus coeruleus


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Scheme of serotonergic and adrenergic synapses

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Pharmacotherapy of Parkinsons disease

Dopamine receptor agonists (D1 and D2)

Apomorphin, Bromocriptin, Cabergolin, Lisurid,

Dihydroergocriptin, Pergolid, Ropinirol, etc.

L-Dopa

Mode of action: L-Dopa is transported across the

blood-brain barrier and converted into dopamine(mainly in dopaminergic neurons)

Is given in combination with inhibitors of Dopa-decarboxylase (Carbidopa, Benserazid) to minimizeperipheral side effects


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Metabolism of L-Dopa


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Antipsychotic drugs

Treatment of schizophrenia

Typical (Dopamine D2 receptor antagonists) Phenothiazine derivatives (Chlorpromazine)

Butyrophenone (Haloperidol)

Numerous side-effects (blockade of Ach, NA, 5-HT

receptors): sedation, autonomic dysfunction,

involuntary movements

Atypical (mechanism of action unknown)

Clozapine

Risperidone


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Effects of antipsychotics on the DA system

Location Clinical effects (due to blockade of D2 receptors)

Mesolimbic,mesocortical

pathway

Antipsychotic action by modulation of neuronal circuitsand regulation of excitatory-inhibitory balance (only

positive symptoms)

Nigrostriatal

pathway

Extrapyramidal motor symptoms (EPS): Parkinson-like

symptoms and dyskinesia

Tuberoinfundibular

projection

Gynaecomasty, milk secretion (due to increased prolactin

secretion)

Medulla oblongata

(area postrema)

Anti-emetic effects


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Extrapyramidal motor symptoms

Syndrom Symptoms Prevalence,

duration

Treatment

Early dyskinesia Head and neck muscle spasms 5%, at start of

therapy

Anti-cholinergic

drugs

Parkinsonoid Akinesis, rigor, tremor, hyper-

salivation

20-30%

up to 8 weeks

Dose,

anti-cholinergic

drugs

Akathisia Agitation, restlessness 25%

up to12 weeks

Dose

benzodiazepines

Late dyskinesia Chronic hyperkinetic syndrome

(irreversible); stereotypic

movements of the lips, tongue,jaws

20%

After

months/years

Change to clozapin;

no anti-cholinergic

drugs

Malignant

neuroleptic

syndrom

Acute emergency (rigor, akinesis,

high fever, tachycardia, coma)

rare

before 2 weeks

Stop therapy;

dentrolene

Relationship between wanted and unwanted effects


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Relationship between wanted and unwanted effects

of neuroleptics


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Tests for cognitive function

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Predicting schizophrenia: a longitudinal study

Differences in gray matter volume prior to first


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Differences in gray matter volume prior to first

psychosis

Differences in gray matter volume after onset of


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Differences in gray matter volume after onset of

psychosis


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New hypotheses about the pathophysiology of schizophrenia

Structural anomalies in the brain can be shown priorto the first psychosis

Functional disturbances occur selectively in prefrontalcortex (thought and memory disorders)

NMDA-Receptor antagonists (e.g. PCP) producepsychoses in healthy volunteers

Schizophrenia may be related to alteredglutamatergic neurotransmission

Selective deficit of GABAergic transmission inprefrontal cortex


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Further hypotheses

Selective glutathion deficit (protection against

oxidative stress) in prefrontal cortex

Altered function of oligodendrocytes ( possible

disturbance of myelination)

Abnormal neuronal migration during formation of theneocortex (reelin hypothesis)

Consequences of a prenatal production of

inflammatory cytokines (disturbance of braindevelopment during a critical period)

Evidence for synaptic alterations in the prefrontal


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Evidence for synaptic alterations in the prefrontal

cortex of schizophrenia patients


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Altered regulation of dopaminergic function in schizophrenia

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Allosteric modulation of GABAergic

transmission by benzodiazepines

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Benzodiazepines


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Benzodiazepines

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Benzodiazepines are drugs with a high affinity and

selectivity for GABAA receptors. They differ mainly in

their pharmacokinetic profile (half-life, activemetabolites)

Clinical applications of benzodiazepine agonists Sleep disorders (sedation, hypnosis)

Anxiety disorders (tranquillizer) Muscle spams, dystonia (muscle relaxant)

Status epilepticus (anticonvulsants)

Side effects

Motor incoordination Anterograde amnesia

Ethanol potentiation

Tolerance

GABA receptors


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GABAA receptors

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Allosteric modulation by benzodiazepines


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Allosteric modulation by benzodiazepines

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Diazepam sensitive GABA receptor subtypes


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Diazepam-sensitive GABAA receptor subtypes

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1

2

3

5

diazepam

H101R: a molecular switch for diazepam sensitivity


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H101R: a molecular switch for diazepam sensitivity

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Wieland and Lddens, 1992

Diazepam-insensitive receptors in 1(H101R) mutants


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Diazepam-insensitive receptors in 1(H101R) mutants

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3H Ro15 4513 + diazepam

wt

1(H101R) 1 subunit immunostaining

3H Ro15 4513 is a ligand bindingto all benzodiazepine sites; it can

be displaced only from diazepam-

sensitive sites

Lack of sedative effect of diazepam in 1(H101R) mutants


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Lack of sedative effect of diazepam in 1(H101R) mutants

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WT 1(H101R)

Further reading


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Further reading

Books:

The biochemical basis of neuropharmacology

(Cooper, Bloom, Roth)

A primer of drug action (R.M. Julien; Freeman and

company, New York)

Molecular Neuropharmacology (E.J. Nestler, S. E.Hyman, R.C. Malenka; The McGraw-Hill

Companies, Inc., New York)

Documents

02042012 Fritschy Neuropharmacology FS2012