3. Umbruch 4.4..2005 - Online Pot

Role of the endocannabinoid system in learning and memory 127
Interactions with GABAergic systems
Cannabinoid receptors also clearly influence hippocampal GABAergic activity,
though the nature of this interaction is far from clear, and may involve
multiple pathways. Several laboratories have reported that CB 1 receptors in
the hippocampus were located almost exclusively on nerve terminals of
cholecystokinin (CCK)-containing GABAergic interneurons [116–119].
Furthermore, cannabinoid agonists have been shown to inhibit GABA release
in several preparations [116, 119–121]. However, several other lines of evidence
have suggested that cannabinoids may also play a facilitating role on
GABAergic transmission by blocking its reuptake. Early studies showed that
∆ 9 -THC could inhibit the uptake of GABA as well as 5-HT, norepinephrine
(NE), and dopamine (DA) in rat brain synaptosomes [122, 123]. In the striatal
synaptosome preparations, WIN-55,212-2 inhibited GABA uptake [124].
However, in the hippocampus, ∆ 9 -THC-induced reductions in acetylcholine
turnover were shown to be dependent on septal GABAergic interneurons, as
this reduction in turnover was completely blocked by intra-septal administration
of the GABA antagonist bicuculline [125]. In addition, WIN-55,212-2
has been shown to produce a tonic hyperpolarization of CA1 pyramidal cells
in hippocampal slices, which was reversed by bicuculline [126]. Compelling
evidence has also come to light suggesting that endocannabinoids act as a retrograde
signal to inhibit GABA-mediated transmission that follows depolarization
of hippocampal pyramidal neurons [121, 127]. In addition, a recent set
of behavioral experiments has demonstrated the importance of GABAergic
transmission in vivo, as shutting down the GABAergic interneuronal system
with the GABA-A antagonist bicuculline completely reversed
∆ 9 -THC-induced deficits in both the Morris water maze working-memory
task and an alternation T-maze task [42].
These results, taken together, suggest a complicated relationship between
endocannabinoid and GABAergic influence in the hippocampus, in which CB 1
receptor stimulation may lead to a multitude of effects that depend on the specific
pathway. Undoubtedly, the challenge is now to determine the functional
significance of each of these pathways on cognition.
Interactions with cholinergic systems
It has long been recognized that an important element of the action of cannabinoids
may be their ability to inhibit cholinergic transmission in the limbic system
and cortex, and the memory deficits observed with cannabinoids resemble
those seen following administration of cholinergic antagonists [39]. Early
studies revealed that ∆ 9 -THC reduced uptake of choline in the hippocampus,
thereby restricting acetylcholine synthesis [128, 129]. More recently, it has
become clear that cannabinoids presynaptically inhibit the release of acetylcholine,
possibly though CB 1 receptors located on the cholinergic nerve ter-