3. Umbruch 4.4..2005 - Online Pot

Role of the endocannabinoid system in learning and memory 129
glutamate release, and has also been demonstrated in several brain areas
including the VTA [142].
Early reports suggested that the retrograde messenger may have been glutamate,
acting on presynaptic metabotropic glutamate receptors [143, 144].
However, Wilson and Nicoll [121] as well as Ohno-Shosaku and colleagues
[127] established that endocannabinoids play a critical role in DSI. Supporting
such a role for endocannabinoids are the findings that DSI in the hippocampus
is completely blocked by CB 1 antagonists [121, 127] and is absent in CB 1 –/–
mice [145]. Similarly, the DSI observed in cerebellar Purkinje cells has been
shown to be mediated by CB 1 receptor activation located on presynaptic neurons
[146–148]. Based on these findings it has been hypothesized that endocannabinoids
are released from the postsynaptic neuron, and travel retrogradely
to presynaptically located CB 1 receptors where they inhibit GABA release.
Despite the potential importance of these phenomena, their physiological significance
remains to be established. Hampson and colleagues attempted to
induce DSI using pulse trains that mimic hippocampal cell-firing patterns that
occur in vivo [149]. However, they found that these normal firing patterns of
hippocampal neurons failed to elicit DSI.
Models of long-term synaptic plasticity: LTP
Initial studies examining the effects of cannabinoids on synaptic plasticity
demonstrated that CB 1 agonists disrupt LTP. LTP refers to the phenomenon in
which brief high-frequency stimulation applied to afferent pathways results in
an increase in the excitatory synaptic potentials of postsynaptic neurons, which
can last from hours to weeks. This phenomenon was first observed in the hippocampus
[150] where it has been most extensively characterized, but has
since been demonstrated in many other brain areas.
Nowicky et al. [151] first reported that ∆ 9 -THC significantly impaired the
induction of LTP induced in CA1 region of hippocampal slices using two
tetanizing trains (200 Hz, 0.5-s duration, 5-s intertrial interval (ITI)) delivered
to the stratum radiatum. This effect of ∆ 9 -THC was also produced by HU-210
[152], and was shown to be mediated via the CB 1 receptor [153]. Terranova et
al. [154] extended these findings to WIN-55212-2 and the endogenous
cannabinoid anandamide, while Stella et al. [155] demonstrated that application
of 2-AG can also inhibited the induction of hippocampal LTP, all of which
were reversed by SR-141716. Furthermore, it has recently been shown that
AM-404, an inhibitor of the putative anandamide transporter that also inhibits
FAAH, can disrupt induction of LTP in an SR-141716-reversible manner
[156]. Interestingly, CB 1 –/– mice demonstrated enhanced hippocampal LTP
induced by high-frequency stimulation to the Shaffer collaterals [50]. One
likely mechanism given for this cannabinoid-induced disruption of LTP is that
presynaptic CB 1 receptors inhibit release of the glutamate necessary to depolarize
the postsynaptic cell and release NMDA receptors from the magnesium