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Cannabinoid CB1 receptor

Cannabinoid CB1 receptor. Role in extinction and sensitization. Say it with me. Kah nab a noid Ka banna boy. outline. Receptor and receptor subtypes Location, function and distribution Endogenous ligand Kamprath paper Pamplona et al paper Results Clinical applications.

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Cannabinoid CB1 receptor

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  1. Cannabinoid CB1 receptor Role in extinction and sensitization

  2. Say it with me • Kah nab a noid • Ka banna boy

  3. outline • Receptor and receptor subtypes • Location, function and distribution • Endogenous ligand • Kamprath paper • Pamplona et al paper • Results • Clinical applications

  4. CB receptor subtypes • CB1-found in brain • CB1A-very little info, but does exist • CB2-found in immune cells (not in brain) • CB1 is of most interest to us today • acts via G-protein which, when activated, inhibits adenylate cyclase as well as voltage gated CA++ channels, stimulates K+ channels

  5. Distribution of CB1 • Cerebellum- • motor function • Cortex- • association • Basal Ganglia • Limbic system • Hippocampus-learning • Amygdala-fear • NO CB1 in thalamus,medulla or brainstem

  6. Limbic CB1 receptors • Exclusively localized to GABA and Cholecystokinin (CCK) containing presynaptic terminals • Receptor activates G-protein that suppresses GABA release • Less GABA=more anxiety? • In hippocampus- release of ACh is inhibited

  7. CB1 in a RAT BRAIN

  8. Relative density of CB1R in select brain regions

  9. Anandamide • Endogenous cannabinoid • Synthesis not known • When bound in high doses, behaviors include: hypothermia, analgesia, hypomobility, catalepsy • LIPID NT, can pass membrane, thought to be synthesized on demand • Acts on membrane bound and intracellular locations

  10. Anandamide • Brain levels rival that of DA(felder et al 96) • Binds to both CB1 and CB2 • Acts as agonist • Highest conc in hippo, striatum, ctx and cerebellum • THC acts as CB1 agonist • Some diet drugs act as CB1 antagonist • Rimonabant (aka SR141716)

  11. Kamprath et al Neuroscience 06 • Sensitization: nonassociative learning • General increase in reponse to potentially harmful stimuli after aversive experience • E.g. inescapable footshock=alter behav& cort • Fear conditioning: tone paired with shock • Re-exposure to tone activates memory of the tone-punishment association and induces response • E.g. rats freeze upon re-exposure to tone

  12. Extinction vs Habituation • Extinction: new association btwn tone and the nonappearance of predicted punisment (safety learning) • Suppresses the expression of the memory of the tone-shock pairing • Habituation: repeated non-reinforced tone presentation will lead to a decrease in response to the tone

  13. Role of CB1 • CB1 role in extinction is limited to aversive testing conditions • Genetic ablation or pharmacological blockade of CB1 impairs the extinction of fear memories • CB1 plays no role in conditioning to tasks involving positive reinforcement

  14. Goals of study • Examine the role of CB1 in extinction and habituation of acquired fear responses • Utilize genetic mutant CB -/- and ‘wild type’ CB+/+ • Utilize SR selective CB1 antagonist

  15. Cond Sens CB-/- showed same freezing Behavior with or without shock CB-/- No difference in acquisition sensitized conditioned Conditioning: 80 dB tone with .7 mA footshock next day tone only in novel envir CB-/- show prolonged and stronger freezing to tone CB+/+ sensitized conditioned Sensitization: .7 mA footshock only NO TONE next day tone only in novel envir CB-/- show prolonged and longer freezing to tone

  16. Can CB-/- associate memories? • Because no difference in freezing was seen between tone-shock pair and tone alone in CB-/- animals, authors wanted to make sure that CB-/- animals could in fact form an associative memory i.e. associate the tone with the impending shock • Utilize electrophysiology to record auditory evoked potentials in CA1 region of hippo

  17. No significant differences between CB-/- and CB+/+ in the potentiation of auditory-evoked potentials • Both groups have similar activation in CA1 region when exposed to loud tone

  18. Within session vs long term • Next, authors wanted to see what changes in extinction are seen over time between the two groups • Testing occurred as before, with the addition of another testing round 5 days after the first test

  19. CB-/- sensitized conditioned CB+/+ sensitized conditioned CB-/- again froze longer And stronger both 1 day and 6 days after conditioning CB+/+ animals treated with SR show same trend as the Mutant strain, even 5 days later SR CB1 controls both within session and long term fear adaptation

  20. Pamplona et al Psychopharmacology 2006 The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in RATS

  21. Main Objectives • Examine whether admin of CB1 agonist WIN could faciliate the extinction of recent and/or remote contextual fear memory in rats • Investigate the role of CB1 antagonist SR in the extinction process • Determine if not only fear memory but also spatial memory was affected by these drugs

  22. Methods • Animals • Male Wistar rats, group housed • Behavorial testing occurred during light phase of the day/night cycle….. Why? • N of 7-10 animals per group

  23. Drugs • Win and SR dissolved in 0.9% saline with 10% DMSO and 0.1% Tween 80 • Controls received vehicle only • Animals injected IP 0.2mL per 100 g BW • Win given 30 min before testing • SR given 20 minutes before testing

  24. Behavioral Procedures • Fear Conditioning • Contextual fear: 3 min in cond chamber and then received 1 sec 1.5 mA shock, 60 seconds after shock they were removed • Tone fear: 3 min in cond chamber and then 10 sec of 80 dB tone that co-terminated with 1 sec 1.5 mA shock, 60 seconds after shock they were removed • Freezing was the behavior measured during subsequent testing

  25. Effects of CB1R on extinction of recent contextual fear memory • Successive exposures to conditioning chamber were used to assess short term (within exposure) and long term (between exposure) extinction of cond fear • 24, 48 and 72 hours after contextual conditioning animals were placed back in chamber and freezing recorded • WIN or SR treatment before each session

  26. Control animals froze less on each successive re-exposure 1.0 mg/Kg dose of SR disrupted this extinction(they froze more than control group) Low dose of WIN facilitated extinction (they froze less than controls); high dose of WIN disrupted extinction Mid dose of WIN mimicked control group Dose Dependant Effects!

  27. In the first 3 minutes (retrieval) of the 9 minute test block SR had no effect But WIN at the mid dose showed Decreased freezing time, this means That there is no effect of WIN on Memory retrieval

  28. Effects of WIN on extinction of remote contextual fear memory

  29. 5 days of exposure to context shows that WIN treated rats freeze less, extinction is facilitated in short term fear memory by WIN Drug free rats 48 hours after the 5 day extinction protocol WIN treated, contextual cond rats froze less than control and SR treated rats WIN facilitates extinction of remote fear memory

  30. Unconditioned freezing behavior • Day 1 rats placed in cond chamber for 3 minutes, shocked (1 sec 1.5mA), 60 seconds later they were removed • Day 2 rats treated with WIN or SR, placed in novel environment and freezing behavior was measured • Also, separate group of rats treated with WIN and SR and placed in open field to measure effects on locomotion

  31. No effect of WIN or SR onunconditioned freezing or on locomotion in open field test

  32. Day 1 and 2 were training, 6 trials each day Drug admin on day 3, platform moved to opposite side, and 6 trials followed WIN treated animals had decreased latency to find platform on first trial, no diff from controls after that SR treated animals showed increased latency on trial 2 Compared to control, no diff from controls after that

  33. Discussion • Disruption of CB1 cannabinoid signaling decreases the ability of rodents to extinguish fear memories • WIN acting as a CB1 agonist facilitates fear extinction • WIN also facilitates spatial memory • Not by disrupting acquisition, memory retrieval or affecting sensory-motor ability

  34. CB1 antagonists • Administration of selective CB1 antagonists (SR or rimonabant) or genetic ablation of CB1 gene leads to a pronounced deficit in the extinction of conditioned fear • Also leads to deficits in previously learned spatial information • In Rats!

  35. Administration of CB1 agonist WIN facilitates the extinction of contextual fear and may have long term implications • In humans, pharmacotherapies directed at the endocannabinoid system may help treat psychiatric disorders such as retrival of fear memories, panic, phobias (like being afraid of russians) and PTSD

  36. You may cease learning……. ………………….now! The End

  37. Pat Ronan Rules!

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