Transcript Ryan Mullaly - USD Biology

POST-TRAINING CB1 CANNABINOID
RECEPTOR AGONIST
ACTIVATION DISRUPTS LONG-TERM
CONSOLIDATION OF
SPATIAL MEMORIES IN THE HIPPOCAMPUS
T.Yim, N. Hong, M. Ejaredar, J. McKenna, & R. McDonald
Cannabis sativa
• Positive effects
– Euphoria
– Analgesia
– Reduction of intraocular pressure
– Appetite enhancement
– Anti-emetic
• Negative effects
– Attention and memory deficits
– Hallucinations
– Respiratory disease
Medical Marijuana
Cannabis sativa
• THC (D9-tetrahydrocannabinol)
– Equal affinity to CB1R and CB2R
– CB2R found in periphery
– CB1R found in CNS
• Anandamide (N-arachidonylethanolamine) = natural
ligand
– Made from arachadonic acid
• Can be converted to PGF2a
– Made in the hippocampus, cortex and cerebellum
THC
• Location of CB1R
– Hippocampus
– Basal ganglia
– Substantia nigra
Previous Studies
• CB1R activation in dorsal hippocampus
impairs spacial memory in rodents
• Reversible by CB1R blockade
• Not clear which stage is affected
– Acquisition, consolidation, or retrieval?
Objective
• Determine if cannabinoid activation affects
memory consolidation
• Activate CB1R after daily training in Morris
water maze
• Assess spatial recall at various retention
intervals
Materials and Methods
• 111 male Long-Evans rats
• 6 day training in MWM
– 1.5 m diameter, .5 m deep
– Invisible platform NE quadrant, 28 cm from
perimeter
– Multiple colored posters in room for cues
Morris water maze
Materials and Methods
• Place learning
– Training for 6 consecutive days
– 8 swimming trials per day
• 2 trials from each of 4 starting positions (N, S, E, W)
– Trial began when rat was placed in water,
ended when rat reached platform or after 60 s
Materials and Methods
• Probe test
– Invisible platform removed from water maze
– Rats placed in pool facing wall from due west
– Test begins when rat is released in water and
ends after 30 s
Experiment 1
• Systemic injections of WIN
• 64 rats assigned to one of four treatment
groups
– .5mg/kg, 1mg/kg, 3mg/kg, or DMSO(control)
• Injections made within 5 min of last swim of
each of the 6 training days
• Probe test given at two retention periods
– 1 week and 4 weeks post-training
Experiment 2
• Intrahippocampal infusions of WIN
– All rats received bilateral cannulae implantation to
dorsal hippocampus
• 47 rats assigned to one of three groups
– Control, 2.5ug WIN, 5.0ug WIN
• Injections made within 5 min of last swim of each
of the 6 training days
• Probe test given at two retention periods
– 1 week and 4 weeks post-training
Results
• Experiment 1
Results
• Experiment 1
Results
• Experiment 1
Results
• Experiment 2
Results
• Experiment 2
Results
• Experiment 2
Histology
•Location of cannulae
Discussion
• CB1 agonist WIN impairs consolidation of
long term memory
– Spares spatial acquisition and short term
retention
• Consolidation impairment due to CB1R
rather than CB2R activation
– CB2R not expressed in hippocampus
• Isolated consolidation with post-training
administration
Discussion
• Short-term vs Long-term
– NMDA-R blockade in dorsal hippocampus
impairs long-term not short-term memory
• CB1R activation inhibits long term
potentiation
– Suppress NMDA-R by inhibiting vg-Ca2+ and
activating K+ channels
Discussion
• Effects of WIN may be dose dependent
• Related to acetylcholine tone
– Low dose WIN enhance cholinergic efflux
– High dose WIN inhibit cholinergic activity
– Low levels of Ach required for memory
consolidation during post-training slow-wave
sleep