Behavioral mechanisms underlying inhibition of food-maintained responding by the cannabinoid receptor antagonist/inverse agonist SR141716A
Introduction
The selective, centrally active, cannabinoid CB1 receptor antagonist/inverse agonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; Rinaldi-Carmona et al., 1994) has been reported to inhibit food intake in a variety of species and models of ingestive behavior (e.g., Arnone et al., 1997, Colombo et al., 1998a, Freedland et al., 2000, Kirkham and Williams, 2001a, Rowland et al., 2001, Simiand et al., 1998). The crucial role of cannabinoid CB1 receptors in the anorectic effect of SR141716A is underscored by the finding that it is abolished in transgenic mice lacking cannabinoid CB1 receptors (Di Marzo et al., 2001). This finding and the fact that cannabinoids are well known to increase food intake indicates that the endogenous cannabinoid (endocannabinoid) system plays a role in the control of ingestive behavior (Kirkham and Williams, 2001b).
As the endocannabinoid system is thought to be involved in the brain reward system, it has been argued that the anorectic effect of SR141716A results from an attenuating effect on feeding-related reward processes (for discussion, see Kirkham and Williams, 2001b). It remains unclear, however, whether the latter effect is due to (1) an attenuating effect of the compound on the orosensory characteristics of food (“palatability hypothesis”), or to (2) an attenuation of the appetitive or incentive aspects of feeding behavior (“appetite hypothesis”; for discussion, see Higgs et al., 2003, Kirkham and Williams, 2001b). In support of the palatability hypothesis, initial studies (e.g., Arnone et al., 1997, Simiand et al., 1998) reported that SR141716A preferentially affects the intake of highly palatable ingesta (food and liquids with a sweet taste). However, the finding that the intake of a highly palatable sucrose solution is reduced by SR141716A in intact rats, but not in rats with a gastric cannula through which ingested sucrose solutions are immediately recovered (sham-feeding), suggests that other mechanisms may underlie the anorectic effect of the compound (Kirkham and Williams, 2001b). Because the intake of bland laboratory chow was reduced by SR141716A after food-restriction, but not under free-feeding conditions, it can be argued that the anorectic effect of SR141716A results from an inhibition of appetitive processes (Kirkham and Williams, 2001b). In addition, the finding that the intake of sucrose pellets in an operant paradigm (Pério et al., 2001) is not more potently suppressed by SR141716A than the intake of normal pellets (Freedland et al., 2000) suggests that the anorectic effect of the compound does not depend on the palatability of the ingesta.
Although the latter studies may imply an effect of SR141716A on appetitive processes, it cannot be ruled out that it is just a consequence of motor/performance deficits. With respect to the latter issue, it has been reported that the compound fails to affect locomotor activity, but these studies have used locomotor assessment times which did not match the time periods used to assess the anorectic effect [e.g., in the Freedland et al. (2000) study the operant session lasted 30 min, whereas the locomotor activity study lasted for 4 h]. Interestingly, in an operant study in which beer-reinforced behavior and locomotor activity was simultaneously measured, it was found that SR141716A suppressed intake in the same dose range which inhibited general behavior (Gallate and McGregor, 1999). Finally, as it has been reported that SR141716A induces emesis in the least shrew (Darmani, 2001) and potentiates lithium-induced conditioned rejection reactions in rats (Parker et al., 2003), it cannot be excluded that drug-induced aversive effects are involved in the anorectic effect of the compound.
The present study was performed to test further possible behavioral mechanisms underlying the anorectic effect of SR141716A. The first experiment tested whether feeding status affects the anorectic effect of the compound, as assessed in a 10-min, fixed ratio 10 operant food-reinforced paradigm. Because of its limited duration, the procedure is highly sensitive to appetitive processes (for discussion, see De Vry et al., in press). In order to manipulate the appetitive component of the model, the effect of SR141716A on food-maintained responding was tested in rats which were either food-restricted or which were given free access to food before the test session. It was argued that if food-restriction resulted in a more potent anorectic effect of the compound, a suppressive effect on appetite could be inferred.
In a subsequent experiment, the efficacy of SR141716A to suppress intracranial self-stimulation was assessed in the same 10-min, fixed ratio 10 operant paradigm. Special attention was given to obtain a similar rate of responding (by adjusting the stimulation parameters) as obtained in the food-reinforced operant procedure. Because the latter experiment was performed in female rats, the same animals were subsequently retrained under the same experimental conditions to lever-press for food, and tested again with SR141716A. This experiment was performed to test whether SR141716A differentially affects operant behavior maintained by food reinforcement and by direct stimulation of the brain reward system. It was argued that absence of a difference in suppressive potency would be supportive for the suggestion that the anorectic effect of SR141716A results from an attenuating effect on feeding-related reward processes.
To test whether the suppressive effect of SR141716A on operant behavior might be confounded by an effect on general activity, the effect of the compound on locomotor activity was assessed during a 10-min session in rats habituated to the test environment. A last experiment tested the possibility that the anorectic effect is a consequence of drug-induced aversive effects. To this end, it was investigated whether SR141716A attenuates saccharin-preference in a conditioned taste aversion paradigm.
Section snippets
Animals
Female (intracranial self-stimulation followed by operant food intake study) and male (all other studies) Wistar rats were purchased from Harlan-Winkelmann (Hsd/cpb: WU, Borchen, Germany). Body weight upon arrival at the laboratory was around 160 (females) and 200 g (males), which gradually increased during the course of the studies to 210–250 and 350–530 g, respectively. Rats were individually housed in Macrolon® type 3 cages (22×37 cm, height 15 cm) under a normal 12-h light period (lights on
Operant food intake experiments in male rats
During the period of pharmacological testing, the food-restricted rats showed a stable and relatively high level of operant responding (500–900 responses/10-min session, obtained after 40 training sessions, and resulting in a mean intake of 2.3–4.1 g food pellets). SR141716A induced a dose-dependent reduction in the number of responses [F(3,56)=56.12, P<0.001], with a MED of 1 mg/kg (Fig. 1A) and an ED50 value (95% confidence limits) of 2.52 (1.40–4.54) mg/kg. At the highest dose tested (10
Discussion
It has been suggested that the well-documented anorectic effect of the cannabinoid CB1 receptor antagonist/inverse agonist SR141716A (Rinaldi-Carmona et al., 1994) results from an attenuating effect on feeding-related reward processes; either by (1) an attenuating effect of the compound on the orosensory characteristics of food (palatability hypothesis), or by (2) an attenuation of the appetitive or incentive aspects of feeding behavior (appetite hypothesis; Higgs et al., 2003, Kirkham and
References (29)
- et al.
Effects of the cannabinoid receptor agonist CP 55,940 and the cannabinoid receptor antagonist SR 141716 on intracranial self-stimulation in Lewis rats
Life Sci.
(2001) - et al.
Appetite suppression and weight loss after the cannabinoid antagonist SR 141716
Life Sci.
(1998) Delta-9-tetrahydrocannabinol and synthetic cannabinoids prevent emesis produced by the cannabinoid CB1 receptor antagonist/inverse agonist SR-141716A
Neuropsychopharmacology
(2001)- et al.
Ethanol intake-reducing effects of ipsapirone in rats are not due to simple stimulus substitution
Pharmacol. Biochem. Behav.
(1996) - et al.
Effects of selected serotonin 5-HT1 and 5-HT2 receptor agonists on feeding behavior: possible mechanisms of action
Neurosci. Biobehav. Rev.
(2000) - et al.
Effects of serotonin 5-HT1 and 5-HT2 receptor agonists in a conditioned taste aversion paradigm in the rat
Pharmacol. Biochem. Behav.
(2000) - et al.
Effects of serotonin 5-HT1/2 receptor agonists in a limited-access operant food intake paradigm in the rat
Eur. Neuropsychopharmacol.
(2003) - et al.
Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding
Pharmacol. Biochem. Behav.
(2000) - et al.
Functional consequences of the acute administration of the cannabinoid receptor antagonist, SR141716A, in cannabinoid-naive and -tolerant animals: a quantitative 2-[14C]deoxyglucose study
Brain Res.
(2003) - et al.
A simple computer-based method for performing and analyzing intracranial self-stimulation experiments in rats
J. Neurosci. Methods
(1993)