Linda A. Parker

The Endocannabinoid System and the Brain

The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research--with an emphasis on recent publications--on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic--lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions.

Cannabidiol: An Overview of Some Pharmacological Aspects

Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis. The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.

Taste avoidance and taste aversion: Evidence for two different processes

The termsconditioned taste avoidance andconditioned taste aversion are often used interchangeably in the literature; however, considerable evidence indicates that they may represent different processes. Conditioned taste avoidance is measured by the amount that a rat consumes in a consumption test that includes both appetitive phases and consummatory phases of responding. However, conditioned taste aversion is more directly assessed with the taste reactivity test, which includes only the consummatory phase of responding. Rats display a conditioned taste aversion as conditioned rejection reactions (gapes, chin rubs, and paw treads) during an intraoral infusion of a nausea-paired flavored solution. Treatments that produce nausea are not necessary for the establishment of taste avoidance, but they are necessary for the establishment of taste aversion. Furthermore, treatments that alleviate nausea modulate neither the establishment nor the expression of taste avoidance, but they interfere with both the establishment and the expression of taste aversion. Considerable evidence exists indicating that these two measures are independent of one another. Taste avoidance may be motivated by conditioned fear rather than conditioned nausea, but taste aversion (as reflected by rejection reactions) may be motivated by conditioned nausea.

THC-induced place and taste aversions in Lewis and Sprague-Dawley rats.

The hedonic properties of delta-9-tetrahydrocannabinol (THC) were assessed in place and taste conditioning paradigms in both Lewis and Sprague-Dawley rat strains. THC produced place avoidance, taste avoidance, and aversive taste reactivity responses in both strains. The Lewis strain displayed more aversive taste reactions and a stronger taste avoidance when conditioned with lower doses of THC than did the Sprague-Dawley strain of rats. THC is an anomalous drug of abuse that appears to be aversive to rats when assessed by these measures.

Morphine- and naltrexone-induced modification of palatability: analysis by the taste reactivity test.

We used the taste reactivity (TR) test, a direct measure of the hedonic properties of a tastant, to assess in Sprague-Dawley rats the ability of morphine (an opiate agonist) and naltrexone (an opiate antagonist) to modify the palatability of a bitter quinine solution and a sweet sucrose solution. Morphine reduced the aversive hedonic properties of both novel and familiar quinine solution (0.05% and 0.1%) but did not modify the palatability of 20% sucrose solution. Naltrexone reduced the positive hedonic properties of sucrose solution (2% and 20%) but did not modify the palatability of 0.05% quinine solution. The pattern of results suggests that the modification of feeding produced by opiate agonists and antagonists may be mediated by an hedonic shift in the palatability of the tastant.

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.

Reinstatement of both a conditioned place preference and a conditioned place aversion with drug primes.

In two experiments, we report that the place-conditioning paradigm can be used to demonstrate reinstatement of place preference/aversion by a drug prime following extinction training. In Experiment 1, rats were trained to prefer a chamber paired with morphine. Following extinction training, a morphine drug prime reinstated the morphine place preference. In Experiment 2, a lithium-induced conditioned place aversion was reinstated following extinction training by a lithium prime prior to testing. These results indicate that not only do rewarding drug primes produce reinstatement of learned responses (as demonstrated in the drug self-administration paradigm), but also aversive drug primes reinstate aversive learned responses.

Cannabinoid CB1 receptor inverse agonists and neutral antagonists: Effects on food intake, food-reinforced behavior and food aversions

Drugs that interfere with cannabinoid CB1 receptor transmission suppress a number of food-related behaviors, and these compounds are currently being assessed for their potential utility as appetite suppressants. In addition to rimonabant (SR141716A), several other compounds have been evaluated, including AM251 and AM1387. Biochemical studies indicate that most of the drugs assessed thus far have been CB1 inverse agonists, and these drugs all act to suppress food intake and disrupt food-reinforced behavior. Behavioral tests involving intake of different diets (i.e., high fat, high carbohydrate, laboratory chow) indicate that consumption of all three food types is disrupted by CB1 inverse agonists, and that, expressed as a percent of baseline intake, the effect is roughly comparable across different diets. Although CB1 inverse agonists do not appear to produce severe motor impairments that disrupt feeding behavior, there is evidence that they can induce nausea and malaise. Recent studies have been undertaken to characterize the behavioral effects of CB1 receptor neutral antagonists such as AM4113 to determine if these drugs can reduce feeding and food-reinforced behaviors. Across a variety of different tests, AM4113 produces effects on food-motivated behavior that are very similar to those produced by CB1 inverse agonists. Moreover, this drug did not induce conditioned gaping in rats or vomiting in ferrets. These results suggest that CB1 receptor neutral antagonists may decrease appetite by blocking endogenous cannabinoid tone, and that these drugs may be less associated with nausea than is the case for CB1 inverse agonists.

Regulation of nausea and vomiting by cannabinoids.

Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti‐emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re‐exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ9‐THC, HU‐210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB‐597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non‐psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti‐nausea/anti‐emetic effects of CBD may be mediated by indirect activation of somatodendritic 5‐HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5‐HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.

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.