NEUROBIOLOGY OF CANNABIS ADDICTION

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

Cannabis sativa

∆9-THC (Gaoni & Mechoulam, 1964)+

More than 60 Actif Compounds

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

cannabinoid receptor

agonist

Β/γα* GTP

G Protein

Protein Kinase A MAP/ERK

Ca++ K+

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

PARADIGMA DE AUTOESTIMULACIÓN

Olds and Milner, 1954

Neuroimagen mediante resonancia magnética funcional : disminución de la actividad

cortical en sujetos cocainómanos

Volkow et al., Nature Rev, 2008

¿ Does ∆9THC administrationproduce reinforcing effects in

rodents?

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

OPERANT DRUG INTRAVENOUS SELF-ADMINISTRATION MODEL

SELF-ADMINISTRATION OF THC IN SQUIRREL MONKEYS THAT PREVIOUSLY SELFTHAT PREVIOUSLY SELF--ADMINISTERED COCAINEADMINISTERED COCAINE

Tanda et al., 2000

SELF-ADMINISTRATION OF THC IN NAÏVE SQUIRREL MONKEYS

Justinova et al., 2003

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

PRO-DYNORPHINDynorphin A (κ)Dynorphin B (κ)

α-neoendorphin (κ)β-neoendorphin (κ)Leu-enkephalin (δ)

PRO-OPIO-MELANOCORTINβ-endorphin (µ , δ)

PRO-ENKEPHALINLeu-enkephalin (δ)Met-enkephalin (δ)

ENDOGENOUS OPIOID PEPTIDES