The dopamine receptor antagonist SCH attenuates feeding induced by D 9 -tetrahydrocannabinol

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1 Brain Research 1020 (2004) Research report The dopamine receptor antagonist SCH attenuates feeding induced by D 9 -tetrahydrocannabinol Aaron N.A. Verty a, Iain S. McGregor b, Paul E. Mallet a, * a School of Psychology, University of New England, Armidale, NSW 2351, Australia b School of Psychology, Sydney University, NSW 2006, Australia Accepted 4 June 2004 Available online 22 July Abstract A large body of evidence supports the notion that D 9 -tetrahydrocannabinol (THC) stimulates food intake by its actions on CB 1 cannabinoid receptors. Indirect evidence also suggests a role for dopamine (DA) receptors in mediating THC-induced feeding. In the present study, a series of experiments involving intraperitoneal drug administration in rats were conducted to further investigate the interaction between cannabinoid and dopamine receptors in feeding behaviour. Male Wistar rats were habituated to the test environment and injection procedure, and then were injected with vehicle alone, the dopamine D 1 -like receptor antagonist SCH (0.005, 0.01, 0.5 or 0.1 mg/kg), THC (0.1, 0.5 or 1.0 mg/kg) or SCH and THC combined. Food intake and locomotor activity were then measured for 120 min. Results revealed that administration of SCH dose-dependently decreased food intake while THC dose-dependently increased feeding. Furthermore, SCH attenuated feeding induced by THC at a dose that did not affect feeding on its own. These findings provide direct evidence for the existence of cannabinoid-dopamine interactions in feeding behaviour and suggest that dopamine D 1 signalling is necessary for cannabinoids to stimulate food intake. Crown Copyright D 2004 Published by Elsevier B.V. All rights reserved. Theme: Neural basis of behavior Topic: Ingestive behavior Keywords: Cannabinoid; Dopamine; Antagonist; Feeding; Rat 1. Introduction It is now well established that marijuana or its principle psychoactive ingredient, D 9 -tetrahydrocannabinol (THC), stimulates appetite in humans [18,25,35,46]. Moreover, animal studies have shown that the brain cannabinoid system is critically involved in the control of feeding behaviour. The administration of THC stimulates appetite [32,33,56,57], while the CB 1 cannabinoid receptor antagonist SR reduces food intake [3,12,48,55]. Furthermore, recent studies have shown that the endogenous * Corresponding author. Tel.: ; fax: address: paul.mallet@une.edu.au (P.E. Mallet). cannabinoid ligands 2-arachidonoylglycerol (2-AG) and anandamide stimulate appetite (for reviews, see Refs. [8,30]). Studies with transgenic mice lacking functional CB 1 receptors provide further evidence that the cannabinoid system is a positive modulator of food intake. For example, CB 1 -deficient mice eat 50% less than their wild-type littermates. Furthermore, SR fails to reduce food intake in CB 1 -deficient mice [15]. A growing body of evidence has firmly established that appetite is modulated by the brain s dopamine (DA) system. Ingestion of highly palatable foods leads to an increase in levels of extracellular DA and its main metabolites, DOPAC and HVA, within the nucleus accumbens (NAC) [27]. Furthermore, 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway lead to aphagia and adipsia [53], and DA D 1 -like receptor antagonists produce /$ - see front matter. Crown Copyright D 2004 Published by Elsevier B.V. All rights reserved. doi: /j.brainres

2 A.N.A. Verty et al. / Brain Research 1020 (2004) extinction-like effects on food-reinforced operant responding [5,6] and reduce food intake [39,45]. There is also evidence for an interaction between the cannabinoid and DA systems. For example, THC enhances electrical self-stimulation of the medial forebrain bundle [22], and increases DA levels in the striatum [34], neostriatum [51], NAC and medial prefrontal cortex [10]. THC induces Fos expression a marker of neural activation in reward pathways [1,17,37] and this effect is blocked by the DA D 1 -like receptor antagonist SCH [38]. Furthermore, SR produces signs of precipitated withdrawal associated with a decrease in extracellular DA concentration in the NAC [50]. It is therefore possible that THC stimulates food intake by altering the incentive properties of food. If this were true, then cannabinoid receptor agonists should facilitate consumption of not only food, but also other reinforcing substances. In support of this hypothesis, cannabinoid agonists have been shown to increase motivation to consume beer, de-alcoholised beer and sucrose solution in rats [21]. THC also advances feeding episodes in satiated rats (for review, see Ref. [30]), and infusion of 2- AG directly into the NAC stimulates appetite [31]. Furthermore, 2-AG and anandamide levels have been shown to increase in the limbic forebrain of food-deprived rats [31]. Conversely, CB 1 receptor blockade by SR has been shown to produce microstructural changes in food intake [28], reduce the number of lever presses required to obtain access to a 3% sucrose solution [19], and attenuates the development of food-induced place preference [9]. Taken together, this evidence suggests that CB 1 receptors mediate the consumption of rewarding substances in part by altering their appetitive value via the stimulation of neural reward circuits. To date, the involvement of the DA system in mediating cannabinoid effects on food intake is at best speculative and no study has examined the role of DA receptor antagonists in THC-induced feeding. Hence, the present study sought to obtain direct evidence for the involvement of the DA system in mediating cannabinoid-induced feeding. In order to assess the suitability of the SCH and THC doses used and to validate the experimental protocol, the first two experiments examined the dose response relationship of the separate administration of SCH and THC on food intake. The third experiment determined whether THC-induced feeding could be reduced by SCH Locomotor activity was also measured in all experiments to ensure that the observed effects could not be solely attributed to a non-specific alteration in motivated behaviour. 2. Materials and methods Animals were treated in accordance with the bprinciples of laboratory animal careq (NIH publication no , revised 1985) and the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes. This study was reviewed and approved by the University of New England Animal Ethics Committee Subjects Experimentally naive male albino Wistar rats, 8 10 weeks of age at the beginning of the experiment, were used. For Experiments 1 and 2, eight separate narve rats were used. The rats used in Experiments 1 and 2 were combined and reused for Experiment 3. Rats were housed four to six per group in opaque polypropylene cages ( mm high) with stainless steel wire lids. Cages were lined with dust-free wood chips and were housed in a climate-controlled room maintained on a 12- h:12-h reverse light dark cycle (lights off at 0800 h). Experimental testing commenced at 0830 h, that is, 30 min following the onset of the dark cycle. Rats had ad libitum access to standard laboratory chow (Rat and mouse chow, Ridley AgriProducts, Australia) and tap water while in their home cages Drugs D 9 -Tetrahydrocannabinol (THC, AGAL, Pymble, NSW, Australia), available as a 2.0 mg THC/ml ethanol solution, was first mixed with a few drops of Tween 80 (polyoxyethylene sorbitan monooleate, ICN Biomedicals). The suspension was stirred continuously under a stream of nitrogen gas until all ethanol was evaporated. Physiological saline was then added and the solution was stirred until the Tween 80 and THC was well dissolved. The final vehicle solution contained 15 Al of Tween 80 per 2 ml saline. THC was administered at a dose of 0.1, 0.5 or 1.0 mg/kg. The solution was stirred between each consecutive injection. SCH (Sigma-Aldrich, Australia) was dissolved in distilled water (DH 2 O) and administered at a dose of 0.005, 0.01, 0.05 and 0.1 mg/kg. All drugs were administered intraperitoneally in a volume of 1 ml/kg body weight Apparatus The experiment was conducted in eight identical chambers dimly lit with white light (13 lux). Each chamber was located within its own sound attenuating box fitted with a fan, which provided ventilation and masking noise [54,55]. The test food (rat and mouse chow, Ridley AgriProducts, Australia; analysis: acid detergent fibre=10.2%, neutral detergent fibre=29.4%, crude protein=22.4%, crude fat=3.8%, crude fibre=6.7%, digestible energy=16.6 MJ/ kg dry matter, average carbohydrate=27.9%) was presented in cylindrical glass dishes (105 mm diameter35 mm high) placed in one corner of the test chambers. Dishes were washed daily at the end of testing with a detergent solution (Pyroneg, DiverseyLever Australia). Each rat

3 190 A.N.A. Verty et al. / Brain Research 1020 (2004) received the same dish for the entire duration of the experiment. Plastic drinking bottles containing tap water were always available in the test chambers. A computer controlled passive infrared detector mounted on the ceiling of each box was used to quantify locomotor activity using custom designed software [54,55]. Locomotor activity was defined as time spent in motion in seconds and recorded in 1-min bins Experiment 1: effects of SCH on feeding Rats (n=8) received one session every 24 h at approximately the same time each day. On the first day, animals were placed in the activity chambers with 100 g of laboratory chow for a single habituation session. During this session, rats were injected with DH 2 O (1 ml/kg) and placed in the apparatus for 2 h with food intake measured by weight every hour. Next, all rats received additional sessions in which they were injected with DH 2 O or SCH (0.005, 0.01, 0.05 or 0.1 mg/kg) and placed in the test chamber for 2 h. The amount of food consumed was determined by weight every hour. Locomotor activity (time in motion) was recorded and grouped into two 1-h bins for statistical analysis. Drug tests were conducted every 48 h and all rats received all treatments. The order of the treatments was counter-balanced across animals. On the day between drug sessions, animals were placed in the apparatus and the session was conducted as usual, but no data were collected Experiment 2: effects of THC on feeding Rats (n=8) received one test session every 24 h at approximately the same time each day. On the first day, rats were placed in the activity chambers with 100 g of laboratory chow for a single habituation session. During this session, rats were given 30 min of drug-free access to the test food (this portion of each session is hereafter called the bsatiation phaseq). A satiation phase was used to facilitate the observation of drug-induced food intake by ensuring low baseline food intake during the testing period. The remaining food was weighed and animals were injected with vehicle and immediately returned to the testing chamber for an additional 2 h. Next, all rats received additional sessions in which, following the prefeed phase, they were injected with vehicle or THC (0.1, 0.5 or 1.0 mg/ kg) and immediately returned to the test chamber for 2 h. The amount of food consumed was determined by weight 1 and 2 h later. Locomotor activity (time in motion) was recorded and grouped into two 1-h bins for statistical analysis. Similar to Experiment 1, drug tests were conducted every 48 h and all rats received all treatments. The order of the treatments was counter-balanced across animals. On the day between drug sessions, animals were placed in the apparatus and the session was conducted as usual, but no data were collected Experiment 3: effects of SCH on THC-induced feeding The procedure was similar to Experiment 2, except that after the satiation phase rats (n=16) were injected with DH 2 O and returned to their home cages where the rats did not have access to food or water. The remaining food was weighed and 25 min later all rats were injected with vehicle for THC and returned to the test chambers with the remaining food for 2 h. Food intake was determined by weight every hour. The drug sessions were similar to the habituation session described above, with the exception that following the satiation phase rats received DH 2 O or SCH (0.005, 0.01, 0.05 or 0.1 mg/kg) followed 25 min later by vehicle or THC (1.0 mg/kg). Animals received all treatments in a counterbalanced order. Locomotor activity (time in motion) was recorded during all sessions and grouped into two 1-h bins for statistical analysis Statistical analysis The amount of food consumed (g) and time spent in motion (sec) were used as dependent variables and were analysed separately. Data for the satiation phase were analysed using a one-way repeated measures ANOVAs. Drug phase data were collapsed into 1-h bins and bin was treated as a factor. Separate two-factor repeated measures (dose by bin) ANOVAs were conducted on each dependent variable. Where significant main effects were found, pairwise comparisons were conducted using Bonferroni adjustments for multiple comparisons. Mauchly s W was computed to check for violations of the sphericity assumption. When Mauchly s W test was significant, the Greenhouse Geisser correction was applied. All analyses were conducted using SPSS 11.0 for Macintosh (SPSS, Chicago, IL) using a= Results 3.1. Experiment 1: effects of SCH on feeding Pre-treatment with SCH attenuated food intake relative to DH 2 O in a dose dependent manner, shown by a significant main effect of dose (Fig. 1, top) [ F(4,28)=31.37, Pb0.001]. Pairwise comparison revealed that the 0.05 and 0.1 mg/kg doses were significantly lower than saline and the mg/kg doses. Furthermore, the 0.1 mg/kg dose was significantly lower than the 0.01 mg/kg dose. In addition, a significant main effect of bin was observed suggesting that more food was consumed in the first hour as opposed to the second hour of testing [ F(1,7)=6.14, Pb0.05]. The dose by bin interaction was also significant [ F(4,28)=3.78, Pb0.05]. One way ANOVAs conducted at each bin revealed a significant effect at the 60- [ F(4,35)=23.85, Pb0.001] and 120-min [ F(4,35)=14.03, Pb0.001] bins. Pairwise compar-

4 A.N.A. Verty et al. / Brain Research 1020 (2004) Table 1 Food consumption and locomotor activity during the pre-drug satiation phase for Experiments 2 and 3 Experiment Treatment Food consumed (gfs.e.m.) Time in motion (sfs.e.m.) 2 V 2.00F F mg/kg THC 2.02F F mg/kg THC 2.20F F mg/kg THC 2.29F F DH 2 O+V 2.21F F38.28 DH 2 O+THC 2.11F F SCH+THC 1.96F F SCH+THC 1.95F F SCH+THC 2.13F F SCH+THC 1.95F F40.14 THC=D 9 -tetrahydrocannabinol, SCH=SCH 23390, V=vehicle. dose (Fig. 2, top) [ F(3,21)=89.47, Pb0.001]. Pairwise comparison revealed that the 0.5 and 1.0 mg/kg doses were significantly higher than vehicle and the 0.1 mg/kg dose. Furthermore, the 1.0 mg/kg dose was significantly higher than the 0.5 mg/kg dose. A significant main effect of bin was observed indicating that more food was consumed in the first hour relative to the second hour of testing [ F(1,7)=77.92, Pb0.001]. The dose by bin inter- Fig. 1. Laboratory chow consumed (top) and locomotor activity (bottom) in non-deprived rats following i.p. administration of DH 2 O, 0.005, 0.01, 0.05 or 0.1 mg/kg SCH Data represent means (+S.E.M.) at two consecutive 60-min measurement intervals. DH 2 O=distilled water, SCH=dose of SCH in mg/kg; *Pb0.05, significantly different from V; y Pb0.05, significantly different from 0.005SCH; # Pb0.05, significantly different from 0.01SCH. ison conducted at each bin revealed that the 0.05 and 0.1 mg/kg doses were significantly lower than DH 2 O, mg/kg and 0.01 mg/kg at the 60- and 120-min measurement intervals. Furthermore, the 0.1 mg/kg dose was significantly lower than the 0.05 mg/kg dose at the 60-min, but not at the 120-min measurement interval. Analysis of the locomotor activity results for the drug test revealed that SCH significantly reduced locomotor activity (Fig. 1, bottom) [ F(4,28)=11.51, Pb0.001]. Pairwise comparison revealed that the 0.1 mg/kg dose was significantly different from DH 2 O, and 0.01 mg/kg doses. The dose by bin interaction was not significant, but the main effect of bin was, showing that locomotor activity was generally higher in the first hour relative to the second hour (Fig. 1, bottom) [ F(1,7)=56.18, Pb0.001] Experiment 2: effects of THC on feeding During the prefeed phase, the amount of food consumed and locomotor activity did not differ significantly between any of the treatments (Table 1). Pre-treatment with THC stimulated food intake relative to vehicle in a dose dependent manner, shown by a significant main effect of Fig. 2. Laboratory chow consumed (top) and locomotor activity (bottom) in non-deprived rats following i.p. administration of vehicle, 0.1, 0.5 or 1.0 mg/kg THC. Data represent means (+S.E.M.) at two consecutive 60-min measurement intervals. V=vehicle, THC=dose of THC in mg/kg; *Pb0.05, significantly different from Sal; y Pb0.05, significantly different from 0.1THC; # Pb0.05, significantly different from 0.5THC.

5 192 A.N.A. Verty et al. / Brain Research 1020 (2004) action was also significant [ F(3,21)=3.07, Pb0.05]. One way ANOVA at each bin revealed a significant effect at the 60- [ F(3,28)=46.32, Pb0.001] and 120-min [ F(3,28)=8.28, Pb0.001] bins. Pairwise comparison conducted at each bin revealed that the 0.5 and 1.0 mg/kg doses were significantly higher than vehicle and the 0.1 mg/kg doses at the 60-min measurement intervals. Furthermore, at the 60-min interval, the 1.0 mg/kg dose was also significantly higher than the 0.5 mg/kg dose. At the 120-min measurement interval, only the 1.0 mg/kg dose was significantly higher than vehicle. Analysis of the locomotor activity results for the drug test revealed that THC affect locomotor activity, as shown by a significant main effect of dose (Fig. 2, bottom) [ F(3,21)=3.89, Pb0.05]. Pairwise comparison revealed that the 0.1 mg/kg dose was significantly different from vehicle. The dose by bin interaction was not significant, but the main effect of bin was, showing that locomotor activity was generally lower in the first hour relative to the second hour (Fig. 2, bottom) [ F(1,7)=309.57, Pb0.001] Experiment 3: effects of SCH on THC-induced feeding The amount of food consumed and locomotor activity during the 30-min drug-free satiation phase was relatively low and did not differ significantly between treatments (Table 1). In the drug test, a repeated measures ANOVA comparing all treatments revealed a significant main effect of dose for food [ F(5,75)=30.97, Pb0.001] (Fig. 3, top), but not for locomotor activity (Fig. 3, bottom). Pairwise comparisons for food consumption revealed that DH 2 O+THC and 0.005SCH+THC was significantly higher than the DH 2 O+vehicle treatment. Furthermore, 0.01SCH+ THC, 0.05SCH+THC and 0.1SCH+THC were significantly lower than DH 2 O+THC. The 0.1SCH+THC treatment was also significantly lower than DH 2 O+vehicle, 0.005SCH+THC, 0.01SCH+THC and 0.05SCH+THC. A significant main effect of bin was observed for food intake [ F(1,15)=19.17, Pb0.01] and locomotor activity [ F (1,15)= 6.69, Pb0.05] showing that food intake and locomotor activity were higher in the first hour relative to the second hour. The dose by bin interaction was significant for food intake [ F(5,75)=4.10, Pb0.01] but not for locomotor activity. One-way ANOVA conducted at each bin revealed a significant effect at the 60- [ F(5,90)=66.02, Pb0.001] and 120-min [ F(5,90)=28.97, Pb0.001] bins. Pairwise comparison conducted at the 60-min measurement interval revealed that DH 2 O+THC and 0.005SCH+THC were significantly higher than DH 2 O+vehicle. Furthermore, 0.01SCH+THC, 0.05SCH+THC and 0.1SCH+THC were significantly lower than DH 2 O+THC. Also, 0.05SCH+THC and 0.1SCH+THC were significantly lower than 0.005SCH+THC. Pairwise comparison conducted at the 120-min measurement interval revealed that DH 2 O+THC was significantly higher than DH 2 O+vehicle. Furthermore, 0.01SCH+THC, 0.05SCH+ Fig. 3. Laboratory chow consumed (top) and locomotor activity (bottom) in non-deprived rats following i.p. administration of vehicle or THC (1 mg/kg) alone or in combination with i.p. administration of DH 2 O, 0.005, 0.01, 0.05 or 0.1 mg/kg SCH Data represent means (+S.E.M.) at two consecutive 60-min measurement intervals. DH 2 O=distilled water, SCH=dose of SCH in mg/kg, V=vehicle, THC=dose of THC in mg/kg; *Pb0.05, significantly different from DH 2 O+V; y Pb0.05, significantly different from DH 2 O+THC; # Pb0.05, significantly different from 0.005SCH+THC; % Pb0.05, significantly different from 0.01SCH+THC; V Pb0.05, significantly different from 0.05SCH+THC. THC and 0.1SCH+THC were significantly lower than DH 2 O+THC. Finally, 0.1SCH+THC was significantly lower than 0.005SCH+THC. 4. Discussion The results of the present study support the notion that D 1 -like receptors are involved in cannabinoid-induced food intake. Results showed that SCH dose-dependently decreased food intake, while THC dose-dependently increased food intake. The D 1 -like receptor antagonist SCH dose-dependently blocked THC-induced feeding. SCH produced a dose dependent suppression of locomotor activity suggesting that reduction in food intake may have been due to a general reduction in motivated behaviour. Conversely, THC produced a biphasic effect on locomotion where lower doses (0.1 and 0.5 mg/kg) were

6 A.N.A. Verty et al. / Brain Research 1020 (2004) found to stimulate locomotor activity, and the highest dose (1.0 mg/kg) was found to suppress locomotor activity. Interestingly, although both 0.1 mg/kg SCH and 1.0 mg/kg THC reduced locomotor activity when administered alone (cf. Figs. 1 and 2), the combination of these two drugs produced locomotor activity values similar to those obtained by the vehicle control treatment (Fig. 3). Systemic administration of SCH inhibited feeding and locomotor activity (Experiment 1) at the highest doses tested (0.05 and 0.1 mg/kg). These results are in good agreement with previous reports demonstrating the involvement of DA receptors in feeding [24,39] and locomotor activity [11] and suggest that the suppression of feeding may be due to a general reduction in motivated behaviour rather than an effect on feeding per se. In Experiment 2, THC significantly increased the amount of food consumed relative to controls. This finding is in good agreement with previous reports [56,57] and further supports the notion that CB 1 receptors play an important role in the regulation of feeding [20]. The finding that THC produced a biphasic effect on locomotor activity complements previous studies with cannabinoids [14,36,49]. It is noteworthy that the highest dose of THC (1.0 mg/kg) used in Experiment 2 suppressed locomotor activity, but increased food intake suggesting that at this dose the locomotor suppressing effects of THC are independent of its appetite stimulating effects. Experiment 3 was designed to provide direct evidence for the involvement of DA D 1 -like receptors in cannabinoidinduced feeding. Results revealed that THC-induced feeding was attenuated by SCH at a dose that did not affect feeding on its own. Moreover, the effect of THC on locomotion observed in Experiment 2 was attenuated by SCH It is also noteworthy that the locomotor suppressive effects of SCH were not observed when SCH was given in combination with THC. Although the results of the present study alone are insufficient to elucidate the specific mechanisms involved, other studies suggest several possibilities. First, it is possible that these interactions may be mediated within the NAC. The NAC plays an important role in mediating the effects of natural reinforcers such as food and incentive and instrumental learning and is an important link between cortical systems and hypothalamic feeding related information (for a review, see Ref. [44]). The NAC contains a high density of CB 1 receptors [26] and administration of the endogenous cannabinoid 2-arachidonoyl glycerol potently and dosedependently stimulates feeding [31]. Further, intra-nac administration of DA stimulates feeding [47]. It is noteworthy that the NAC receives DA projections from the lateral hypothalamus (LH) [42] and electrical stimulation of the LH leads to appetitive behaviours [29], which are enhanced by THC [52]. Hence, the NAC-LH pathway may be an important mediator of cannabinoid-da interaction in feeding. Second, cannabinoid and DA receptors may interact in the gastrointestinal tract to mediate food intake. Evidence suggests that cannabinoid-induced food intake may be mediated via central CB 1 receptors (for a review, see Ref. [30]). However, recent evidence suggests that peripheral CB 1 receptors may also be involved in stimulating food intake [23]. Indeed, CB 1 and DA receptors are located on nerve terminals known to innervate the gastrointestinal tract [2,13], which are involved in mediating satiety signals originating from the gut [43] and food deprivation stimulates the endogenous cannabinoid anandamide within the intestines [23]. Hence, SCH may be blocking DA receptors in the gastrointestinal tract leading to a suppression of peripheral cannabinoid activity. Several studies have suggested that cannabinoids influence food intake by enhancing the motivational properties of food (for a review, see Ref. [30]). However, other evidence seems to refute this suggestion. Drugs that influence palatability, such opiates, enhance taste hedonics as measured by the dtaste reactivity testt [41] and preferentially stimulate intake of highly palatable substances [16]. A study using the Lewis strain of rats, known for their sensitivity to cannabinoids, has shown that THC produces taste aversion [40]. A closer examination of the intake of highly palatable diets [32,57] and rat chow (present study) shows that THC produces similar patterns of food intake irrespective of the macronutrient content of the diet. This suggests that cannabinoid administration increases food intake in response to caloric stimulus and is not specific to the macronutrient content. Support for this hypothesis comes from a recent study from our group showing that SR reduces feeding irrespective of the macronutrient content of the food [55]. These reports and the results obtained in the present study suggest that THC stimulates behavioural response necessary for obtaining a caloric goal object rather than enhancing the hedonic properties of food. However, this hypothesis needs further testing. It is also noteworthy that DA appears to play a broad role in adaptive motor behaviour and learning, rather than a specific role in food intake. Indeed, previous studies have shown that stimulating DA may increase behavioural responses necessary for obtaining a goal object (food), while DA antagonists depress this behaviour [4,7]. These studies suggest that the role of DA may not be to enhance the appetitive value of food reward. The SCH induced attenuation of THC stimulated feeding observed here may therefore be due to a general reduction of goal directed behaviour rather than a reduction in the hedonic value of food. This hypothesis warrants further investigation. In conclusion, we have shown that SCH reduces food intake while THC stimulates feeding. Furthermore, THC-induced stimulation of food intake was potently and dose-dependently reduced by SCH This is the first study of its kind demonstrating an interaction between cannabinoid and DA systems in feeding behaviour. It is not presently known whether the involvement of DA in

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