ICRS Sat 2008

FACILITATION OF CONTEXTUAL FEAR MEMORY

EXTINCTION AND ANTI-ANXIOGENIC EFFECTS OF

AM404 AND CANNABIDIOL IN CONDITIONED RATS

Fabrício Pamplona, on behalf ofProf. Reinaldo N. Takahashi

Depto. de Farmacologia, CCB, UFSC, Florianópolis – SC, Brazi l

Therapeutic Potential of the Cannabinoids: Present and Future

Cannabinoid agonists induce complex and contradictory effects, being either anxiolytic or anxiogenic depending on the drug.

Enhancement of endocannabinoid transmission induces anxiolytic effects.

Antagonism of CB1 receptors induces anxiogenic effects.

Patel and Hillard (2006)Patel and Hillard (2006)

C A N N A B I N O I D S vs A N X I E T Y

Generalized anxiety disorderPanic disorder with/without Agoraphobia Post-traumatic stress disorder (PTSD)Specific phobiaAgoraphobia without history of panic disorderSocial phobiaObsessive-compulsive disorderAcute stress disorderAnxiety disorder due to a general medical conditionSubstance-induced anxiety disorder

A N X I E T Y

Yehuda (2002)Yehuda (2002)

• Generalized anxiety disorder• Panic disorder with/without Agoraphobia • Post-traumatic stress disorder (PTSD)• Specific phobia• Agoraphobia without history of panic disorder• Social phobia• Obsessive-compulsive disorder• Acute stress disorder• Anxiety disorder due to a general medical condition• Substance-induced anxiety disorder

A N X I E T Y

Group of Symptoms:- Fear - Avoidance- Hyperarousal - Social withdrawal- Emotional Numbing

Yehuda (2002)Yehuda (2002)

• Generalized anxiety disorder• Panic disorder with/without Agoraphobia • Post-traumatic stress disorder (PTSD)• Specific phobia• Agoraphobia without history of panic disorder• Social phobia• Obsessive-compulsive disorder• Acute stress disorder• Anxiety disorder due to a general medical condition• Substance-induced anxiety disorder

A N X I E T Y

Group of Symptoms:- Fear - Avoidance- Hyperarousal - Social withdrawal- Emotional Numbing

Limited pharmacotherapyLimited pharmacotherapy(5HT re-uptake inhibitors)(5HT re-uptake inhibitors)

Association with exposure-based Association with exposure-based psychotherapiespsychotherapies

Yehuda (2002)Yehuda (2002)

C O N T E X T U A L F E A R vs P T S D

Conditioned fear responses have been extensively used

to understand how aversive memories are formed and as

putative animal models of disorders such as PTSD.

Conditioned fear PTSD

C A N N A B I N O I D S AND FEAR M E M O R I E S

C A N N A B I N O I D S USED

Pacher et al (2006)Pacher et al (2006)

C A N N A B I N O I D S USED

Pacher et al (2006)Pacher et al (2006)

stereotaxic surgery

Day 1 (conditioning): 3 min shock (1.5

mA, 1s) 1 min

Day 2-4 (extinction): 9 min context exposure.

3 X at 24 h intervals

Freezing evaluation

Day 5 (drug-free test):3 min context

exposure

C O N T E X T U A L F E A R C O N D I T I O N I N G

Freezing evaluation

Experiment 1:AM404 (0.2, 1, 2 ug/uL, i.c.v.), CBD (0.2, 1, 2 ug/uL, i.c.v.) or control (10% DMSO) 5min before extinction sessions

Experiment 2:SR141716A (0.2 mg/kg, i.p.) 20 min before

AM404 or CBD i.c.v. injections

Experiment 3:Capsazepine (5 ug/uL, i.c.v.) 5 min before

AM404 or CBD i.c.v. injections

stereotaxic surgery

Day 1 (conditioning): 3 min shock (1.5

mA, 1s) 1 min

Day 2-4 (extinction): 9 min context exposure.

3 X at 24 h intervals

Day 5 (drug free test):3 min context

exposure

C O N T E X T U A L F E A R C O N D I T I O N I N G

Freezing evaluation

Freezing evaluation

R E S U L T S

Experiment 1: Effects of AM404 and CBD on contextual fear extinction

R E S U L T S

Experiment 2: Role of CB1 cannabinoid receptors

R E S U L T S

Experiment 3: Role of TRPV1 vanilloid receptors

R E S U L T S

Possible contribution of anxiolytic-like effects?

R E S U L T S

Experiment 4: Effects of DZP on contextual fear extinction

R E S U L T S

Experiment 5: Effects of AM404, CBD and DZP in the fear-potentiated EPM test.

R E S U L T S

Experiment 5: Effects of AM404, CBD and DZP in the fear-potentiated EPM test.

R E S U L T S

Experiment 5: Effects of AM404, CBD and DZP in the fear-potentiated EPM test.

R E S U L T S

Experiment 5: Effects of AM404, CBD and DZP in the fear-potentiated EPM test.

• The eCB uptake/metabolism inhibitor AM404 and the phytocannabinoid CBD facilitate extinction of contextual fear memory in rats.

• These facilitative effects were antagonized by the selective-CB1

receptor antagonist SR141716A, but not by the selective-TRPV1

receptor antagonist capsazepine.

• Anxiolytic-like effects might have contributed to the facilitation of extinction as suggested by anti-anxiogenic effects by AM404 and CBD in the fear-potentiated EPM test.

• …and highlight that the phytocannabinoid CBD could be an interesting pharmacological tool to reduce the anxiogenic effects of stress and promote the extinction of fear memories.

C O N C L U S I O N S

A C K N O W L E D G E M E N T S

Rafael BitencourtRafael BitencourtPhD studentPhD student

Fabrício PamplonaFabrício PamplonaPhD studentPhD student

Prof. Dr. Reinaldo Prof. Dr. Reinaldo N. TakahashiN. Takahashi

CANNABINOID BOYS Hi Rik,Thanks a lot for your help

Muito Obrigado!