NEUROBIOLOGY OF CANNABIS ADDICTION Part I

Transcription

1 NEURBILGY F CANNABIS ADDICTIN Part I

2 1. Definition and mechanism of action of cannabinoids 2. Addictive potential of cannabinoids and mechanisms involved 3. Cognitive effects of cannabinoids and mechanisms involved

3 9 -THC (Gaoni & Mechoulam, 1964) + More than 60 Actif Compounds Cannabis sativa

4 NATURAL CANNABINIDS Me Me H H Me Me Me Me 9 -THC 8 -THC Me Me H H Me Me H Cannabinol Cannabidiol

5 SYNTHETIC CANNABINIDS H H Me N H Me Me N CP-55,940 WIN 55,212-2

6 Endocannabinoids are produced on demand from the cell membrane Phospholipid remodeling Phospholipid-derived precursors N H R 1 P - -R 2 -R 3 CH H NAPE-PLD DAG Lipase Endocannabinoids N H H H CH H Anandamide 2-Arachidonoylglycerol Degradation products H 2 N H Fatty Acid Amide Hydrolase H MAG Lipase H H CH H act locally are immediately metabolized after their action

7 Cannabinoid Receptors 1 M L 1 Hippocampus Basal Ganglia Cerebellum ther brain areas Peripheral tissues CB 1, CB 2 Cells of the GPR E immune system

8 agonist cannabinoid receptor Ca++ K+ G Protein α* GTP Β/γ Protein Kinase A MAP/ERK

9 Endocannabinoids act as neuromodulators EC reuptake & degradation The endocannabinoid system is a silent system that is activated in a transitory way in order to maintain the homeostatic equilibrium GLU Di Marzo V, 2005 Di Marzo V, 1998 Wilson R, 2002

10 CANNABINID SYSTEM PERIFERAL GASTRINTESTINAL INH. INT. MTILITY F. INMUNMDULATIN IMMUNITY METABLIC METABLISMEF. CARDIVASCULAR VASDILATATIN F. CENTRAL LEARNING AND CGNITIVE MEMRY DEFICITS APPETITE EATING INCREASE CNTRL ANALGESIA PAIN HIPACTIVITY MTR ANSILYSIS/ EMTINS ANXIGENESIS REINFRCEMENT ADICCTIN

11 1. Definition and mechanism of action of cannabinoids 2. Addictive potential of cannabinoids and mechanisms involved 3. Cognitive effects of cannabinoids and mechanisms involved

12 PARADIGMA DE AUTESTIMULACIÓN lds and Milner, 1954

13 Neuroimagen mediante resonancia magnética funcional : disminución de la actividad cortical en sujetos cocainómanos Volkow et al., Nature Rev, 2008

14 Does 9THC administration produce reinforcing effects in rodents?

15 The reinforcement properties of cannabinoids are very difficult to reveal in experimental animal models Conditioned Place Preference (CPP) Intravenous Self-Administration (isa)

16 PRE- CNDITINING PHASE CNDITINING PHASE TESTING PHASE ANIMAL MDELS F REWARD: CNDITINED PLACE PREFERENCE THC = Aversive Effects

17 Protocol to induce THC conditioned place aversion THC VEH THC VEH THC VEH THC VEH THC VEH PRE- CNDITI- NING PHASE CNDITINING PHASE TESTING PHASE THC (1 mg/kg, i.p.) THC (5 mg/kg, i.p.) VEHICLE (i.p.) Valjent & Maldonado, 2000

18 THC-INDUCED CNDITINED PLACE AVERSIN IN MICE Score (sec) VEHICLE THC 1 THC 5 Valjent & Maldonado, 2000

19 Protocol to induce THC conditioned place preference THC THC VEH THC VEH THC VEH THC VEH THC VEH PRE- CNDITI- NING PHASE PRIMING INJECTIN CNDITINING PHASE THC (1 mg/kg, i.p.) THC (5 mg/kg, i.p.) VEHICLE (i.p.) TESTING PHASE Valjent & Maldonado, 2000

20 THC-INDUCED CNDITINED PLACE PREFERENCE IN MICE 400 Score (sec) VEHICLE THC 1 THC 5 Valjent & Maldonado, 2000

21 PERANT DRUG INTRAVENUS SELF- ADMINISTRATIN MDEL

22 SELF-ADMINISTRATIN F THC IN SQUIRREL MNKEYS THAT PREVIUSLY SELF-ADMINISTERED CCAINE Tanda et al., 2000

23 SELF-ADMINISTRATIN F THC IN NAÏVE SQUIRREL MNKEYS Justinova et al., 2003

24 WIN 55,212-2 SELF-ADMINISTRATIN IN MICE WIN (µg/kg/inf) Nose-pokes/2 h Active hole Inactive hole Session Mendizabal et al., 2006

25 Common neurobiological substrate of the rewarding effects of the different drugs of abuse Limbic System Ventral Tegmental Area Acute administration of different drugs of abuse : Enhancement of the dopaminergic and opioid activity in the mesolimbic system

26 EFFECT F INTRAVENUS CANNABINIDS N DA DIALYSATES IN THE N. ACC F THE RAT THC (mg/kg) WIN 55,212-2 (mg/kg) Shell Core Saline Rimonabant Naloxone Tanda et al., 1997

27 ENDGENUS PIID PEPTIDES PR-PI- MELANCRTIN β-endorphin (µ, δ) PR-ENKEPHALIN Leu-enkephalin (δ) Met-enkephalin (δ) PR-DYNRPHIN Dynorphin A (κ) Dynorphin B (κ) α-neoendorphin (κ) β-neoendorphin (κ) Leu-enkephalin (δ)