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 endocannabinoid system has been proposed to modulate a variety of physiological processes, including those that underlie cognition. The present study tested whether this system is tonically active in learning and memory by comparing CB 1 receptor knockout mice (CB 1 Ϫ/Ϫ ) to wild-type mice (CB 1 ϩ/ϩ ) in several Morris water maze tasks. Also, the effects of three cannabinoid agonists, (WIN 55,, and methanandamide, were evaluated in a working memory procedure. Both genotypes exhibited identical acquisition rates in a fixed platform procedure; however, the CB 1 Ϫ/Ϫ mice demonstrated significant deficits in a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. This phenotype difference was most likely due to an increased perseverance of the CB 1 Ϫ/Ϫ mice in that they continued to return to the original platform location, despite being repeatedly shown the new platform location. In addition, ⌬ 9 -THC (ED 50 ϭ 1.3 mg/ kg), WIN 55,212-2 (ED 50 ϭ 0.35 mg/kg), and methanandamide (ED 50 ϭ 3.2 mg/kg) disrupted the performance of CB 1 ϩ/ϩ mice in the working memory task at doses that did not elicit motivational or sensorimotor impairment as assessed in a cued version of the task. Furthermore, doses of each drug that were maximally disruptive in CB 1 ϩ/ϩ mice were ineffective in either N-(pip-ϩ/ϩ or CB 1 Ϫ/Ϫ mice. These results provide strong evidence that cannabinoids disrupt working memory through a CB 1 receptor mechanism of action, and suggest that the endocannabinoid system may have a role in facilitating extinction and/or forgetting processes.

Whereas RBC saturated, mono- and polyunsaturated FA levels are generally stable across the lifespan, there is a shift in the composition of the latter, with an increase in the Omega-3 Index and a decrease in linoleic acid. Higher DHA and lower EPA levels in younger women is consistent with enhanced conversion of EPA to DHA during the early reproductive years. The availability of RBC FA norms will facilitate research into the relationships between altered FA status and human disease, and will help physicians evaluate the n-3 FA status of their patients.

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.

These findings indicate that disruption of CB(1) receptor signaling impairs extinction processes in the Morris water maze, thus lending further support to the hypothesis that the endocannabinoid system plays an integral role in the suppression of non-reinforced learned behaviors.

OBJECTIVELatent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.RESEARCH DESIGN AND METHODSWe performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396).RESULTSThe leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1–associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.CONCLUSIONSOur results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Although it is widely accepted that ⌬ 9 -tetrahydrocannabinol (⌬ 9 -THC) is the primary psychoactive constituent of marijuana, questions persist as to whether other components contribute to marijuana's pharmacological activity. The present experiments assessed the cannabinoid activity of marijuana smoke exposure in mice and tested the hypothesis that ⌬ 9 -THC mediates these effects through a CB 1 receptor mechanism of action. First, the effects of ⌬ 9 -THC on analgesia, hypothermia, and catalepsy were compared with those of a marijuana extract with equated ⌬ 9 -THC content after either i.v. administration or inhalation exposure. Second, mice were exposed to smoke of an ethanol-extracted placebo plant material or low-grade marijuana (with minimal ⌬ 9 -THC but similar levels of other cannabinoids) that were impregnated with varying quantities of ⌬ 9 -THC. To assess doses, ⌬ 9 -THC levels in the blood and brains of drug-exposed mice were determined following both i.v. and inhalation routes of administration. Both marijuana and ⌬ 9-THC produced comparable levels of antinociception, hypothermia, and catalepsy regardless of the route of administration, and these effects were blocked by pretreatment with the CB 1 an-. Importantly, the blood and brain levels of ⌬ 9 -THC were similar in mice exhibiting similar pharmacological effects, regardless of the presence of non-⌬ 9 -THC marijuana constituents. The present experiments provide evidence that the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from ⌬ 9 -THC content acting at CB 1 receptors and that the non-⌬ 9 -THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.Interest in investigating both the risks and potential benefits of marijuana as a therapeutic agent, as well as understanding the negative consequences of long-term recreational use, has been reinvigorated over the past several years. ⌬ 9 -THC, the primary psychoactive ingredient of marijuana, has been available for several years in an oral form (Marinol) for treatment of nausea and vomiting associated with cancer chemotherapy and for use in loss of appetite and weight loss related to AIDS. Additionally, cannabinoids may be useful in treating neurological/movement disorders, chronic pain, glaucoma, in neuroprotection, as well as other disease states (for recent review, see Baker et al., 2003;Croxford, 2003;Drysdale and Platt, 2003). There are also many unanswered questions about the negative consequences of long-term marijuana consumption or use of cannabinoid therapeutics, particularly when it comes to the issues of dependence liability and the possibility of long-term cognitive deficits. Although there is no controversy regarding whether ⌬ 9 -THC is the major psychoactive constituent in marijuana, questions have persisted regarding the degree to which other constituents of marijuana may contribute to its pharmacological effects, both beneficial and harmful...

Background and purpose: To follow up in vitro evidence that D 9 -tetrahydrocannabivarin extracted from cannabis (eD 9 -THCV) is a CB 1 receptor antagonist by establishing whether synthetic D