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Notes from the article:
Cannabinoids take the brain by STORM
Wed, 12/10/2014 -- Holly Brothers PhD
http://www.sciguru.org/newsitem/18095/cannabinoids-take-brain-storm


WHY WE HAVE RECEPTORS FOR CANNABINOIDS AND WHAT THEY DO
brain cannabinoid receptors evolved to respond to endocannabinoids
endocannabinoids travel backwards (??)
normal brain signaling: from axon terminal of one neuron, across synapse to receptor of postsynaptic neuron
endocannabinoids are released from the postsynaptic neuron and travel "retrogradely" across the synapse to a receptor on the presynaptic neuron
neurons have a conversation instead of just forwarding message
postsynaptic neuron says "less signal please"

CB1 CANNABINOID RECEPTOR
one of the most copiously expressed presynaptic receptors in brain
distribution poorly understood
generally found on inhibitory interneurons in the hippocampus
two locations in cell: neuronal surface or intracellular compartment

TWO KINDS OF CONNECTIONS
axons from interneurons have two imp kinds of cnxns to post-synaptic neurons, affected differently by cannabinoids:
axo-somatic: strongly effective cnxn to cell body
axo-dendritic: weaker cnxn to receptive dendritic branches

DIFFERENT EFFECTS
low dose: prevents release of GABA from ado-somatic connections but not from axo-dendritic cnxns
retrograde signaling to CB receptors more likely to reduce GABA than glutamate

altered distrib/fx of CB1 assoc c epilepsy, Fragile X synd in mice

DUDOK STUDY
Published online ahead of print in Nature Neuroscience
New technique: stochastic optical reconstruction microscopy (storm)
to visualize CB1 receptors in mouse brains on nanometer scale
Combined STORM imaging with patch-clamp technique allowing observation of individual cells for response, filled them with dye and watch with confocal microscopy
Captures both physiological and morphological data from same cell
Characterized distrib of CB1 receptors on surface of cell and inside
suggestion: distance of CBR from synaptic machinery (vesicle makers) determines strength of endocannabinoid signaling and hence influences reduction in presynaptic signaling

CB1 receptors are spread homogenously on pre-synaptic terminal
more CB1 receptors on larger axo-somatic terminals
axo-somatic terminals have proportionately less vesicle machinery
More CB1 receptors relative to this machinery-->axo-somatic synapses respond more sensitively to low concentrations of endocannabinoid signaling

Both synapse types respond similarly to endocannabinoid levels that saturate the CB1 receptors

ADDING THC
Txd mice with Δ9-tetrahydrocannabinol (THC) at two doses

Low dose
(sim to human medicinal dose)
-->little change in CB1R

High dose
(sim to humans smoking mj with low THC content)
??(did she get these dose levels backwards? my experience is that medicinal doses are stout)
-->behavioral tolerance, change in CB1R receptor distribution
loss of pre-synaptic CB1 receptors
internalization of remaining CB1 receptors

Tested after 6 wks tx
Chronic exposure-->fewer pre-synaptic CB1 receptors on the surface -->reduced ability of endocannabinoids to supress GABA release from inhibitory interneurons

WITHDRAWAL
CB1 receptors returned to normal after 6 weeks

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