Recent reports have demonstrated that disruption of CB 1 receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (À/À) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAHcompromised mice also exhibited a significant increase in acquisition rate. The CB 1 receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB 1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, D 9 -tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB 1 receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

Rationale-Disruption of CB 1 receptor signaling through the use of CB 1 (-/-) mice or the CB 1 receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB 1 (-/-) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task.Objectives-The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks.Materials and methods-Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session.Results-Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task.Conclusions-These results support the hypothesis that the CB 1 receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.

Marijuana (Cannabis sativa) and its primary psychoactive component, ␦-9-tetrahydrocannabinol (⌬ 9 -THC), have long been known to disrupt cognition in humans. Although ⌬ 9 -THC and other cannabinoids disrupt performance in a wide range of animal models of learning and memory, few studies have investigated the effects of smoked marijuana in these paradigms. Moreover, in preclinical studies, cannabinoids are generally administered before acquisition, and because retention is generally evaluated soon afterward, it is difficult to distinguish between processes related to acquisition and retrieval. In the present study, we investigated the specific effects of marijuana smoke and injected ⌬ 9 -THC on acquisition versus memory retrieval in a mouse repeated acquisition Morris water-maze task. To distinguish between these processes, subjects were administered ⌬ 9 -THC or they were exposed to marijuana smoke either 30 min before acquisition or 30 min before the retention test. Inhalation of marijuana smoke or injected ⌬ 9 -THC impaired the ability of the mice to learn the location of the hidden platform and to recall the platform location once learning had already taken place. In contrast, neither drug impaired performance in a cued task in which the platform was made visible. Finally, the cannabinoid-1 (CB 1 ) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (rimonabant) blocked the memory disruptive effects of both ⌬ 9 -THC and marijuana. These data represent the first evidence demonstrating that marijuana impairs memory retrieval through a CB 1 receptor mechanism of action and independently of its effects on sensorimotor performance, motivation, and initial acquisition.Marijuana (Cannabis sativa) produces a constellation of effects in humans, including alterations in perception and mood, intoxication, euphoria, increased heart rate, physical dependence upon chronic use, and cognitive impairment (Pacher et al., 2006;Ranganathan and D'Souza, 2006). During the more than 40 years since ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) was first identified as marijuana's primary psychoactive ingredient (Gaoni and Mechoulam, 1964), great strides have been made in understanding its actions in the brain. ⌬ 9 -THC and related chemicals, known as cannabinoids, produce their psychoactive effects by acting at the cannabinoid-1 (CB 1 ) receptor in brain areas associated with learning and memory and elsewhere (Herkenham, 1991). Particular interest has focused on the effects of cannabis on cognition, because both naturally occurring and synthetically derived cannabinoids disrupt performance in a variety of rodent spatial (Lichtman et al

This is the first demonstration of which we are aware showing that GABA(A) receptors may play a necessary role in Delta(9)-THC-induced memory impairment in whole animals.

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