Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior

Rationale Cannabinoid CB1 antagonists/inverse agonists suppress food-motivated behaviors and are being evaluated as potential appetite suppressants. It has been suggested that the effects of CB1 antagonism on food motivation could be related to actions on mesolimbic dopamine (DA). If this were true, then the effects of interference with cannabinoid CB1 transmission should closely resemble the effects of interference with DA transmission. Objective To directly compare the effects of DA antagonists with those of CB1 antagonists/inverse agonists, the present studies employed a concurrent lever-pressing/chow-intake procedure. With this task, interference with DA transmission shifts choice behavior such that lever pressing for a preferred food is decreased but chow intake is increased. Results Rats treated with IP injections of the DA D1 antagonist SCH39166 (ecopipam; 0.05–0.2 mg/kg) or the D2 antagonist eticlopride (0.025–0.1 mg/kg) showed substantial decreases in lever pressing and concomitant increases in chow consumption. In contrast, IP administration of the CB1 neutral antagonist AM4113 (4.0–16.0 mg/kg) or the CB1 antagonist/inverse agonist AM251 (2.0–8.0 mg/kg) decreased operant responding for pellets, but there was no corresponding increase in chow intake. Conclusions These effects of CB1 antagonists/inverse agonists were similar to those produced by the appetite suppressant fenfluramine and by prefeeding. In contrast, low doses of DA antagonists leave primary food motivation intact, but shift behaviors toward food reinforcers that can be obtained with lower response costs. These results suggest that the effects of interference with CB1 transmission are readily distinguishable from those of reduced DA transmission.     

The cannabinoid CB1 antagonists SR 141716A and AM 251 suppress food intake and food-reinforced behavior in a variety of tasks in rats

Cannabinoid CB1 receptor agonists, including delta-9-tetrahydrocannabinol (Delta 9-THC) (the main psychoactive ingredient in marijuana) have been shown to increase feeding in rats and humans. Conversely, it has been reported that acute administration of the CB1 receptor antagonist SR 141716A reduces food intake in rats. Based upon this observation, it has been suggested that CB1 antagonists could be useful as appetite suppressant drugs. The present studies were designed to provide a detailed examination of the effects of CB1 antagonists on food intake across a range of paradigms. Two CB1 antagonists (SR 141716A and AM 251) were administered to rats trained on fixed-ratio schedules with two different ratio requirements (fixed-ratio 1 and fixed-ratio 5). Both drugs produced a dose-dependent decrease in lever pressing, and had a relatively long duration of action (T1/2: SR 141716A, 15.1 h; AM 251, 22.0 h). Furthermore, intake of three diets with differing macronutrient composition (lab chow, high fat, high carbohydrate) was studied. Both drugs significantly suppressed intake of all three foods, and there were no significant interactions between drug dose and diet type. These findings support the hypothesis that CB1 receptor antagonists could be useful pharmacological tools for the suppression of appetite.     

Oral bioavailability of the novel cannabinoid CB1 antagonist AM6527: effects on food-reinforced behavior and comparisons with AM4113

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors, and may be clinically useful as appetite suppressants. Several CB1 receptor inverse agonists, such as rimonabant and AM251, as well as the CB1 receptor neutral antagonist, AM4113, have been assessed for their effects on food-motivated behavior. One important criterion for establishing if a drug may be useful clinically is the determination of its oral bioavailability. The present studies compared the effects of AM4113 and a novel CB1 antagonist, AM6527, on the suppression of food-reinforced behavior following intraperitoneal (IP) and oral administration. AM4113 and AM6527 both suppressed lever pressing after IP injections. The ED₅₀ for the effect on FR5 responding was 0.78 mg/kg for IP AM4113, and 0.5763 mg/kg for IP AM6527. AM6527 also was effective after oral administration (ED₅₀ = 1.49 mg/kg), however, AM 4113 was ineffective up to oral doses of 32.0 mg/kg. AM 4113 may be very useful as a research tool, but its lack of oral activity suggests that this drug might not be effective if orally administered in humans. In contrast, AM 6527 is an orally active CB1 antagonist, which may be useful for clinical research on the appetite suppressant effects of CB1 antagonists.     

Suppression of food intake and food-reinforced behavior produced by the novel CB1 receptor antagonist/inverse agonist AM 1387

Cannabinoid CB1 receptor antagonist/inverse agonists are becoming increasingly recognized for their potential therapeutic utility as appetite suppressants. In the current paper we characterize the biochemical and behavioral effects of AM 1387, which is a novel CB1 antagonist. AM 1387 exhibited binding affinity and selectivity for the CB1 over the CB2 receptor. Moreover, AM 1387 decreased GTPgammaS (EC50: 22.82 nM) and increased forskolin-stimulated cAMP (EC50: 274.6 nM), as did the CB1 inverse agonist AM 251 (GTPgammaS EC50: 25.82 nM; cAMP EC50: 363.8 nM), indicating that AM1387 also has inverse agonist properties in vitro. In the behavioral characterization in rats, AM 1387 suppressed lever pressing for food on two operant schedules (fixed-ratio 1 and 5). Timecourse of the effect on fixed-ratio 5 responding was then determined, and the half-life (t1/2=4.87 h) was found to be threefold shorter than what has been shown for SR 141716A, and fourfold shorter than AM 251. Finally, AM 1387 was found to suppress food intake using three diets of differing macronutrient composition and palatability. It was concluded that AM 1387 may be a useful tool for examining the effects of CB1 receptor antagonism or inverse agonism on food intake.     

The CB1 inverse agonist AM251, but not the CB1 antagonist AM4113, enhances retention of contextual fear conditioning in rats

The effects of CB1 antagonist/inverse agonists on the acquisition and consolidation of conditioned fear remain uncertain. Recent studies suggest that the CB1 antagonist/inverse agonist AM251 affects acquisition or consolidation of both contextual and discretely cued fear memories. AM251 is frequently referred to as a CB1 antagonist; however in vitro signal transduction assays indicate that this drug also elicits inverse agonist activity at CB1 receptors. The present studies were undertaken to compare the effects of AM251 on conditioned fear with those produced by AM4113, a novel CB1 antagonist with minimal inverse agonist activity. All drugs were administered prior to conditioning. In retention tests conducted two weeks after conditioning, both AM251 (4.0 mg/kg) and AM4113 (6.0 mg/kg)-treated animals exhibited reduced freezing during a conditioned tone cue played within a novel context. In contextual fear retention tests, animals previously treated with 4.0 or 8.0 mg/kg AM251 exhibited enhanced freezing. By contrast, no dose of AM4113 had any significant effect on contextual fear memory, which is consistent with the lower signal transduction activity of AM4113 at CB1 receptors compared to AM251. These results suggest that CB1 neutral antagonists may be less likely than CB1 inverse agonists to facilitate the acquisition or consolidation of contextual fear that may contribute to some clinical disorders.     

Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviors in rats

We examined open-field effects in rats of the cannabinoid 1 receptor (CB1R) agonist WIN55,212-2 (WIN; 3 mg/kg) and its interaction with the CB1R putative neutral antagonist AM4113 (0.3 to 3 mg/kg). Separate studies examined AM4113 alone (0.3 to 5.6 mg/kg). Unlike the CB1R antagonist rimonabant, in vitro (e.g., [Sink K.S., McLaughlin P.J., Wood J.A., Brown C., Fan P., Vemuri V.K., Pang Y., Olzewska T., Thakur G.A., Makriyannis A., Parker L.A., Salamone J.D. The novel cannabinoid CB(1) receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 2008a; 33: 946-955.; Sink K.S., Vemuri V.K., Olszewska T., Makriyannis A., Salamone J.D. Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior. Psychopharmacology (Berl) 2008b; 196: 565-574.]) AM4113 produced no change in cAMP accumulation (neutral antagonism vis-a-vis inverse agonism). Recorded behaviors were: ambulation, rearing, circling, latency, scratching, grooming, defecation, urination and vocalization/squeaking. WIN reduced ambulation and rearing; AM4113 completely (ambulation) or partially (rearing) antagonized these behaviors. WIN alone resulted in circling and an increased latency to leave the start area; effects blocked by AM4113. AM4113 increased scratching and grooming, effects attenuated but not abolished by WIN. AM4113 alone tended to reduce ambulation and rearing and had no effect on latency or circling. AM4113 alone increased scratching and grooming. Effects on defecation, urination and vocalization were non-significant. The open-field effects of AM4113 are similar to those reported for rimonabant in rats. Yet, unlike the inverse agonists rimonabant and AM251, the putative neutral CB1R antagonist AM4113 did not produce signs of nausea in ferrets and rats ([Chambers A.P., Vemuri V.K., Peng Y., Wood J.T., Olszewska T., Pittman Q.J., Makriyannis A., Sharkey K.A. A neutral CB1 receptor antagonist reduces weight gain in rat. Am J Physiol Regul Integr Comp Physiol 2007; 293: R2185-2193.; Sink K.S., McLaughlin P.J., Wood J.A., Brown C., Fan P., Vemuri V.K., Pang Y., Olzewska T., Thakur G.A., Makriyannis A., Parker L.A., Salamone J.D. The novel cannabinoid CB(1) receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats. Neuropsychopharmacology 2008a; 33: 946-955.; Sink K.S., Vemuri V.K., Olszewska T., Makriyannis A., Salamone J.D. Cannabinoid CB1 antagonists and dopamine antagonists produce different effects on a task involving response allocation and effort-related choice in food-seeking behavior. Psychopharmacology (Berl) 2008b; 196: 565-574.]).     

The novel cannabinoid CB1 antagonist AM6545 suppresses food intake and food-reinforced behavior

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors, and may be useful clinically as appetite suppressants. However, there may also be undesirable side effects (e.g., nausea, malaise, anxiety, and depression) that are produced by the current generation of CB1 inverse agonists such as rimonabant and taranabant. For that reason, it is important to continue research on novel cannabinoid antagonists. The present studies examined the effects of the novel compound AM6545, which is a neutral antagonist of CB1 receptors that is thought to have relatively poor penetrability into the central nervous system. Intraperitoneal administration of AM6545 significantly reduced food-reinforced operant responding at doses of 4.0, 8.0 and 16.0 mg/kg. AM6545 also produced a strong suppression of the intake of high-carbohydrate and high-fat diets in the same dose range, but only produced a mild suppression of lab chow intake at the highest dose (16.0 mg/kg). Although AM6545 did not affect food handling, it did reduce time spent feeding and feeding rate. Taken together, these results suggest that AM6545 is a compound that warrants further study as a potential appetite suppressant drug.     

The novel cannabinoid agonist AM 411 produces a biphasic effect on accuracy in a visual target detection task in rats

Cannabinoid agonists have been shown to produce dose-related impairments in several measures of cognitive performance. However, it is unclear if low doses of cannabinoid CB1 agonists, or CB1 antagonists, can facilitate aspects of stimulus detection. The present study employed an operant procedure involving visual stimulus detection in rats. The task was found to be sensitive to the muscarinic acetylcholine antagonist scopolamine. The CB1 antagonist AM 251 did not affect stimulus detection processes across a broad range of doses. However, the novel CB1 agonist AM 411 produced a biphasic effect, with the two lowest doses (0.25 and 0.5 mg/kg) enhancing accuracy. AM 411 changed patterns of responding toward runs of consecutive errors on only one of the two levers. It produced a biphasic effect on consecutive errors on the lever associated with a higher level of errors, with decreases in errors following the lower doses (0.25 and 0.5 mg/kg) and increases following the highest dose (2.0 mg/kg). These effects were not accompanied by changes in measures of bias commonly used to uncover such patterns in rodent operant models of cognitive performance. In contrast to the cognitive impairment seen after administration of moderate to high doses of CB1 agonists, it appears that low doses of some CB1 agonists may be capable of enhancing stimulus detection processes.     

The cannabinoid CB1 antagonist AM 251 produces food avoidance and behaviors associated with nausea but does not impair feeding efficiency in rats

Rationale A growing body of evidence suggests that cannabinoid CB1 receptor antagonists have potential therapeutic utility as appetite suppressants. However, the specific mechanisms underlying the reduction in food intake produced by these drugs are not well understood.Objective Considering the known antiemetic and motor-suppressive effects of CB1 agonists, the present studies were conducted to determine if the reductions in food intake induced by the CB1 antagonist AM 251 could result from nausea or impairments in intake-related motor control, rather than solely from appetite suppression.Methods Three experiments were conducted to examine the effects of AM 251 (2.0, 4.0, or 8.0 mg/kg or vehicle) on detailed parameters of food intake, on the development of conditioned taste avoidance, and on taste reactivity.Results In the first experiment, acute administration of AM 251 dose-dependently decreased food intake; nevertheless, feeding rate (grams consumed per time spent eating) and food handling were unaffected, which suggests that food intake was not reduced because of severe motor impairments. In the second experiment, AM 251 dose-dependently reduced intake of a flavor with which it had previously been associated, indicating that conditioned taste avoidance had developed. Lastly, AM 251 was found to induce conditioned rejection reactions in a dose-dependent manner.Conclusions The CB1 antagonist AM 251 may reduce food intake in part by inducing nausea or malaise, but not because of incoordination or motor slowing related to feeding.     

Pharmacological characterization of performance on a concurrent lever pressing/feeding choice procedure: effects of dopamine antagonist,cholinomimetic, sedative and stimulant drugs

This experiment was undertaken to provide a pharmacological characterization of performance on a task involving food-related instrumental and consummatory behavior. Rats were tested in an operant chamber in which there was a choice between pressing a lever to receive a preferred food (Bioserve pellets) or approaching and consuming a less-preferred food (Lab Chow). The lever pressing schedule was a fixed ratio 5 (FR5). Rats usually pressed the lever at high rates to obtain the preferred food, and typically ate little of the lab chow even though it was freely available in the chamber concurrently with the lever pressing schedule. Previous work has shown that injection of dopamine (DA) antagonists, or depletion of DA in the nucleus accumbens, caused a substantial shift in behavior such that lever pressing was reduced but chow consumption increased. In the present study it was shown that the DA antagonist haloperidol decreased lever pressing and increased chow consumption at doses of 0.1 and 0.15 mg/kg. The D1 antagonist SCH 23390 (0.05, 0.1 and 0.15 mg/kg) and the non-selective DA antagonistcis-flupenthixol (0.3 and 0.45 mg/kg) decreased lever pressing and produced substantial increases in chow consumption. The D2 antagonist sulpiride decreased lever pressing, but produced only slight increases in chow intake at the highest dose. Pentobarbital reduced lever pressing and increased chow consumption at 10.0 mg/kg. The muscarinic agonist pilocarpine produced dose-related decreases in lever pressing, but failed to increase chow consumption. Amphetamine produced dose-related decreases in both lever pressing and chow consumption. These results indicate that low/moderate doses of the DA antagonists haloperidol,cis-flupenthixol and SCH 23390 can suppress lever pressing in doses that leave the animal directed towards food acquisition and consumption.     

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.     

The cannabinoid CB1 receptor antagonist AM251 does not modify methamphetamine reinstatement of responding

Cannabinoid CB(1) receptor antagonists can decrease methamphetamine self-administration. This study examined whether the CB(1) receptor antagonist AM251 [N-(piperidin-1-yl)-5-(4-indophonyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] modifies reinstatement in rats that previously self-administered methamphetamine. Rats (n=10) self-administered methamphetamine (0.1 mg/kg/infusion) under a fixed ratio 2 schedule. Non-contingent methamphetamine (0.01-1.78 mg/kg, i.v.) yielded responding for saline (reinstatement) that was similar to responding for self-administered methamphetamine. AM251 (0.032-0.32, i.v.) did not affect methamphetamine-induced reinstatement but significantly attenuated Delta(9)-tetrahydrocannabinol (2.0 mg/kg, i.p.)-induced hypothermia. These data fail to support a role for endogenous cannabinoids or cannabinoid CB(1) receptors in reinstatement and, therefore, relapse to stimulant abuse.     

The adenosine A<Subscript>2A</Subscript> antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists

Rationale  Brain dopamine (DA) participates in the modulation of instrumental behavior, including aspects of behavioral activation and effort-related choice behavior. Rats with impaired DA transmission reallocate their behavior away from food-seeking behaviors that have high response requirements, and instead select less effortful alternatives. Although accumbens DA is considered a critical component of the brain circuitry regulating effort-related choice behavior, emerging evidence demonstrates a role for adenosine A_2A receptors. Objective  Adenosine A_2A receptor antagonism has been shown to reverse the effects of DA antagonism. The present experiments were conducted to determine if this effect was dependent upon the subtype of DA receptor that was antagonized to produce the changes in effort-related choice. Materials and methods  The adenosine A_2A receptor antagonist MSX-3 (0.5–2.0 mg/kg IP) was assessed for its ability to reverse the effects of the D1 family antagonist SCH39166 (ecopipam; 0.2 mg/kg IP) and the D2 family antagonist eticlopride (0.08 mg/kg IP), using a concurrent lever pressing/chow feeding procedure. Results  MSX-3 produced a substantial dose-related reversal of the effects of eticlopride on lever pressing and chow intake. At the highest dose of MSX-3, there was a complete reversal of the effects of eticlopride on lever pressing. In contrast, MSX-3 produced only a minimal attenuation of the effects of SCH39166, as measured by regression and effect size analyses. Conclusions  The greater ability of MSX-3 to reverse the effects of D2 vs. D1 blockade may be related to the colocalization of D2 and adenosine A_2A receptors on the same population of striatal neurons.     

Anandamide mediates hyperdynamic circulation in cirrhotic rats via CB(1) and VR(1) receptors

BACKGROUND AND PURPOSE: Hyperdynamic circulation and mesenteric hyperaemia are found in cirrhosis. To delineate the role of endocannabinoids in these changes, we examined the cardiovascular effects of anandamide, AM251 (CB(1) antagonist), AM630 (CB(2) antagonist) and capsazepine (VR1 antagonist), in a rat model of cirrhosis. EXPERIMENTAL APPROACH: Cirrhosis was induced by bile duct ligation. Controls underwent sham operation. Four weeks later, diameters of mesenteric arteriole and venule (intravital microscopy), arterial pressure, cardiac output, systemic vascular resistance and superior mesenteric artery (SMA) flow were measured after anandamide, AM251 (with or without anandamide), AM630 and capsazepine administration. CB(1), CB(2) and VR1 receptor expression in SMA was assessed by western blot and RT-PCR. KEY RESULTS: Anandamide increased mesenteric vessel diameter and flow, and cardiac output in cirrhotic rats, but did not affect controls. Anandamide induced a triphasic arterial pressure response in controls, but this pattern differed markedly in cirrhotic rats. Pre-administration of AM251 blocked the effects of anandamide. AM251 (without anandamide) increased arterial pressure and systemic vascular resistance, constricted mesenteric arterioles, decreased SMA flow and changed cardiac output in a time-dependent fashion in cirrhotic rats. Capsazepine decreased cardiac output and mesenteric arteriolar diameter and flow, and increased systemic vascular resistance in cirrhotic rats, but lacked effect in controls. Expression of CB(1) and VR1 receptor proteins were increased in cirrhotic rats. AM630 did not affect any cardiovascular parameter in either group. CONCLUSIONS AND IMPLICATIONS: These data suggest that endocannabinoids contribute to hyperdynamic circulation and mesenteric hyperaemia in cirrhosis, via CB(1)- and VR1-mediated mechanisms.     

D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption

Although interference with dopamine (DA) systems can suppress lever pressing for food reinforcement, it is not clear whether this effect occurs because of a general disruption of food motivation. One way of assessing this has been a choice procedure in which a rat responds on an fixed ratio 5 (FR5) schedule for preferred Bioserve pellets while a less preferred lab chow is concurrently available in the operant chamber. Untreated rats consume little of the chow, preferring to respond for the Bioserve pellets. Previous studies have shown that depleting DA in the accumbens substantially decreased lever pressing while increasing chow consumption. In the present study, low doses (0.0625-1.0 microg) of the D1 antagonist SCH 23390 or the D2 antagonist raclopride were injected into the either the core or shell subregions of nucleus accumbens, and rats were tested on the concurrent lever pressing/feeding task. Analysis of the dose response curves showed that injections of SCH 23390 into the core were more potent than injections into the shell for suppressing lever pressing (i.e., the ED(50) was lower in the core). Nevertheless, injections of either drug into either site suppressed lever pressing and increased intake of the concurrently available chow. Across both drugs and at both sites, the amount of chow consumed was negatively correlated with the total number of responses. Neither drug significantly increased response duration, suggesting that accumbens DA antagonism did not produce the type of motor impairment that leads to severe alterations in the form of lever pressing. In summary, the blockade of D1 or D2 receptors in nucleus accumbens core or shell decreased lever pressing for food reinforcers, but rats remained directed toward the acquisition and consumption of food. These results indicate that accumbens D1 antagonism does not decrease lever pressing because of a general reduction in food motivation. Nevertheless, interference with accumbens DA does appear to set constraints upon which responses are selected for obtaining food, and may impair the ability of animals to overcome work-related response costs in order to obtain food.     

The effect of am 251, a cannabinoid CB1 receptor antagonist, on food intake in rats

The anorectic effect of AM 251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), a CB1 receptor antagonist, was studied in rats. AM 251 (0.5-2.0 mg/kg i.p.) significantly and dose-dependently reduced food intake in both free-feeding and food-deprived rats. The obtained results support the anorectic activity of CB1 receptors antagonists.     

Cannabinoid CB1 receptor antagonists attenuate cocaine's rewarding effects: experiments with self-administration and brain-stimulation reward in rats.

Previous studies suggest that cannabinoid CB1 receptors do not appear to be involved in cocaine's rewarding effects, as assessed by the use of SR141716A, a prototypic CB1 receptor antagonist and CB1-knockout mice. In the present study, we found that blockade of CB1 receptors by AM 251 (1-10 mg/kg), a novel CB1 receptor antagonist, dose-dependently lowered (by 30-70%) the break point for cocaine self-administration under a progressive-ratio (PR) reinforcement schedule in rats. The same doses of SR141716 (freebase form) maximally lowered the break point by 35%, which did not reach statistical significance. Neither AM 251 nor SR141716 altered cocaine self-administration under a fixed-ratio (FR2) reinforcement schedule. AM 251 (0.1-3 mg/kg) also significantly and dose-dependently inhibited (by 25-90%) cocaine-enhanced brain stimulation reward (BSR), while SR141716 attenuated cocaine's BSR-enhancing effect only at 3 mg/kg (by 40%). When the dose was increased to 10 or 20 mg/kg, both AM 251 and SR141716 became less effective, with AM 251 only partially inhibiting cocaine-enhanced BSR and PR cocaine self-administration, and SR141716 having no effect. AM 251 alone, at all doses tested, had no effect on BSR, while high doses of SR141716 alone significantly inhibited BSR. These data suggest that blockade of CB1 receptors by relatively low doses of AM 251 dose-dependently inhibits cocaine's rewarding effects, whereas SR141716 is largely ineffective, as assessed by both PR cocaine self-administration and BSR. Thus, AM 251 or other more potent CB1 receptor antagonists deserve further study as potentially effective anti-cocaine medications.     

The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats.

Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dose-dependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists.     

Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: Comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142

Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0–8.0 mg/kg), the CB1 antagonist AM4113 (3.0–12.0 mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0–20.0 mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.     

Behavioral effects of the novel cannabinoid full agonist AM 411

AM 411 ((-)-1-adamantyl-Delta8-tetrahydrocannabinol) is a novel full agonist at cannabinoid CB1 receptors. The present studies were conducted to provide behavioral characterization of this compound in rats. It was hypothesized that AM 411 should produce behavioral effects similar to known cannabinoid agonists, and that these effects should be inhibited by co-treatment with a CB1 antagonist. In Experiments 1 and 2, AM 411 dose-dependently produced behaviors consistent with CB1 agonism, including analgesia, hypothermia, catalepsy and reductions in locomotion, which were blocked by a CB1-selective antagonist. In Experiment 3, AM 411 produced a dose-dependent suppression of lever-pressing on a fixed-ratio 5 (FR5) schedule, a task known to be sensitive to administration of CB1 agonists. Detailed analysis of the temporal patterns of operant responding showed that AM 411 altered the distribution of interresponse times. Experiment 4 showed that AM 411 decreased relative interior activity in the open field, which is suggestive of an anxiogenic effect. It is concluded that AM 411 produces CB1 agonist-like behavior with potency between that of WIN 55,212-2 and AM 356. AM 411 could be a useful tool for understanding the behavioral and neural effects of CB1 receptor stimulation.