3. Umbruch 4.4..2005 - Online Pot

Role of the endocannabinoid system in learning and memory 123
either a spaced extinction procedure (i.e. a single 60-s extinction trial given
every 2–4 weeks) or a massed extinction procedure (i.e. four daily 120-s trials
given on 5 consecutive days). In the spaced extinction task, the control
mice exhibited extinction across the probe trials, while both SR-141716-treated
mice and CB 1 –/– mice continued to return to where the platform had been
located, indicating extinction deficits. Importantly, an additional group of
wild-type mice that was given only a single probe trial 9 weeks following
acquisition exhibited near-perfect performance, indicating that this task
assessed extinction and not merely time-dependent forgetting. In contrast,
disruption of CB 1 receptor signaling did not alter the rate of extinction when
the massed extinction procedure was used. Collectively, these results suggest
that the endocannabinoid system may play a specific role in long-term or
spaced extinction procedures.
An implication of endocannabinoid modulation of extinction is that disruption
of CB 1 receptor signaling may interfere with learning tasks that require
the suppression of previously learned responses. In support of this notion,
CB 1 –/– mice as well as SR-141716-treated mice learn the location of the
fixed-platform Morris water maze task at identical rates to wild-type mice [40,
65]. Following acquisition, however, CB 1 –/– mice exhibited a significant
impairment in a reversal task in which the location of the hidden platform was
moved to the opposite side of the tank [40]. While the wild-type mice readily
learned the new platform location, the CB 1 –/– mice continued to swim to the
original platform location, despite being repeatedly shown the new platform
location. Endocannabinoid modulation of extinction also has implications
related to drug abuse. Specifically, it has recently been demonstrated that
∆ 9 -THC and cannabidiol, a structurally related component of marijuana that
does not bind to the CB 1 receptor, enhances extinction of cocaine-induced and
amphetamine-induced conditioned place preference learning in rats [66].
Thus, augmenting the endocannabinoid system may be useful in treating a
wide range of perseverant, maladaptive behaviors related to aversive situations,
including post-traumatic stress disorders [14] and persistent drug-seeking
behavior [66].
Potential confounds in manipulations altering CB 1 receptor signaling
Although findings in which SR-141716-treated animals or CB 1 –/– mice exhibit
altered performance in mnemonic tests are generally interpreted as evidence
supporting endocannabinoid tone, other explanations can also account for
these types of finding. In the former case, SR-141716 does not appear to act
solely as a CB 1 receptor antagonist. For example, SR-141716 has been found
to decrease [ 35 S]guanosine-5'-(γ-O-thio)triphosphate (GTPγS) binding in
membranes isolated from human cannabinoid CB 1 receptor-transfected
Chinese hamster ovary cells [67, 68], an effect opposite to that of cannabinoid
agonists [69–71], suggesting inverse agonist activity. Since cannabinoid ago-