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PHARMACOLOGIE DE LA COGNITION

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					PHARMACOLOGIE DE LA COGNITION
« Des Neurosciences à la Prescription » Hervé ALLAIN Stéphane SCHUCK Nicolas MAUDUIT

Université de Rennes I

HYPOTHESIS : EFFECTS OF DRUGS ON COGNITIVE FUNCTIONS ?

• Quantitative : Performance
• Positive = Clinical trials • Négative = Pharmacovigilance*

• Qualitative : Distortion
• ex = Anxiety = Drugs, hallucinogens

WHAT ARE COGNITIVE FUNCTIONS ?
• Intellectual functions = definition of human being
– – – – – – Language Learning Memory Decision-Making Action Planing Waiting capacity ...

HOW TO EXPLORE THE COGNITION ?
– – – – – – – Experimental psychology Neuropsychology Neuroimaging Neurochemistry Signals and data analysis Computer sciences Philosophy

INFORMATION PROCESSING MODEL OF COGNITION
• Environment Attention Cognition

Emotion

Memory • Reward • Behaviour Responses

Motivation

– All those steps are within the brain

PREREQUISITES FOR A PHARMACOLOGY OF COGNITON
• • • • Genetics Neurobiology Tools for cognition measurement Drug cognitive mapping

Rationale for a Pharmacology of Cognition (1)
• Daily living :
– – – – – Decision-making/choice Use of computers, telephones … Quality of life Learning at school Socialization

• Pathology
– Psychiatry – Alzheimer ’s disease

Rationale for a Pharmacology of Cognition (2)
• Law
– – – – Accidents Catastrophs Violence Suicide

• Bioethics
– Phineas Gage (Damasio)

GENETICS AND COGNITIVE FUNCTION (I)
• Molecular basis of single-gene disorders or chromosomal abnormalities => cognitive impairment (mental retardation) • Mapping and cloning gene variants => variation in intellectual abilities (dyslexia) • Mutations in mice => models (memory)

Examples of the duo genetics/cognition
• Four-generation family : impairment in grammar (plural of words ; inflected forms of regular verbs)

– Grammar genes ! (Pinker, 1994)
• Dyslexia : inability to recognize phonemes/6 p 21.3 (reading-related locus)

A link between genetics and conventional neurobiology
• Non-specific mental retardation
– 3 genes : GDI1, oligophrenin, PAK 3 – Involved in Rho GTPase signalling networks :
• • • • development of axonal connections neurotransmitter release recruitment of synaptic vesicles for exocytose formation of dendrites

• Alzheimer ’s disease
– ApoE/Ach neurons/plasticity

Neurobiology of cognition (I)
• • • • Neurotransmission Second-messengers Transcription factors Gene

Neurobiology of cognition (II)
• • • • Function localisation Electrophysiology Neurochemistry Genetics
• An example : learning and memory

Biologie moléculaire de l ’apprentissage et de la mémorisation
ESPECE APPRENTISSAGE NEUROCHIMIE GENE CODANT POUR

APLYSIE

réflexe de retrait

ARN ; synthèse protéique AMPc ; Protéine Kinase A

CREB

1

; CREB

2

()

DROSOPHILE

association odeur / choc électrique

AMPc ; Protéine Kinase A ; CREB : dunce : camp-specific phosphodiesterase rutabaga : adényl-cyclase dCREB2a  mémoire olfactive dCREB2b  «

MAMMIFERES

- Long-Term Potentiation (LTP) - son/choc électrique - mémoire spatiale

Récepteurs NMDA ; phosphatases (calcineurine)

ApCREB2 gene)

(memory suppressor

CREB1 ; CAM KII ; FYN

Aperçu historique
• Alois Alzheimer, 1907, 1 cas • Tacrine, Cognex®, 1994

• James Parkinson, 1817, 6 cas
• Jean Martin Charcot, 1878

• Levodopa, 1960
• Riluzole, Rilutec®,

1998

Les médicaments des MN
Maladie Classes Symptomatique Cytoprotecteur
+ ? + + + + + Cytotoxique ? + +

Avenir
Antisecrétases Agonistes nicotiniques Antioxydants LGF1, CRF Antiinflammatoire Anti-NMDA Greffes Neurostimulation Facteurs trophiques (BDNF) Antiapoptotiques Antiradicaux

Anticholinesterasiques (Cognex, Aricept, Exelon) Alzheimer Antiglutamate (memantine) Nootropes ? Levodopa Agonistes dopaminergiques Parkinson Anti-NMDA Potentialisateurs de Dopa Antiglutamate Rilutek

Charcot

+

+

Anomalies génétiques / conséquences
• Mutations
– Gain de fonction toxique pour les cellules
• répetition de triplets CAG (résidus de glutamine)

– Perte d ’une fonction, manque d ’une protéine
• exemple de l ’Ataxie de Friedreich

• Conséquences
– Tout concourt à la mort cellulaire probablement par apoptose (« chute des feuilles en automne). Activation des gènes de mort cellulaire

La sérotonine
• Neuromédiateur clé dans la migraine

• Récepteurs 5-HT1B / 5-HT1D
– impliqués dans l’action thérapeutique DHE et Triptans

Famille 5-HT1

Sous type 5HT1A 5HT1B 5HT1D 5HT1E 5HT1F 5HT1-like

Transduction Adénylcyclase Adénylcyclase Adénylcyclase Adénylcyclase Adénylcyclase

Agonistes 8-OH-DPAT, buspirone CP 93129, 5-CP Sumatriptan, 5-CT 5 HT 5 HT

Localisation Remarques SNC (système limbique surtout) SNC (ganglions de la base, nerfs périph.) SNC (ganglions de la 2 variantes existent :  et base principalement)  SNC Fonctions ? SNC Fonctions ?

5HT2

5HT2A 5HT2B 5HT2C

Adénylcyclase Phospholipase C Phospholipase C Phospholipase C Ouverture canal

5HT3 5HT4 5HT5 5HT6 5HT7 -

Sumatriptan, 5-CT  -méthyl-5-HT, DOI  -méthyl-5-HT, DOI  -méthyl-5-HT, DOI 2-méthyl-5-HT, mcp Cisapride, SC 53116 5HT 5HT 5HT

Vaisseaux cérébraux Muscle lisse, SNC plaquettes, poumons Estomac surtout SNC (plexus choroïde) Neurones centraux et périphériques SNC, cœur, vessie, digestif SNC SNC SNC Ancien 5HT1C Antagonisés par l’ondansétron, le granisétron...

Adénylcyclase ? Adénylcyclase Adénylcyclase

Fonctions ? Fonctions ? Fonctions ?

La migraine : les structures en cause
Cerveau Ganglion Vaisseau Tronc cérébral

V

ANTIPSYCHOTICS/COGNITION/SCHIZOPHRENIA From MY MELTZER and SR Mc GURK Schizophrenia Bulletin 1999 ; 25 : 233-255

Cognitive function

Clozapine 

Risperidone 

Olanzapine 

Perceptual/Motor processing Attention Reaction Time Executive function Working memory Verbal/Visual learning memory Verbal fluency Motor functionning

= =   =

=   = =

 =   ?

 : improvement

= unchanged

IMPROVEMENT OF COGNITIVE COMPONENTS : CLINICAL CONSEQUENCES IN SCHIZOPHRENIA Occupational and community functionning learning and memory Entire schizophrenia syndrome Learning at school Attention Verbal Fluency Social life Function

Verbal

Working Memory Memory ;

Executive

INTERHEMISPHERIC INTERACTION AFFECTED BY IDENTIFICATION OF CHINESE CARACTERS (From : W. Zhang and L. Feng in Brain and Cognition 1999 ; 39 : 93-99)

THEORY :

split brain research ; 2 H are specialized for different language functions

HYPOTHESIS : inter-H interaction improves information processing efficiency ? Notably if complexity increases PROCEDURE : . Chinese character matching task . 3 types : visually similar ; homonymous ; synonymous (form, sound, meaning) . Within field and across field presentation . Reactions times ; errors RESULTS : inter-H interaction improves semantic and phonetic (less errors ! ) matching.

Drugs can improve inter-H connectivity (ie : piracetam)

PIANO PLAYING IN ALZHEIMER'S DISEASE LONGITUDINAL STUDY OF A SINGLE CASE BEATTY WW, ROGERS CL, ROGERS RL et al Neurocase 1999 ; 5 : 459-469

HYPOTHESIS : implicit musical

Preserved musical performance in AD due to intact system for cognition (RH)

OVER 3 YEARLY EVALUATIONS : * Subtle losses in the quality of piano playing of familiar songs ; transfer from the piano to the xylophone * Progressive deterioration in : language, attention, visuospatial functions, sequencing picture priming, recognition of familiar songs discrimination of rhythm, meter, transposition and major from minor keys . Use of the implicit musical cognition in rehabilitation and socialization . Drugs and implicit memory ?

Intellects artificiels : « Artilects »
• Circuits électroniques
– loi de Moore – taille d ’une molécule

• • • •

Ingénierie évolutive Field programmable gate arrays Algorithmes génétiques Le cerveau artificiel (Hugo de Garis)

Les acteurs rennais
Neurologie (Pr Edan, Pr Vérin) Gériatrie (Pr Jouanny) Biotrial Pharmacologie (Pr Allain, Dr Schück) Essais cliniques Pharmaco-épidémiologie Pharmacovigilance Epidémiologie
(Pr Chaperon) Informatique médicale Pr Lebeux

Psychologie (Pr Lieury)

(JM Gandon)

CONCLUSION
• Pharmacological approaches of CNS diseases through cognitive processes • Quick switch from a receptor to…intelligence! • Decision and choice of drugs • Future : new drugs

Colin Mc Ginn
• « The water of the physical brain is turned into the wine of consciousness »
– (from : Brains to consciousness, Steven Rose, 1998)

– www.med.univ-rennes1.fr/etud/pharmaco


				
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