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Pharmacological and neurobiological aspects of drug addiction

Pharmacological and neurobiological aspects of drug addiction. Paul Verbanc. Sedatives Opiates Alcohol Benzodiazepine Others Psychostimulants Cocaine Amphetamine Amphetamine Methoxyline. Hallu cinogens Mescaline Ps ylocibine LSD Cannabis Others Nicotine PCP Others.

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Pharmacological and neurobiological aspects of drug addiction

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  1. Pharmacological and neurobiological aspects of drug addiction Paul Verbanc

  2. Sedatives Opiates Alcohol Benzodiazepine Others Psychostimulants Cocaine Amphetamine Amphetamine Methoxyline Hallucinogens Mescaline Psylocibine LSD Cannabis Others Nicotine PCP Others Classification of substances leading to toxicomani

  3. Consumption Repetition Tolerance Increase of consumption Physical dependence Classic models in addiction

  4. « Contrary to sedative substances like alcohol, barbiturates and other opiates, psycho stimulants do not lead to physical dependence!»

  5. Positive reinforcement of consumption • Primary factors: Euphoria, «Pleasure», « Stimulation », etc. • Secondary factors:anxiolyse,antidepressor effect, effect on sleep etc. • Tertiary factors:control of symptoms during abstinance

  6. Reinforcing effect Associative stimuli (Environment) Discriminativeeffects connected with consumption or lack of drugs Selfadministration Place preference Light association of selfadministration Behavioral aspects of consumption of drugs

  7. New Zealand • Cohort of 198 people who have used cannabis before the age of 16 traced between the age of 16 -21 • Relation of the effects of cannabis during the first consumption at the age of 16 • Positive(high / happy / relaxed / did silly things / laughed a lot) • Negative(ill / frightened / passed out) Risk of dependence at the age of 21. symptoms + risk 0 5.2% 1 8.5% 2 13.3% 3 19.9% 4 28.7% 5 39.1% p < 0.001 symptoms - risk 0 19.2% 1 31.3% 2+ 22.7% p = 0.19 FERGUSSON DM, HORWOOD J, LYNSKEY MTand MADDEN PAF Early reactions to cannabis predict later dependence. Arch Gen Psychiatry 60 : 1033 – 1039, 2003.

  8. Induction of euphoria in the beginning of consumption can be observed in almost all substances which cause addiction • The anatomical substrate of this activity is the activation of mesolimbic dopaminergic process, consisting natural part«circle of recompense»

  9. DI CHIARA G and IMPERATO A.Drugs abused by humans preferentially increase synaptic dopamine concentration in the mesolimbic system of freely moving rats. PNAS 85, 5274-5278 , 1988

  10. Cocaine and amphetamineMode of action • Increase in the quantity of noradrenaline and dopamine at the level of synapticcleft. Noradrenergic system: responisble for high spirits Dopaminergic system: responsible for the regulation of movements, and also for “circle of recompense ”

  11. If psychostimulants did not lead to tolerance development ,then what would happen with the repetition of consumption?

  12. Psychostimulants Behaviour sensibility • Repetative and intermittant consumption • Progressive increase in motor response • Parallel increase in the release of dopamine at the level of limbic system • Where does the progressive increase of stimulating effect come from?

  13. Effect of cocaine on genetic regulation DA D1 DA : dopamine D1 : D1 receptor G : protein G cAMP : cyclic AMF PKA : cAMF- dependent protein kinase CREB : cAMP response element binding protein IEG : immediate early genes Gi cAMP Transcription IEG PKA CREB

  14. Immediate early genes • Proto - oncogenes • c-fos • jun • ... • Neuropeptides • somatostatine • VIP • tyrosine hydroxylase • prodynorphine • ......

  15. PsychostimulantsBehavioral sensibility • Increased during stress exposure • Role of glucocorticoids? Locomotive activity at intervals of 60 mins after injection

  16. The role of abstinant syndrome as a stress factor DE WITTE, P., PINTO, E., ANSSEAU, M. and VERBANCK, P. Alcohol and withdrawal : from animal research to clinical issues. Neuroscience & Biobehavioral Reviews 27: 189-197, 2003

  17. Stress • Sensibility • Neurotoxicity AAE CRF cortisol

  18. Hippocampus Role of memory

  19. Prefrontal cortex Role in executive functions

  20. Executive functions • Memory • Attention • Inhibition • Flexibility • Planning • Abstract explaination • Speed of performance

  21. Pharmacokinetics

  22. VOLKOW N.D. et SWANSON J.M. Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD American Journal of Psychiatry 160: 1909-1918, 2003 • Dose • Pharmacokinetics • Individual variability • Context of acceptance of substance

  23. Long term use of psychostimulants • Continuous consumption: progressive development of tolerance and frequent appearance of abstinant behaviour • Increase of cateholamines and mostly dopamine • Intermittent consumption: behavioral sensibility and loss of control over drinking • Increase in the release of dopamine during consumption

  24. Behavioral sensibility • Progressive increase of motor response during repetitive comsumption of psychostimulants. • Parallel increase in the release of dopamine in « circle of recompense » leading to increase of reinforcing effect of the products and loss of control over consumption. • Crossed for psychostimulant ,alcohol,opiates, etc. • Irreversibilty during exposure of stress factor • Irreversiblity during continuous consumption? • Parallel modification of genetic expression.

  25. Crossed sensiblity 150 mg/kg THC 0.5 mg/kg morphine Cadoni and al. Psychopharmacology (2001),158 : 259-266 150 mg/kg THC

  26. Repeated consumption of toxicomanogenetic substances:tolerance and sensibility?

  27. Repeated consumption of toxicomanogenetic substances • Tolerance in relation to possible sedative effect of the substance • Sensibility in relation to stimulative (leading to euphoria) effects of the substance

  28. Questionnaire for the habits of alcohol intake (I. PELC)Research on 80 patients addicted to alcohol during detoxication % des patients

  29. Classic Consumption Continuous consumption Тolerance Increase in consumption Physical dependence Actual Consumption Reinforcing effect and repetitive comsumption Sensibility and loss of control over consumption Tolerance Physical dependence Models of addiction

  30. Natural reinforcing substance(Food Liquids, etc.) intensity desire for consumption consumption Time StimulusX

  31. Substances leading to addiction intensity wish for consumption consumption Time Stimulus X

  32. Just one more and we leave ,is it ok?

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