3. Umbruch 4.4..2005 - Online Pot

128 S.A. Varvel and A.H. Lichtman
minals. Several cannabinoid agonists have been shown to inhibit electrically
evoked acetylcholine release in hippocampal slices [130–132] and synaptosomes
[133]. Similarly, microdialysis studies in awake rats also showed
cannabinoid-induced decreases in acetylcholine release [134–136]. This effect
on hippocampal acetylcholine release is clearly CB 1 receptor mediated, as all
the afore-mentioned studies demonstrated that SR-141716 blocks the effect.
Conversely, higher doses of SR-141716 increased the amount of released
acetylcholine in the hippocampus, indicating either inverse agonist activity of
SR-141716 or blockade of a tonic inhibitory influence by endocannabinoids.
In support of the latter possibility, electrically evoked hippocampal (but not
striatal) acetylcholine release was found to be 100% greater in CB 1 –/– mice
compared to wild-type controls [137]. Behavioral studies also support the
hypothesis that acetylcholine plays a role in cannabinoid-induced memory
impairment. Although an initial study found that the cholinesterase inhibitor
physostigmine failed reverse ∆ 9 -THC-induced deficits in an eight-arm radial
maze [61], subsequent studies demonstrated that low doses of physostigmine
as well as other cholinesterase inhibitors blocked cannabinoid-induced memory
impairment [35, 36].
Role of endocannabinoids in synaptic plasticity
Given that endocannabinergic mechanisms have been strongly implicated in
behavioral paradigms of learning and memory, it is not surprising that a growing
body of work has focused on understanding the role of the endocannabinoid
system in the electrophysiological correlates of learning, synaptic plasticity.
Synaptic plasticity is a network attribute of synapses, referring to their
ability to change in structure and function in response to particular patterns of
activation. These processes are believed to represent the neurobiological basis
of learning in which the experiences of an organism can modify subsequent
responses to stimuli.
Short-term plasticity
Great strides have been made in understanding the physiological role of the
endocannabinoid system with the discovery that endocannabinoids may serve
to mediate a short-term plasticity phenomenon referred to as depolarization-induced
suppression of inhibition (DSI) and its corollary depolarization-induced
suppression of excitation (DSE). DSI occurs on GABAergic
synapses and has been studied in hippocampal CA1 pyramidal cells [138, 139]
and in cerebellum [140, 141]. Depolarization of the postsynaptic cell results in
the release of a retrograde messenger which diffuses back across the synapse
and inhibits further GABA release, thus diminishing inhibitory tone for a brief
period of a few seconds. Conversely, DSE involves the short-term inhibition of