3. Umbruch 4.4..2005 - Online Pot

Role of the endocannabinoid system in learning and memory 131
by WIN-55212 or amphetamine was blocked by AM-251, and the amphetamine-induced
LTD was facilitated by AM-404 [163]. Additionally, LTD in the
neocortex [164] as well as in the nucleus accumbens [165, 166] has been
shown to be dependent on presynaptic activation of CB 1 receptors.
Interestingly, chronic exposure to ∆ 9 -THC or WIN-552-2 has been shown to
prevent the induction of LTD, suggesting a functional tolerance that may partially
underlie putative, long-lasting cognitive deficits associated with chronic
marijuana use [166].
This hypothesized role of endocannabinoids as initiators/mediators of LTD
is also consistent with a series of experiments examining the effects of
cannabinoid agonists and CB 1 antagonists on synaptic plasticity in the prefrontal
cortex [167]. Tetanic stimulation induced plasticity in slightly more
than half of the neurons examined, with approximately equal numbers of cells
developing LTP and LTD. However, in the presence of WIN-55212-2 almost
all of the plastic synapses showed LTD, while in the presence of SR-141716
almost all of the plastic synapses developed LTP. The consequences of such a
shift on learning are unclear, though it may suggest that forms of learning
heavily dependent on LTP could be attenuated by endocannabinoids, while
forms of learning heavily dependent on LTD could actually be enhanced.
Other forms of synaptic plasticity
Endocannabinoids have also been shown to modify other forms of synaptic
plasticity. For example, anandamide has been shown to inhibit an interesting
though poorly understood phenomena referred to as long-term transformation
(LTT), where GABAergic inhibition is “transformed” into excitation when
presynaptic tetanic stimulation is paired with postsynaptic depolarization
[168]. This LTT has been shown to play an important role in pairing-induced
LTP, which is also inhibited by anandamide [168].
In addition to changes in presynaptic transmitter release and postsynaptic
sensitivity, synaptic plasticity can be supported by the growth of new synapses,
a process that has also been shown to be sensitive to CB 1 stimulation.
Anandamide, ∆ 9 -THC, and WIN-55212-2 have all been shown to inhibit new
synapse formation induced by forskolin, probably due to CB 1 receptor-mediated
decreases in cAMP [169].
Conclusions on the effects of endocannabinoids on cognition
The weight of evidence clearly demonstrates that the endocannabinoid system
is critically involved with physiological mechanisms underling learning and
memory. It can be stated with a high degree of confidence that CB 1 receptors
located in brain areas associated with learning and memory, including the hippocampus,
frontal cortex, and striatum, are a crucial element of this influence.