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SENSORY AFFERENTS

Psyche. MOTOR OUTPUTS. SENSORY AFFERENTS. Prefrontal Cortex. Hippocampus. Sept/Acc. Amygdala. DA. HT. DA. DA. DA. VTA/SN. PLEASURE. THE WORD « ADDICTION ». OLD FRENCH : « ETRE ADDICTE ». ?. DEBTS. TO PAY ONE’S DEBTS. ENGLISH : TO BE ADDICTED TO DRUGS. ADDICTION.

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SENSORY AFFERENTS

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  1. Psyche MOTOR OUTPUTS SENSORY AFFERENTS

  2. Prefrontal Cortex Hippocampus Sept/Acc Amygdala DA HT DA DA DA VTA/SN

  3. PLEASURE

  4. THE WORD « ADDICTION » OLD FRENCH : « ETRE ADDICTE » ? DEBTS TO PAY ONE’S DEBTS ENGLISH : TO BE ADDICTED TO DRUGS ADDICTION

  5. THE WORD « ADDICTION » OLD FRENCH : ETRE ADDICTE DEBTS TO PAY ONE’S DEBTS ? ENGLISH : TO BE ADDICTED TO DRUGS ADDICTION

  6. THE WORD « ADDICTION » OLD FRENCH : ETRE ADDICTE DEBTS TO PAY ONE’S DEBTS PLEASURE ENGLISH : TO BE ADDICTED TO DRUGS ADDICTION

  7. Dopamine Cocaine synaptic cleft Post-synaptic neuron Dopamine receptors

  8. INJECTION PUMP COMPUTER INACTIVE HOLE ACTIVE HOLE SELF-ADMINISTRATION

  9. COCAINE Rocha et al., 1998

  10. 1600 1 2 3 4 5 6 7 8 9 1400 1200 1000 Locomotor activity (counts/60 min) 800 600 400 200 0 0 5 10 15 20 25 30 Time (days)

  11. acute Repeat. (withdraw. 4-days) -80 -40 0 40 80 120 160 200 Time (min) Frontal Cortex

  12. A 2500 acute repeat. (withdraw. 4-days) 2000 repeat. (withdraw. 1-month) 1500 NE (% baseline) Amph. 1000 Frontal cortex 500 0 B 150 100 Locomotor activity (1/4 turn per 5min.) 50 0 0 80 120 40 160 200 -40 Time (min.)

  13. GABA D1 D2 PCF AMPA Glu GABAA NAcc GABA DA GABA VTA

  14. GABA D1 D2 α1b PCF - 5-HT2A AMPA Glu GABAA NAcc GABA DA GABA VTA LC DR 5-HT GABA GABA GABA NA

  15. GABA D1 D2 α1b PCF 5-HT2A AMPA Glu GABAA NAcc GABA DA GABA VTA LC DR GABA 5-HT GABA GABA NA α1b-R

  16. GABA D1 D2 α1b PFC 5-HT2A AMPA Glu GABAA NAcc GABA DA GABA VTA LC DRD 5-HT2AR GABA 5-HT GABA GABA NA α1b-R NA/ 5-HT COUPLING UNCOUPLING

  17. D1R D2R α1bR CPF 5-HT2AR Glutamate R Glu DA ATV RD LC 5-HT2AR GABA 5-HT GABA GABA NA α1b-R UNCOUPLING INDUCES NA/ 5-HT HYPERREACTIVITY AND DESYNCHRONIZATION

  18. REPEATED DRUGS OF ABUSE UNCOUPLING NA/5-HT NA/5-HT HYPERREACTIVITY AND DESYNCHRONIZATION CHRONIC DISTRESS WHY DO ADDICTS TAKE DRUGS ? BECAUSE DRUGS OF ABUSE ARTIFICIALLY RE-COUPLE AND BRING TEMPORARY RELIEF

  19. No prediction Reward occurs (No CS) R Reward predicted Reward occurs CS R Reward predicted No reward occurs -1 0 1 2s CS (No R)

  20. ABSENCE D’EFFET HYPERLOCOMOTEUR DE LA NICOTINE CHEZ LA SOURIS

  21. Nicotine / Saline *** * *** *** *** *** * Tranyl / Saline Activité locomotrice (1/4 tour par 10 min.) Temps (min.) EFFET HYPERLOCOMOTEUR DE LA NICOTINE CHEZ LA SOURIS PRE-TRAITEE PAR LA TRANYLCYPROMINE

  22. R NR (RENFORCE) (NON RENFORCE) AUTO-ADMINISTRATION

  23. Réponses (/3heures) Temps (jours) AUTO-ADMINISTRATION DE NICOTINECHEZ LE RAT PRE-TRAITE PAR LA TRANYLCYPROMINE ***

  24. d-amphetamine B A 1000 NE (% of baseline) 500 0 para-chloro-amphetamine D C 1500 5-HT (% of baseline) 1000 500 0 0 40 120 200 0 40 120 200 -40 80 160 -40 80 160 Time (min) Time (min)

  25. d-amphetamine B A 1000 NE (% of baseline) 500 0 para-chloro-amphetamine D C 1500 5-HT (% of baseline) 1000 500 0 0 40 120 200 0 40 120 200 -40 80 160 -40 80 160 Time (min) Time (min)

  26. A C B D _ _ Repeated (SR/Pz) Repeated (tranyl/nico) Repeated saline Repeated (tranyl/nico + SCH) Repeated (SCH) Repeated (tranyl/nico + SR/Pz) - - - - -

  27. A B C

  28. A C D B Repeated saline Repeated (WAY + Nico) Repeated (WAY + saline)

  29. PROPOSITIONS ET OBSERVATIONS - L’addiction résulte d’un découplage des neurones NA et 5-HT. - Ce découplage (obtenu avec l’amphétamine. la cocaïne, la morphine et l’alcool) est dû à la stimulation intense et répétée des récepteurs a1b-adrénergiques et/ou 5-HT2A. • Le découplage n’est pas obtenu avec la nicotine seule. • Le découplage est obtenu en présence de nicotine + IMAO • ou de nicotine + un antagoniste des récepteurs 5-HT1A.

  30. CONCLUSIONS La nicotine n’est pas addictive par elle-même. Elle le devient mélangée au tabac car les IMAOs qu’il contient désensibilisent les récepteurs 5-HT1A. Anne-Sophie Villégier (SFT)/ Lucas Salomon (MRT)/Christophe Lanteri (MILDT)

  31. REMERCIEMENTS Collaborations Agnès Auclair Gérard Blanc Joëlle Adrien Patricia Cougnot Jean-Pierre Changeux Laurent Darracq Emilie Doucet Susanna Cotecchia Candice Drouin Jay Gingrich Jacques Glowinski Sylvie Granon Gérard Godeheu Vanessa Houades Michel Hamon Christophe Lanteri Sandra Jimena Hernández Vallejo Lucas Salomon Yvette Torrens Laurence Lanfumey Fabrice Trovero Philip Seeman Anne-Sophie Villégier

  32. A 2500 acute repeat. (withdraw. 4-days) 2000 repeat. (withdraw. 1-month) 1500 NE (% baseline) Amph. 1000 Frontal cortex 500 0 B 150 100 Locomotor activity (1/4 turn per 5min.) 50 0 0 80 120 40 160 200 -40 Time (min.)

  33. Injection AIGUË Morphine / test SR46349B WT α1b- AR KO Saline – Morphine (20 mg/kg) SR46349B - Morphine

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