A. Makriyannis

Endocannabinoids control spasticity in a multiple sclerosis model

Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2‐arachidonoyl glycerol (2‐AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non‐spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re‐uptake and hydrolysis—probably through the enhancement of endogenous levels of AEA, and, possibly, 2‐arachidonoyl glycerol—significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.

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.

Dopaminergic modulation of effort-related choice behavior as assessed by a progressive ratio chow feeding choice task: pharmacological studies and the role of individual differences.

Mesolimbic dopamine (DA) is involved in behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. In the present study, the effects of several drug treatments were assessed using a progressive ratio (PROG)/chow feeding concurrent choice task. With this task, rats can lever press on a PROG schedule reinforced by a preferred high-carbohydrate food pellet, or alternatively approach and consume the less-preferred but concurrently available laboratory chow. Rats pass through each ratio level 15 times, after which the ratio requirement is incremented by one additional response. The DA D2 antagonist haloperidol (0.025–0.1 mg/kg) reduced number of lever presses and highest ratio achieved but did not reduce chow intake. In contrast, the adenosine A2A antagonist MSX-3 increased lever presses and highest ratio achieved, but decreased chow consumption. The cannabinoid CB1 inverse agonist and putative appetite suppressant AM251 decreased lever presses, highest ratio achieved, and chow intake; this effect was similar to that produced by pre-feeding. Furthermore, DA-related signal transduction activity (pDARPP-32(Thr34) expression) was greater in nucleus accumbens core of high responders (rats with high lever pressing output) compared to low responders. Thus, the effects of DA antagonism differed greatly from those produced by pre-feeding or reduced CB1 transmission, and it appears unlikely that haloperidol reduces PROG responding because of a general reduction in primary food motivation or the unconditioned reinforcing properties of food. Furthermore, accumbens core signal transduction activity is related to individual differences in work output.

A novel peripherally restricted cannabinoid receptor antagonist, AM6545, reduces food intake and body weight, but does not cause malaise, in rodents

BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects.

Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis

Effects of locally administered agonists and antagonists for cannabinoid CB1 and CB2 receptors on mechanical and thermal hypersensitivity were compared after the establishment of chronic inflammation.

Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats

The ability of cannabinoids to suppress mechanical hypersensitivity (mechanical allodynia) induced by treatment with the chemotherapeutic agent vincristine was evaluated in rats. Sites of action were subsequently identified.

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 (2.0-8.0mg/kg), the CB1 antagonist AM4113 (3.0-12.0mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0mg/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.

Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats

BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists/inverse agonists, potentiate toxin‐induced nausea and vomiting in animal models. Here, we sought to determine if this potentiated nausea was mediated by inverse agonism or neutral antagonism of the CB1 receptor, and if the potentiated nausea would be produced by intracerebroventricular (icv) administration of an inverse agonist.

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.

Medicinal chemistry of cannabinoids

The endocannabinoid system comprises the two well characterized Gi/o‐protein coupled receptors (cannabinoid receptor 1 (CB1) and CB2), their endogenous lipid ligands, and the enzymes involved in their biosynthesis and biotransformation. Drug discovery efforts relating to the endocannabinoid system have been focused mainly on the two cannabinoid receptors and the two endocannabinoid deactivating enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). This review provides an overview of cannabinergic agents used in drug research and those being explored clinically.