Preferential
effects of the cannabinoid CB(1) receptor
antagonist, SR 141716, on food intake and body
weight gain of obese ( fa/fa) compared to lean
Zucker rats.
Rationale : The selective CB(1)
receptor antagonist, SR 141716, has been
demonstrated to reduce food consumption in a
range of animal species.
Objective: To assess the effect of
chronic administration of SR 141716 on body
weight and ingestive behaviour of lean and obese
( fa/fa) Zucker rats.
Methods: Lean and obese Zucker rats
were orally dosed with SR 141716 (3, 10, 30
mg/kg PO), sibutramine (5 mg/kg PO) or vehicle
for one week. Pair-fed controls provided insight
as to whether the effect of SR 141716 on body
weight was attributable to drug-induced
hypophagia. Subsequently, the effect of chronic
oral administration of SR 141716 (1, 3, 10
mg/kg) was assessed for 28 days. At the end of
this period, all animals were given vehicle for
14 days. The incidence of wet-dog shakes,
yawning, scratching, and grooming
behaviours, was assessed after acute
administration and at weekly intervals
thereafter for 4 weeks.
Results : SR 141716 dose-dependently
decreased food intake and body weight gain in
both lean and obese animals. The inhibition of
food intake and body weight gain was greater in
obese Zuckers than in lean Zucker controls.
Changes in the body weights of pair-fed controls
closely paralleled those of their drug-treated
counterparts. Chronic 28-day treatment led to a
maintained reduction of body weight gain.
Withdrawal of SR 141716 on day 28 resulted in
rebound hyperphagia and a significant weight
gain. On acute administration, SR 141716
dose-dependently induced motor behaviours that
showed tolerance upon repeated
administration.
Conclusion: These data indicate that
chronic oral treatment with SR 141716
significantly reduces the food intake and body
weight gain of obese and lean Zucker rats, an
effect that is greater in obese animals and
reversible upon drug withdrawal.
Models to
predict cannabinoid-induced disturbances
Edery, H. Arch Toxicol 1983; Suppl 6;
91-103.
The most commonly used animal models to
evaluate the psychoactivity of cannabinoids have
been reviewed. The need for suitable models is
acute considering the present interest to
develop drugs based on the cannabinoid moiety
but preferably dissociated from psychoactivity.
Conceivably, a satisfactory assay should show
features of cannabinoid-induced disturbances
relevant to man as well as sensitivity,
specificity and simplicity. These requisites
seemed better fulfilled in the monkey model.
Various lines of evidence have demonstrated the
close pattern of the behavioural response to
psychoactive and inactive cannabinoids in man
and monkeys. Rhesus monkeys showed development
of tolerance and withdrawal symptoms, which have
been frequently reported in humans after
prolonged exposure to cannabinoids. The exposure
was reported also to cause in monkeys
alterations of electrical activity and organic
damage in deep brain structures. The monkey
model has been particularly useful to determine
the relative potency of naturally occurring
cannabinoids and metabolites, which was
adequately compared to that in man, and to
establish the structural requirements for
psychoactivity in large series of synthetic new
compounds. In addition it appeared that rhesus
monkeys react similarly to man with respect to
proposed antidotes against cannabinoids. Four
newly synthetized amino-cannabinoids were tested
in baboons. All these compounds were virtually
void of typical cannabinoid psychoactivity but
two trans-analogs differed from the cis-analogs
in that they provoked bouts of vigorous
scratching and yawning. This unusual
drug-effect, at difference from scratching alone
has not been previously observed after
administration of cannabinoids. In this
presentation some terms of cannabis terminology
have been discussed.
