3. Umbruch 4.4..2005 - Online Pot

Role of the endocannabinoid system in learning and memory 117
ited after an interposed delay. Nakamura et al. found that low dose of
1.25 mg/kg ∆ 9 -THC was shown to produce small deficits in retention (i.e. more
errors) after a short delay that became more pronounced after daily administration
[32]. These experiments suggested a cumulative detrimental effect of
chronic ∆ 9 -THC on spatial memory, though the deficits disappeared after a period
of drug washout. Lichtman et al. [33] showed that ∆ 9 -THC, WIN-55,212-2,
and a potent bicyclic cannabinoid analog CP-55,940 all disrupted choice accuracy,
while ∆ 9 -THC and CP-55,940 did so at doses lower than were required to
increase task completion time (WIN-55,212-2 produced both effects at similar
doses). While ∆ 9 -THC-induced memory impairment was blocked by
SR-141716, the cholinesterase inhibitor physostigmine failed to diminish this
effect [34]. However, the dose of physostigmine employed (0.06–0.24 mg/kg)
produced excessive cholinergic activity (e.g. excessive salivation) and thus confounded
the interpretation of this study. However, a subsequent study reported
that a decreased doses range of physostigmine (0.01–0.05 mg/kg), as well as
another cholinesterase inhibitor tetrahydroaminoacridine, improved
∆ 9 -THC-induced memory impairment in the radial-arm maze task [35].
Similarly, epstastigmine, a more selective cholinesterase inhibitor, reversed
∆ 9 -THC-induced deficits in the radial-arm maze [36]. Studies of serotonergic
function found no relation between ∆ 9 -THC-induced deficits in the radial-arm
maze and 5-hydroxytryptamine (5-HT) turnover [37].
Another spatial learning and memory task that has become increasingly popular
is the Morris water maze. Unlike the radial-arm maze, this task does not
entail food deprivation, but requires the subjects to navigate in a pool of water
to locate a hidden platform by learning its relationship relative to salient visual
cues. The highly potent cannabinoid agonist, (–)-11-hydoxy-∆ 8 -THC-dimethylheptyl
(HU-210), has been found to impair the ability of rats to acquire the hidden
platform task, without disrupting their performance in a version of the
maze in which the location of the platform was directly visible [38]. These
deficits were accompanied by signs that are thought to reflect heightened anxiety,
such as increased time spent around the outer edges of the pool (thigmotaxia)
and increased vocalizations. Thus it was hypothesized that cannabinoids
may produce an anxiety-like state that could contribute to their effects on
learning [38].
∆ 9 -THC also disrupted the performance of mice in a working-memory version
of the water maze in which the location of the platform was changed
before each session [39]. These effects were relatively selective as they
occurred at significantly lower doses than those required to disrupt a reference
memory version of the task (in which the platform remained in a constant position),
or produce other effects characteristic of cannabinoid activity such as
antinociception, hypothermia, catalepsy, and hypomotility. Subsequent
water-maze experiments showed that the working-memory deficits produced
by ∆ 9 -THC, as well as WIN-55,212 and methanandamide, at doses that did not
impair a cued version of the task were fully reversed by SR-141716, and were
not observed in CB 1 –/– mice [40].