Characteristics of Learning and Memory Impairment Induced by ⊿9-Tetrahydrocannabinol in Rats

Mishima, Kenichi; Egashira, Nobuaki; Hirosawa, Nobue; Fujii, Megumi; Matsumoto, Yoshiaki; Iwasaki, Katsunori; Fujiwara, Michihiro

doi:10.1254/jjp.87.297

Cited by 76 publications

(51 citation statements)

References 33 publications

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“…Some evidence supports the idea that the natural and synthetic cannabinoids impair cognitive processes in humans, nonhuman primates, and rodents (Braida and Sala, 2000) and seem to inhibit hippocampal extracellular acetylcholine release (Terranova et al, 1996). Rimonabant reverses many of the biochemical physiological and behavioral effects of cannabinoid receptor agonists; e.g., it attenuates the memory impairment produced by AEA and THC (Mallet and Beninger, 1998;Mishima et al, 2001). Rimonabant, which per se does not influence memory processes at the dose of 0.5 mg/kg, completely antagonizes the impairment produced by the synthetic cannabinoid CP 55,940 (Braida and Sala, 2000).…”

Section: Other Effects Of Rimonabantmentioning

confidence: 84%

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Bifulco¹,

Grimaldi²,

Gazzerro³

et al. 2007

Mol Pharmacol

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The advent of the highly selective cannabinoid receptor (CB1) antagonist, rimonabant (SR141716; Acomplia) can revolutionize the ability of the clinicians to manage obesity. Large-scale clinical trials have demonstrated that rimonabant therapy can reduce obesity. Although, the precise mechanisms of action of rimonabant have to be further dissected, it is emerging, from both preclinical and clinical research, that not only is rimonabant an antiobesity drug, but also its pleiotropic functions affect a broad range of diseases, from obesity-related comorbidities to drug dependence and cancer. Here we review recent data from the literature and discuss the full pharmacological potential of this drug.Studies on the effect of marijuana psychoactive principle ⌬ 9 -tetrahydrocannabinol (THC) have evolved into the discovery and description of the endocannabinoid system. So far, this system is composed of two receptors (the widely expressed CB1 and the more restricted CB2), five endogenous lipid-like ligands [including the well known endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol], and the enzymes involved in their biosynthesis and degradation (for review, see Mechoulam et al., 1998;De Petrocellis et al., 2004;Di Marzo et al., 2004). Starting from the discovery of the endocannabinoid system, a number of studies have pointed out that altered endocannabinoid signaling and CB1 receptor expression are involved in several pathophysiological situations, ranging from neurological and psychiatric diseases to eating, cardiovascular, and reproductive disorders. More recently, it has been described that CB1 receptor stimulation by the endocannabinoid AEA can negatively modulate cancer cell proliferation in vitro (Bifulco et al., 2001 as well as tumor growth and metastatic spreading in vivo (Portella et al., 2003;Bifulco et al., 2006Bifulco et al., , 2007. CB1 or CB2 antagonistic or inverse agonistic compounds have been used to investigate the endocannabinoid network and its integration with other signaling transduction pathways (for review, see Lange and Kruse, 2005). The first highly selective CB1 receptor antagonist, rimonabant (SR141716; Acomplia) was discovered by Sanofi-Aventis (Bridgewater, NJ) (Rinaldi-Carmona et al., 1994). It showed a number of biological effects in vitro and in vivo in several pathological situations. An update on the pleiotropic effects of rimonabant does not exist, whereas the knowledge concerning endocannabinoid system has been expanded considerably; therefore, we critically analyze the current literature on the pharmacological potential of rimonabant. We aim to describe both We thank the Associazione Educazione e Ricerca Medica Salernitana (ERMES) for supporting our studies. A.S. was supported by a fellowship from Associazione Italiana Ricerca sul Cancro.Article, publication date, and citation information can be found at

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Section: Other Effects Of Rimonabantmentioning

confidence: 84%

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Bifulco¹,

Grimaldi²,

Gazzerro³

et al. 2007

Mol Pharmacol

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“…⌬ 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, 1995;Lichtman and Martin, 1996;Mishima et al, 2001;Nava et al, 2001) and operant (Heyser et al, 1993;Hampson and Deadwyler, 1999) models of learning and memory.…”

Section: N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(24-dichlorophenyl)-mentioning

confidence: 99%

“…The Morris water maze has been a particularly useful tool to investigate both the physiological function of the endocannabinoid system (Varvel and Lichtman, 2002;Varvel et al, 2005a) and the impact of exogenous cannabinoid administration on learning and memory (Mishima et al, 2001;Varvel et al, 2001). Repeated injections of either ⌬ 9 -THC (da Silva and Takahashi, 2002) or the potent cannabinoid receptor agonist HU-210 (Ferrari et al, 1999) before each acquisition session have been shown to disrupt the ability of rodents to learn the location of a hidden platform that remains in a fixed location.…”

Section: N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(24-dichlorophenyl)-mentioning

confidence: 99%

Exposure to Marijuana Smoke Impairs Memory Retrieval in Mice

Niyuhire

Varvel²,

Martin³

et al. 2007

J Pharmacol Exp Ther

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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

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“…All paired comparisons performed with Tukey procedure. (Castellano et al 1997(Castellano et al , 2003Mishima et al 2001;Niyuhire et al 2007). This suggests that indirect cannabinergic effects of URB597 (i.e., increased anandamide levels) could produce a learning impairment.…”

mentioning

confidence: 99%

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

Mazzola¹,

Medalie²,

Scherma³

et al. 2009

Learn. Mem.

116

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Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB 1 -receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR-a) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-a agonist WY14643, and these enhancements were blocked by the PPAR-a antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR-a, either directly by administering a PPAR-a agonist or indirectly by administering a FAAH inhibitor.Peroxisome proliferator-activated receptor-a (PPAR-a) is a ligandactivated transcriptional factor that regulates the expression of genes involved in lipid utilization, fatty acid oxidation, and inflammation (van Raalte et al. 2004;LoVerme et al. 2006). Immunolocalization studies of PPAR-a in the adult rat brain suggest that this nuclear receptor might have specific functions in regulating expression of genes involved in cholinergic neurotransmission and learning and memory processes (Moreno et al. 2004;Cimini et al. 2005). For example, there are high concentrations of PPAR-a receptors in the hippocampus and amygdala (Moreno et al. 2004). However, the potential involvement of PPAR-a in learning and memory processes has not been systematically investigated.Endogenous ligands for PPAR-a include the lipid mediators N-oleoylethanolamide (OEA) and N-palmitoylethanolamide (PEA). In addition, anandamide (N-arachidonoylethanolamine), which has primarily been studied as an endogenous ligand for G-proteincoupled cannabinoid CB 1 receptors that mediate the behavioral effects of cannabis and its active constituent D 9-tetrahydrocannabinol (THC) (Devane et al. 1992;Solinas et al. 2008), has recently begun to receive attention as a potential endogenous PPAR-a ligand (O'Sullivan 2000;Mackie and Stella 2006;Sun et al. 2007). OEA has primarily been studied as a satiety factor (Rodriguez de Fonseca et al. 2001;Fu et al. 2003) and PEA as an anti-inflammatory factor (Kuehl et al. 1957;Calignano et al. 1998;Jaggar et al. 1998). OEA and PEA are structurally similar to anandamide but do not bind to or activate cannabinoid CB 1 receptors. Anandamide, OEA, and PEA are all inactivated primarily by the intracellular serine enzyme, fatty acid amide hydrolase (FAAH) (Cravatt and Lichtman 2002;Fegley et al. 2005). Consequently, selective FAAH-inhibiting drugs such as cyclohexyl carbamic acid 39-carbamoyl-3-yl ester (URB597) increase endogenous levels of anandamide, OEA, and PEA in the brain (Fegley et al. 2005;Piomelli et al. 2006).In the present experiments, the effects of FAAH inhibition on learning and memory processes and the involvement of cannabinoid CB 1 receptors and PPAR-a nuclear receptors in those effects were studied using a passive-avoidance procedure in rats. FAAH inhibition was accomplished by administering U...

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Characteristics of Learning and Memory Impairment Induced by ⊿9-Tetrahydrocannabinol in Rats

Cited by 76 publications

References 33 publications

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Rimonabant: Just an Antiobesity Drug? Current Evidence on Its Pleiotropic Effects

Exposure to Marijuana Smoke Impairs Memory Retrieval in Mice

Fatty acid amide hydrolase (FAAH) inhibition enhances memory acquisition through activation of PPAR-α nuclear receptors

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