The Leaf THE LEAF November-December 2017 | Page 12

Adenosine System
Adenosine acts as a signalling molecule both
within the brain and outside it. Caffeine,
famous for its stimulant effect, is an
antagonist of the four adenosine receptors
(A1, A2A, A2B, and A3).
Both THC and CBD can enhance adenosine
activity, but they don’t do this by directly
interacting with the receptors. After
adenosine is released, it is cleared by being
transported back inside the cell. Both THC
and CBD can potently inhibit adenosine
cellular uptake (IC50=270 & 120 nM),
leaving more adenosine to activate the
receptors. The cannabinoids accomplish this
by inhibiting the equilibrative nucleoside
transporter 1 (ENT1).
Indirect activation of the A1A receptor may
mediate
the
anti-inflammatory
and
immunosuppressive effects of CBD.
However, activation of adenosine receptors
may also cause drowsiness and memory
impairment.
Glycine Receptors
Glycine receptors (GlyRs) are ligand-gated
ion channels which inhibit nerve activation.
GlyRs regulate both pain and inflammation.
Just as anandamide is a postive allosteric
modulator at GlyRs, both THC and CBD can
increase channel activation by glycine. The
GlyR channel modulation was moderately
potent with EC50 values of 2.4 μM (THC)
and 2.7 μM (CBD).
Animal studies have shown the importance of
cannabinoids acting at these channels to
inhibit transmission of pain signals up the
spinal cord.
GABA Receptors
The effects of the inhibitory neurotransmitter
gamma-aminobutyric acid (GABA) are
mediated by two receptors, GABA-A and
GABA-B. GABA-A is a ligand-gated ion
channel which mediates the effects of
barbiturates, benzodiazepines, and alcohol.
GABA-A receptors are formed with 5
subunits – each subunit is from one of 19
different genes.
In response to the anti-seizure activity
observed with CBD, interactions with
GABA-A were explored. CBD was found to
be a positive allosteric modulator of GABA-
A. The potency for enhancing GABA effects
depended on the subunit configuration of the
receptor and ranged from 0.9 to 16.1 μM.
The CBD binding site was separate from the
benzodiazepine binding site. CBD showed
greater potency at the ß3 subunit, which can
produce less sedation while maintaining the
anxiolytic effect.
GABA-A modulation by THC was not tested,
but there is no strong rationale to think that
THC would directly interact like CBD does.
Past studies have shown that THC can
indirectly activate GABA receptors through
inhibition of GABA reuptake. This was
dependent on activation of CB1 receptors.
Acetylcholine Receptors
The nicotinic acetylcholine (nACh) receptor
is another ligand-gated ion channel consisting
of 5 subunits. The α7-nACh receptor
(consisting of 5 of the α7 subunits) is
expressed in the cerebral cortex, thalamus,
and hippocampus and is found on both
excitatory and inhibitory nerves. This
receptor is involved in memory, learning, and
attention and mediates many of the cognitive
effects of nicotine. It also has a role in cancer
cell proliferation and metastasis.
CBD acts as a negative allosteric modulator
of the α7-nACh receptor, although it is has
low potentency (IC50=11.3 μM). THC did
not have any effect on α7-nACh receptors.