3. Umbruch 4.4..2005 - Online Pot

130 S.A. Varvel and A.H. Lichtman
blockade existent under normal conditions. The opening of these NMDA
receptors and the subsequent influx of calcium triggers calcium-dependent
second-messenger systems that initiate the induction of LTP [157]. While the
studies described above lend support to the hypothesis that endocannabinoids
may serve to diminish induction of LTP, these effects have been shown to
depend on the induction method. In all of the cases mentioned above, LTP was
induced by high-frequency titanic stimulation. However, LTP can also be
observed following a theta burst protocol, which is thought to reflect a more
physiologically relevant process. Lees and Dougalis [156] showed that while
WIN-55,212 will block induction of LTP under both conditioning protocols in
an AM-251-reversible manner, anandamide only prevents high-frequency
stimulation LTP.
In contrast to the clear disruption of LTP observed when CB 1 agonists are
exogenously administered to whole tissues, more subtle and potentially interesting
effects have been reported when the effects of endocannabinoids have
been looked at within their endogenous context. For example Carlson et al.
[158] showed that endocannabinoids released via induction of DSI led to a
facilitation of LTP in targeted cells, but not neighboring ones, by selectively disinhibiting
postsynaptic cells (through decreased presynaptic GABA release)
and lowering their thresholds for LTP. It was hypothesized that exogenous
application of cannabinoids may disrupt learning by disrupting the spatial and
temporal selectivity of coding mediated by endocannabinoids. Additionally,
cannabinoids have been shown to promote signaling pathways such as ERK,
which are known to be important for synaptic plasticity and learning [159].
Models of long term synaptic plasticity: long-term depression (LTD)
In contrast to high frequency stimulation that can lead to LTP, low-frequency
stimulation leads to another form of long-term synaptic plasticity, known as
LTD, in which synapse strength is weakened. LTD has been demonstrated in
several brain areas, including the hippocampus, striatum, cerebellum, and various
parts of the cortex (for reviews see [160, 161]). Over the past few years,
endocannabinoids have been demonstrated to be crucial components of LTD
in several brain areas including the striatum, amydala, frontal cortex, and
nucleus accumbens.
LTD in the striatum, a process believed to be important in certain forms of
learning, has been shown to be CB 1 receptor-dependent. LTD was absent in
CB 1 –/– mice and greatly reduced in slices preincubated with SR-141716, while
it was potentiated by AM-404 (an inhibitor of both FAAH and the anandamide
transporter) [162]. In addition, postsynaptic loading of anandamide resulted in
reduced presynaptic excitatory transmission. These findings support the notion
that endocannabinoids serve as retrograde messengers to reduce excitatory
cortical inputs to striatal output neurons. A similar facilitative role of endocannabinoids
on LTD has been proposed in the amygdala, where LTD induced