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Cannabinoid CB2 Receptor (CB2) activation has been shown to have immunomodulatory properties without psychotropic effects. The hypothesis of this study is that selective CB2 agonist treatment can attenuate cerebral ischemia/reperfusion injury. Selective CB2 agonists (O-3853, O-1966) were administered intravenously 1 h before transient middle cerebral artery occlusion (MCAO) or 10 mins after reperfusion in male mice. Leukocyte/endothelial interactions were evaluated before MCAO, 1 h after MCAO, and 24 h after MCAO via a closed cranial window. Cerebral infarct volume and motor function were determined 24 h after MCAO. Administration of the selective CB2 agonists significantly decreased cerebral infarction (30%) and improved motor function (P < 0.05) after 1 h MCAO followed by 23 h reperfusion in mice. Transient ischemia in untreated animals was associated with a significant increase in leukocyte rolling and adhesion on both venules and arterioles (P < 0.05), whereas the enhanced rolling and adhesion were attenuated by both selective CB2 agonists administered either at 1 h before or after MCAO (P < 0.05). CB2 activation is associated with a reduction in white blood cell rolling and adhesion along cerebral vascular endothelial cells, a reduction in infarct size, and improved motor function after transient focal ischemia.

Although conditioned place preferences (CPPs) are seen with most abused drugs, nicotine does not always produce a preference in this design. The goals of the present experiment were to (1) examine various factors that could contribute to these inconsistent results and (2) begin to evaluate the specific nicotinic receptors involved in the nicotine CPP. The influences of prior handling, environmental habituation, and injection habituation on a nicotine CPP were first evaluated in ICR mice. Subsequently, various nicotine doses were assessed for their abilities to produce a CPP, and the effectiveness of nicotinic receptor antagonists in attenuating this preference was examined. Finally, nicotine CPPs were assessed in C57BL/6J and DBA/2J mice to examine the influence of strain in this design. Nicotine CPPs were seen in handled/environmentally habituated, but not in unhandled, ICR mice. Habituation to the injection techniques failed to strengthen the preference. In ICR mice, a CPP was seen with one intermediate dose of nicotine. This CPP was attenuated by mecamylamine and dihydro-beta-erythroidine (DHbetaE). A nicotine CPP was also seen in C57BL/6J, but not in DBA/2J, mice. Earlier handling experience and strain are important factors when evaluating a nicotine CPP in the mouse. In addition, certain nicotinic receptors underlie the nicotine CPP, indicating that this model can elucidate underlying mediators of nicotine reward.

Manipulations of the endocannabinoid/fatty acid amide hydrolase (FAAH) signaling systems result in conflicting and paradoxical effects in rodent models of emotional reactivity. In the present study, we tested the hypothesis that the inhibition of FAAH would elicit significant effects in murine models used to screen anxiolytic and antidepressant drugs. FAAH (-/-) mice and wild-type mice treated with FAAH inhibitors (URB597 and OL-135) were evaluated in standard behavioral screening models for antidepressant (i.e., tail suspension and forced-swim tests) and anxiolytic (i.e., elevated plus maze) agents. The doses of URB597 and OL-135 selected were based on their ability to augment the pharmacological effects (i.e., analgesia, catalepsy, and hypothermia) of exogenously administered anandamide. FAAH (-/-) mice, anandamide-injected FAAH (-/-) mice, or wild-type mice injected with FAAH inhibitors or anandamide failed to exhibit significant effects in standard tests of emotional reactivity, although the antidepressant desipramine and the anxiolytic agent midazolam were active in the appropriate assays. FAAH- (-/-) and URB597-treated mice finally displayed significant effects in the tail suspension test when substantial methodological changes were made (i.e., altered ambient light and increased sample sizes). Although FAAH suppression can elicit significant effects under some instances in which consequential procedural modifications are made, the present results indicate that the pharmacological inhibition or genetic deletion of FAAH is ineffective in standard mouse models of emotional reactivity. It remains to be established whether the effects of FAAH inhibition in these modified tasks are predictive of their efficacy in treating emotional disorders.

The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive alternative to marijuana-based therapeutics would be to target the molecular pathways that mediate the effects of this drug. To date, these neural signaling pathways have been shown to comprise a cannabinoid receptor (CB1) that binds the active constituent of marijuana, tetrahydrocannabinol (THC), and a postulated endogenous CB1ligand anandamide. Although anandamide binds and activates the CB1receptor in vitro, this compound induces only weak and transient cannabinoid behavioral effects in vivo, possibly a result of its rapid catabolism. Here we show that mice lacking the enzyme fatty acid amide hydrolase (FAAH-/-) are severely impaired in their ability to degrade anandamide and when treated with this compound, exhibit an array of intense CB1-dependent behavioral responses, including hypomotility, analgesia, catalepsy, and hypothermia. FAAH-/--mice possess 15-fold augmented endogenous brain levels of anandamide and display reduced pain sensation that is reversed by the CB1antagonist SR141716A. Collectively, these results indicate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception. FAAH may therefore represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.

1 Marijuana's appetite‐increasing effects have long been known. Recent research suggests that the CB1 cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB1 cannabinoid receptors in the pharmacological effects of cannabinoids on food intake. 2 Mice were food‐restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB1 antagonist SR141716A dose‐dependently decreased food consumption at doses that did not affect motor activity, Δ9‐tetrahydrocannabinol (Δ9‐THC) increased food consumption at doses that had no effect on motor activity. O‐3259 and O‐3257, structural analogs of SR141716A, produced effects similar to those of the parent compound. 3 Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB2 cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity. 4 SR141716A decreased feeding in wild‐type mice, but lacked pharmacological activity in CB1 knockout mice; however, basal food intake was lower in CB1 knockout mice. Amphetamine decreased feeding in both mouse genotypes. 5 These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB1 receptors may play a role in regulation of feeding behavior. British Journal of Pharmacology (2005) 145, 293–300. doi:10.1038/sj.bjp.0706157

Recognition of the importance of the endocannabinoid system in both homeostasis and pathologic responses raised interest recently in the development of therapeutic agents based on this system. The CB 2 receptor, a component of the endocannabinoid system, has significant influence on immune function and inflammatory responses. Inflammatory responses are major contributors to central nervous system (CNS) injury in a variety of diseases. In this report, we present evidence that activation of CB 2 receptors, by selective CB 2 agonists, reduces inflammatory responses that contribute to CNS injury. The studies demonstrate neuroprotective effects in experimental autoimmune encephalomyelitis, a model of multiple sclerosis, and in a murine model of cerebral ischemia/reperfusion injury. In both cases, CB 2 receptor activation results in reduced white cell rolling and adhesion to cerebral microvessels, a reduction in immune cell invasion, and improved neurologic function after insult. In addition, administration of the CB 1 antagonist SR141716A reduces infarct size following ischemia/reperfusion injury. Administration of both a selective CB 2 agonist and a CB 1 antagonist has the unique property of increasing blood flow to the brain during the occlusion period, suggesting an effect on collateral blood flow. In summary, selective CB 2 receptor agonists and CB 1 receptor antagonists have significant potential for neuroprotection in animal models of two devastating diseases that currently lack effective treatment options.

Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that \"abnormal cannabidiol\" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 μ g/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 μ M) or by cannabidiol (10 μ M). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K+-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.

The chemotactic response of murine peritoneal macrophages to RANTES/CCL5 was inhibited significantly following pretreatment with delta-9-tetrahydrocannabinol (THC), the major psychoactive component in marijuana. Significant inhibition of this chemokine directed migratory response was obtained also when the full cannabinoid agonist CP55940 was used. The CB 2 receptor-selective ligand O-2137 exerted a robust inhibition of chemotaxis while the CB 1 receptor-selective ligand ACEA had a minimal effect. The THC-mediated inhibition was reversed by the CB 2 receptor-specific antagonist SR144528 but not by the CB 1 receptor-specific antagonist SR141716A. In addition, THC treatment had a minimal effect on the chemotactic response of peritoneal macrophages from CB 2 knockout mice. Collectively, these results suggest that cannabinoids act through the CB 2 receptor to transdeactivate migratory responsiveness to RANTES/CCL5. Furthermore, the results suggest that the CB 2 receptor may be a constituent element of a network of G protein-coupled receptor signal transductional systems, inclusive of chemokine receptors, that act coordinately to modulate macrophage migration.

Although nicotine dependence and tolerance develop in rats, few studies have examined these processes in the mouse. Establishing such mouse models would eventually allow for an examination of the role of specific nicotinic receptor subtypes in mediating these processes (i.e. through the use of receptor knockouts). The goals of the present study were to establish mouse models of nicotine dependence and tolerance. Mice were chronically exposed to nicotine (0-200 mug/ml) in their drinking solution and assayed for plasma nicotine and cotinine levels, withdrawal signs following nicotine cessation (spontaneous withdrawal) or nicotinic antagonist administration (precipitated withdrawal), or nicotine tolerance. Dependence assays included somatic sign observations (paw tremors, backing and head shakes), tail-flick, plantar stimulation, elevated plus-maze and spontaneous activity. Tolerance was assayed using tail-flick, hot-plate and body temperature tests. Plasma nicotine and cotinine levels were elevated during oral nicotine exposure (15.85 ng/ml and 538.00 ng/ml, respectively) and quickly declined following nicotine cessation (<1 ng/ml and <2 ng/ml, respectively), providing evidence that the oral route was pharmacologically relevant. Nicotine withdrawal increased numbers of somatic signs (spontaneous and mecamylamine-precipitated withdrawal) and/or hyperalgesia (spontaneous withdrawal only). Chronic nicotine exposure also produced tolerance, as indicated by reduced responsivity to acute nicotine in assays of analgesia and hypothermia. These results indicate that chronic oral nicotine produces dependence and tolerance in the mouse. Further, nicotine dependence may be mediated by multiple nicotinic receptor subtypes, since specific nicotinic receptor antagonists failed to precipitate withdrawal.

The pharmacology of monoacylglycerol lipase (MAGL) is not well understood. In consequence, the abilities of a series of analogues of 2‐arachidonoylglycerol (2‐AG) to inhibit cytosolic 2‐oleoylglycerol and membrane‐bound anandamide hydolysis by MAGL and fatty acid amide hydrolase (FAAH), respectively, have been investigated. 2‐AG and its 1‐regioisomer (1‐AG) interacted with MAGL with similar affinities (IC50 values 13 and 17 μM, respectively). Shorter homologues of 2‐AG (2‐linoleoylglycerol and 2‐oleoylglycerol) had affinities for MAGL similar to 2‐AG. This pattern was also seen when the arachidonoyl side chain of arachidonoyl trifluoromethylketone was replaced by an oleoyl side chain. Arachidonoyl serinol (IC50 value 73 μM) was a weaker inhibitor of MAGL than 2‐AG. The IC50 values of noladin ether towards MAGL and FAAH were 36 and 3 μM, respectively. Arachidonoyl glycine interacted with FAAH (IC50 value 4.9 μM) but only weakly interacted with MAGL (IC50 value >100 μM). α‐Methyl‐1‐AG had similar potencies towards MAGL and FAAH (IC50 values of 11 and 33 μM, respectively). O‐2203 (1‐(20‐cyano‐16,16‐dimethyl‐eicosa‐5,8,11,14‐tetraenoyl) glycerol) and O‐2204 (2‐(20‐hydroxy‐16,16‐dimethyl‐eicosa‐5,8,11,14‐tetraenoyl) glycerol) were slightly less potent, but again affected both enzymes equally. α‐Methyl‐1‐AG, O‐2203 and O‐2204 interacted only weakly with cannabinoid CB1 receptors expressed in CHO cells (Ki values 1.8, 3.7 and 3.2 μM, respectively, compared with 0.24 μM for 1‐AG) and showed no evidence of central cannabinoid receptor activation in vivo at doses up to 30 mg kg−1 i.v. It is concluded that compounds like α‐Methyl‐1‐AG, O‐2203 and O‐2204 may be useful as leads for the discovery of selective MAGL inhibitors that lack direct effects upon cannabinoid receptors. British Journal of Pharmacology (2004) 143, 774–784. doi:10.1038/sj.bjp.0705948