icrs sat 2008
DESCRIPTION
Palestra proferida no Satélite sobre potencial terapêutico de canabinóides da ICRS no Chipre 2008TRANSCRIPT
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!