3. Umbruch 4.4..2005 - Online Pot

222 F. Barth and M. Rinaldi-Carmona
induced by cannabinoid agonists such as ∆ 9 -THC [28], anandamide [20] and
2-AG [23].
More interestingly, SR-141716 also produced changes in ingestive behaviors
when administered alone. This was first shown by Arnone et al. [29], who
described the effects of SR-141716 [0.3–3 mg/kg, taken per os (p.o.)] on spontaneous
sucrose feeding (sucrose pellets versus standard chow) and spontaneous
or neuropeptide Y (NPY)-induced sucrose drinking in rats. SR-141716
markedly and dose-dependently reduced the consumption of sucrose, with
only a marginal effect on regular chow and water consumption. Moreover, it
also decreased ethanol consumption in C57BL/6 mice, a strain known for its
genetic predisposition for ethanol consumption, without affecting water intake
[29]. In another study, marmosets were given the choice between standard
food or a sweet cane-sugar mixture; administration of SR-141716 (1–3 mg/kg
p.o.) significantly and dose-dependently reduced the amount of sweet food
ingested during the 6-h test period, with no effect on the standard food intake
[30]. This preferential effect on palatable food intake compared with standard
food suggested that an endogenous cannabinoid tone may modulate the appetitive
value of food. Similar results were obtained by Colombo et al. [31], who
described an overall decrease in food intake and body weight in rats treated
with SR-141716 (2.5–10 mg/kg i.p.) for 14 days. Using a self-administration
protocol it was also shown that SR-141716 reduces sucrose intake by acting on
both the appetitive and the consummatory aspects of ingestive behavior in rats
[32].
These results suggested a potential for cannabinoid antagonists in the treatment
of eating disorders and, in particular, obesity. Therefore, the effect of
chronic administration of SR-141716 in pharmacological models more relevant
to obesity was investigated. One of these model is the diet-induced obese
(DIO) mice, in which the animals are made obese simply through eating of a
high-fat diet. Daily administration of SR-141716 (10 mg/kg/day p.o.) for 5
weeks produced a transient decrease in food intake with a sustained reduction
in body weight. At the end of the treatment period, a significant 20% weight
loss was obtained, together with a 50% reduction of adiposity. Moreover raised
plasma leptin, insulin and free fatty acid levels were decreased to values found
in lean (non-DIO) mice [33].
Similar results were obtained with AM-251, a close analogue of SR-141716
(Fig. 1). DIO mice were treated with AM-251(3–30 mg/kg/day p.o.) using a
chronic, interrupted dosing schedule (2 weeks on treatment, 2 weeks off and a
further 2 weeks on treatment). A significant reduction of body weight together
with a reduction of adipose tissue mass was observed. While the anti-obesity
effect was lost during the off-treatment period, it was recovered during the
second treatment period, suggesting that chronic treatment of obese individuals
with CB 1 antagonists is a viable pharmacological approach [34].
Other obesity models involve genetically obese animals; these include the
ob/ob mice, which have an inherited lack of leptin, db/db mice, which have a
defective leptin receptor, and Zucker (fa/fa) rats, which lack the leptin recep-