During neuroinflammation, activated microglial cells migrate toward dying neurons, where they exacerbate local cell damage. The signaling molecules that trigger microglial cell migration are poorly understood. In this paper, we show that pathological overstimulation of neurons by glutamate plus carbachol dramatically increases the production of the endocannabinoid 2-arachidonylglycerol (2-AG) but only slightly increases the production of anandamide and does not affect the production of two putative endocannabinoids, homo-γ-linolenylethanolamide and docosatetraenylethanolamide. We further show that pathological stimulation of microglial cells with ATP also increases the production of 2-AG without affecting the amount of other endocannabinoids. Using a Boyden chamber assay, we provide evidence that 2-AG triggers microglial cell migration. This effect of 2-AG occurs through CB2 and abnormal-cannabidiol-sensitive receptors, with subsequent activation of the extracellular signal-regulated kinase 1/2 signal tran...

Consumers of marijuana feel a strong compulsive desire to consume food. The role of CB2 receptors in food and alcohol consumption and the behavioral effects of CB2 receptor ligands are not well understood. We tested the effects of CB2 agonist PEA and CB...

Hormetic dose-response relationships suggest that opposing physiological responses can be driven by a single substance, however, detection and quantification of hormetic relationships is often difficult. One potential therapeutic application of hormesis...

Two endogenous ligands for cannabinoid CB1 receptors, anandamide ( N -arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG), have been identified and characterized. 2-AG is the most prevalent endogenous cannabinoid ligand in the brain, and electrophysiological studies suggest 2-AG, rather than anandamide, is the true natural ligand for cannabinoid receptors and the key endocannabinoid involved in retrograde signaling in the brain. Here, we evaluated intravenously administered 2-AG for reinforcing effects in nonhuman primates. Squirrel monkeys that previously self-administered anandamide or nicotine under a fixed-ratio schedule with a 60 s timeout after each injection had their self-administration behavior extinguished by vehicle substitution and were then given the opportunity to self-administer 2-AG. Intravenous 2-AG was a very effective reinforcer of drug-taking behavior, maintaining higher numbers of self-administered injections per session and higher rates of responding than vehicle across a wide...

To maximize their chances of survival, animals need to rapidly and efficiently respond to aversive situations. These responses can be classified as active or passive and depend on the specific nature of threats, but also on individual fear coping styles. In this study, we show that the control of excitatory and inhibitory brain neurons by type-1 cannabinoid (CB1) receptors is a key determinant of fear coping strategies in mice. In classical fear conditioning, a switch between initially predominant passive fear responses (freezing) and active behaviors (escape attempts and risk assessment) develops over time. Constitutive genetic deletion of CB1 receptors in CB1 −/− mice disrupted this pattern by favoring passive responses. This phenotype can be ascribed to endocannabinoid control of excitatory neurons, because it was reproduced in conditional mutant mice lacking CB1 receptors from cortical glutamatergic neurons. CB1 receptor deletion from GABAergic brain neurons led to the opposite phenotype, characterized...

Cannabinoids can exert both hedonic and aversive effects. While some human users report euphoria following cannabis use, others report anxiety, and animal studies suggest cannabis is minimally reinforcing or dysphoric. However, the neural mechanisms und...

Several evidence suggests that cannabinoids act upon the brain reward circuitry, namely the mesolimbic dopamine (DA) pathway, influencing drug-seeking and drug-taking behaviors in a manner strikingly similar to that of other abused drugs. Passive administrations of Δ9-tetrahydrocannabinol (THC) and synthetic CB1 receptor agonist WIN 55,212-2 are reported to enahance extracellular DA overflow in the nucleus accumbens and other reward-related forebrain areas, as measured by in vivo brain microdialysis. Few years ago we characterized a reliable model of cannabinoid intravenous self-administration (IVSA) in rats, in which animals were trained to self-administer the cannabinoid CB1 receptor agonist WIN 55,212-2 (12.5 μg/kg inf) under a fixed ratio (FR1) schedule of reinforcement (Fattore et al. 2001). In the present study we used this model to investigate the effect of active cannabinoid administration on the DA extracellular accumbal concentrations during cannabinoid IVSA. DA levels were measured in perfusate ...

Several studies have demonstrated that cannabinoids may induce specific biological effects by interacting with an orphan G protein-coupled receptor. Recently, it has been suggested that GPR55 might constitute such a receptor. Indeed, we found that THC (5 µM) increased intracellular calcium in HEK293 cells expressing GPR55. GPR55 mRNA was present in spleen, microglial cells and astrocytes, as well as BV2 and N9 cells (two mouse microglia cell lines), suggesting its involvement in regulating neuroinflammation. On the other hand, GPR55 mRNA was not detected in OLN cells, an oligodendrocyte progenitor cell line, DBT, D1A and D3O, three astrocytic cell lines, suggesting that undifferentiated glial cells do not express this receptor subtype. Finally, we found that THC (5 µM) only modestly increased IP3 production in BV2 cells, suggesting that mechanisms in addition to phospholipase C may be involved in GPR55-mediated increases in intracellular calcium. Our data identify GPR55 as a bona fide cannabinoid receptor ...

Experimental animals can be differentiated on the basis of their horizontal or vertical activity as high responders (HR) and low responders (LR) upon exposure to a novel environment. These individual differences have been associated with discrete behavi...

We demonstrated previously that a class of number words- quantifiers- rely on a cortical network of number processing regions. Our model of quantifier comprehension includes a numerosity component supported by number processing portions of the brain and...