3. Umbruch 4.4..2005 - Online Pot

142 R.E. Musty
Since the discovery of the synthetic, highly potent CB 1 receptor antagonist,
SR-141716, by Rinaldi-Carmona et al. [7] several other studies seem to support
the hypothesis that CB 1 receptor antagonists have anxiolytic properties.
Onaivi et al. [8] used two tests of anxiety in mice, the elevated-plus maze (discussed
above) and the two-compartment black and white box test. When
administered SR-141716 in the elevated-plus maze, mice spent more time in
the open arms, indicating a reduction of anxiety. In the second test, mice were
allowed to choose to spend time in a two-compartment box, one of which was
white and brightly lit, the other of which was black and dimly lit. Time spent
in the dark compartment was taken as an index of anxiety. When administered
SR-141716, mice spent more time in the white, brightly lit compartment, indicating
a reduction in anxiety.
In a recent study Rodgers et al. [9], administered the CB 1 receptor antagonist
SR-141716A and a reference benzodiazepine chlordiazepoxide (CDP).
They argued that there were “qualitative” differences of cannabinoid ligands
depending on the number of exposures (trials) in the elevated-plus maze. They
tested the effects of SR-141716A (0.1–10.0 mg/kg) and the reference CDP
(15 mg/kg) in mice that had never been exposed to the elevated-plus maze
compared with mice that were given an exposure to the maze undrugged (day
1). Then, 24 h later (day 2), both groups of mice were given the same drug regimen
as above. Those mice that had received CDP on day 1 did not exhibit any
anxiolytic response. The authors suggest this indicated an immediate tolerance
to CDP. On the other hand, mice given SR-1411716 on day 1 showed no anxiolytic
response, but did so on day 2. This result is in contrast to the afore-mentioned
study in which the effect of SR-141716 was observed on the first exposure
to the elevated-plus maze. The authors state: “The apparent experientially
induced ‘sensitization’ to the anxiolytic-like effects of SR-141716 in the
plus-maze contrasts markedly with the widely reported loss of benzodiazepine
efficacy in test-experienced animals.” Further research is required to resolve
these differences.
Cannabinoid receptor agonists
It seems that low doses of cannabinoid receptor agonists are anxiolytic in
mice. In the light/dark box test cited above, 0.3 mg/kg of ∆ 9 -tetrahydrocannabinol
(∆ 9 -THC) reduced anxiety [10], but in lower doses of 0.03 and
0.1 mg/kg no effect was found. On the other hand, with doses of 5.0 [10] and
4.0 mg/kg, using a THC extract (Deyo R et al., personal communication), anxiogenic
effects have been observed. Similarly, the potent CB 1 receptor agonist
HU 210 has been shown to have anxiolytic effects at low doses (4 µg/kg) in the
defensive withdrawal test in a novel environment (associated with fear/anxiety
in rodents), but anxiogenic effects in a familiar environment [11]. These data
seem to show that the context of administration is an important variable in the
effect of CB 1 agonists.