NEURBILGY F CANNABIS ADDICTIN Part I
1. Definition and mechanism of action of cannabinoids 2. Addictive potential of cannabinoids and mechanisms involved 3. Cognitive effects of cannabinoids and mechanisms involved
9 -THC (Gaoni & Mechoulam, 1964) + More than 60 Actif Compounds Cannabis sativa
NATURAL CANNABINIDS Me Me H H Me Me Me Me 9 -THC 8 -THC Me Me H H Me Me H Cannabinol Cannabidiol
SYNTHETIC CANNABINIDS H H Me N H Me Me N CP-55,940 WIN 55,212-2
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
Cannabinoid Receptors 1 M L 1 Hippocampus Basal Ganglia Cerebellum ther brain areas Peripheral tissues CB 1, CB 2 Cells of the 1990 1992 GPR55 2008 E 360 472 immune system
agonist cannabinoid receptor Ca++ K+ G Protein α* GTP Β/γ Protein Kinase A MAP/ERK
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
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
1. Definition and mechanism of action of cannabinoids 2. Addictive potential of cannabinoids and mechanisms involved 3. Cognitive effects of cannabinoids and mechanisms involved
PARADIGMA DE AUTESTIMULACIÓN lds and Milner, 1954
Neuroimagen mediante resonancia magnética funcional : disminución de la actividad cortical en sujetos cocainómanos Volkow et al., Nature Rev, 2008
Does 9THC administration produce reinforcing effects in rodents?
The reinforcement properties of cannabinoids are very difficult to reveal in experimental animal models Conditioned Place Preference (CPP) Intravenous Self-Administration (isa)
PRE- CNDITINING PHASE CNDITINING PHASE TESTING PHASE ANIMAL MDELS F REWARD: CNDITINED PLACE PREFERENCE THC = Aversive Effects
Protocol to induce THC conditioned place aversion THC VEH THC VEH THC VEH THC VEH THC VEH 1 3 4 5 6 7 8 9 10 11 12 13 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
THC-INDUCED CNDITINED PLACE AVERSIN IN MICE 300 200 Score (sec) 100 0-100 -200-300 VEHICLE THC 1 THC 5 Valjent & Maldonado, 2000
Protocol to induce THC conditioned place preference THC THC VEH THC VEH THC VEH THC VEH THC VEH 1 2 3 4 5 6 7 8 9 10 11 12 13 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
THC-INDUCED CNDITINED PLACE PREFERENCE IN MICE 400 Score (sec) 300 200 100 0-100 VEHICLE THC 1 THC 5 Valjent & Maldonado, 2000
PERANT DRUG INTRAVENUS SELF- ADMINISTRATIN MDEL
SELF-ADMINISTRATIN F THC IN SQUIRREL MNKEYS THAT PREVIUSLY SELF-ADMINISTERED CCAINE Tanda et al., 2000
SELF-ADMINISTRATIN F THC IN NAÏVE SQUIRREL MNKEYS Justinova et al., 2003
WIN 55,212-2 SELF-ADMINISTRATIN IN MICE 12.5 6.25 3.125 WIN (µg/kg/inf) Nose-pokes/2 h 25 15 5 Active hole Inactive hole 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Session Mendizabal et al., 2006
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
EFFECT F INTRAVENUS CANNABINIDS N DA DIALYSATES IN THE N. ACC F THE RAT THC (mg/kg) WIN 55,212-2 (mg/kg) 0.15 0.30 0.15 0.30 Shell Core Saline Rimonabant Naloxone Tanda et al., 1997
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)