1. Definition and mechanism of action of cannabinoids
2. Addictive potential of cannabinoids and mechanisms involved
3. Cognitive effects of cannabinoids and mechanisms involved
NATURAL CANNABINOIDS
Me
OH
O
Me
Me
Me
OH
O
Me
Me
Me
OH
OHMe
Me
OH
OMe
∆9-THC ∆8-THC
Cannabinol Cannabidiol
Me
OH
O
Me
Me
Me
OH
O
Me
Me
Me
OH
O
Me
Me
Me
OH
O
Me
Me
Me
OH
O
Me
Me
Me
OH
OHMe
Me
OH
OHMe
Me
OH
OHMe
Me
OH
OMe
Me
OH
OMe
Me
OH
OMe
∆9-THC ∆8-THC
Cannabinol Cannabidiol
SYNTHETIC CANNABINOIDS
CP-55,940 WIN 55,212-2
OH
HO
OH
Me Me
O
N
O
N
O
Me
CP-55,940 WIN 55,212-2
OH
HO
OH
Me Me
OH
HO
OH
Me Me
O
N
O
N
O
Me
O
N
O
N
O
Me
Endocannabinoids are producedon demand from the cell membrane
• are immediately metabolized after their action
NH
OO
PO
O-O
O-R2
R1O
O
O
CHO-R3
OH
NH
OH
O
O
O
CH
OH
OH
NAPE-PLD DAG Lipase
Phospholipid-derivedprecursors
Endocannabinoids
Degradation products
2-ArachidonoylglycerolAnandamide
Phospholipid remodeling
• act locally
O
OHH2N
OH HO CHOH
OH
Fatty Acid Amide Hydrolase MAG Lipase
Cannabinoid Receptors
E
LL
M
472
1
1
360
CB1 , CB2 •Cells of the immune system
•Hippocampus•Basal Ganglia•Cerebellum•Other brain areas•Peripheral tissues
1990 1992
GPR552008
The endocannabinoidsystem is a “silent”
system that is activatedin a transitory way in order to maintain the
homeostatic equilibrium
Endocannabinoids act asneuromodulators
Di Marzo V, 2005Di Marzo V, 1998Wilson R, 2002
EC reuptake & degradation
GLU
CANNABINOID SYSTEM
PERIFERAL
CENTRALLEARNING AND
MEMORY
EATING CONTROL
PAIN
MOTOR ACTIVITY
EMOTIONS
REINFORCEMENT
COGNITIVE DEFICITS
APPETITE INCREASE
ANALGESIA
HIPOACTIVITY
ANSIOLYSIS/ANXIOGENESIS
ADICCTION
GASTROINTESTINAL F.
IMMUNITY
METABOLISM
CARDIOVASCULAR F.
INH. INT. MOTILITY
INMUNOMODULATION
METABOLIC EF.
VASODILATATION
1. Definition and mechanism of action of cannabinoids
2. Addictive potential of cannabinoids and mechanisms involved
3. Cognitive effects of cannabinoids and mechanisms involved
Neuroimagen mediante resonancia magnética funcional : disminución de la actividad
cortical en sujetos cocainómanos
Volkow et al., Nature Rev, 2008
Conditioned Place Preference (CPP)
Intravenous Self-Administration (iSA)
The reinforcement properties of cannabinoids are very difficult to
reveal in experimental animal models
PRE-
CO
ND
ITION
ING
PHA
SE
TESTING
PHA
SEC
ON
DITIO
NIN
G PH
ASE
ANIMAL MODELS OF REWARD:
CONDITIONED PLACE PREFERENCE
THC = Aversive Effects
Protocol to induce THC conditioned place aversion
DAY1
THC VEHTHC VEHTHC VEHTHC VEHTHC VEH
DAY3
DAY4
DAY5
DAY6
DAY7
DAY8
DAY9
DAY10
DAY11
DAY12
DAY13
PRE-CONDITIO-NING PHASE
TESTINGPHASECONDITIONING PHASE
THC (1 mg/kg, i.p.)THC (5 mg/kg, i.p.) VEHICLE (i.p.)
Valjent & Maldonado, 2000
THC-INDUCED CONDITIONED PLACE AVERSION IN MICE
Scor
e(s
ec)
-100
0
100
200
300
VEHICLE THC 5
-200
-300
THC 1
Valjent & Maldonado, 2000
Protocol to induce THC conditioned place preference
DAY1
THC VEHTHC VEHTHC VEHTHC VEHTHC VEHTHC
DAY2
DAY3
DAY4
DAY5
DAY6
DAY7
DAY8
DAY9
DAY10
DAY11
DAY12
DAY13
PRE-CONDITIO-NING PHASE
TESTINGPHASECONDITIONING PHASE
PRIM
ING
INJE
CT
ION
THC (1 mg/kg, i.p.)THC (5 mg/kg, i.p.) VEHICLE (i.p.)
Valjent & Maldonado, 2000
THC-INDUCED CONDITIONED PLACE PREFERENCE IN MICE
Scor
e(s
ec)
-100
0
100
200
300
400
VEHICLE THC 1 THC 5
Valjent & Maldonado, 2000
SELF-ADMINISTRATION OF THC IN SQUIRREL MONKEYS THAT PREVIOUSLY SELFTHAT PREVIOUSLY SELF--ADMINISTERED COCAINEADMINISTERED COCAINE
Tanda et al., 2000
WIN 55,212-2 SELF-ADMINISTRATION IN MICE
Session
Active hole
Inactive hole
3.12512.5 6.25 WIN (µg/kg/inf)
5
15
25
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Nos
e-po
kes/
2 h
Mendizabal et al., 2006
Common neurobiological substrate of the rewarding effectsof the different drugs of abuse
Acute administration of different drugs of abuse :Enhancement of the dopaminergic and opioid activity in the mesolimbic
system
Limbic System
VentralTegmentalArea
EFFECT OF INTRAVENOUS CANNABINOIDS ON DA DIALYSATES IN THE N. ACC OF THE RAT
THC (mg/kg) WIN 55,212-2 (mg/kg)0.15 0.30 0.15 0.30
Shell
Core
SalineRimonabantNaloxone
Tanda et al., 1997