Recent studies have shown that the endocannabinoid system is involved in the common neurobiological mechanism underlying drug addiction. This system participates in the primary rewarding effects of cannabinoids, nicotine, alcohol and opioids, through the release of endocannabinoids in the ventral tegmental area. Endocannabinoids are also involved in the motivation to seek drugs by a dopamine-independent mechanism, demonstrated for psychostimulants and opioids. The endocannabinoid system also participates in the common mechanisms underlying relapse to drugseeking behaviour by mediating the motivational effects of drug-related environmental stimuli and drug reexposure. In agreement, clinical trials have suggested that the CB1 cannabinoid antagonist rimonabant can cause smoking cessation. Thus,...

Although adverse effects of cannabinoids on pregnancy have been indicated for many years, the mechanisms by which they exert their actions were not clearly understood. Only recently, molecular and biochemical approaches have led to the identification of two types of cannabinoid receptors, brain-type receptors (CB1-R) and spleen-type receptors (CB2-R), which mediate cannabinoid effects. These findings were followed by the discovery of endocannabinoids, anandamide and 2-arachidonoylglycerol (2-AG). The natural cannabinoids and endocannabinoids exert their effects via cannabinoid receptors and share similar pharmacological and physiological properties. Recent demonstration of expression of functional CB1-R in the preimplantation embryo and synthesis of anandamide in the pregnant uterus of...

Although endocannabinoid signaling is important for certain aspects of gastrointestinal homeostasis, the role of the cannabinoid receptors (CB) in colorectal cancer has not been defined. Here we show that CB1 expression was silenced in human colorectal cancer due to methylation of the CB1 promoter. Our genetic and pharmacologic studies reveal that loss or inhibition of CB1 accelerated intestinal adenoma growth in ApcMin/+ mice whereas activation of CB1 attenuated intestinal tumor growth by inducing cell death via down-regulation of the antiapoptotic factor survivin. This down-regulation of survivin by CB1 is mediated by a cyclic AMP–dependent protein kinase A signaling pathway. These results indicate that the...

Mitochondria: a possible nexus for the regulation of energy homeostasis by the endocannabinoid system?. Am J Physiol Endocrinol Metab 307: E1–E13, 2014. First published May 6, 2014; doi:10.1152/ajpendo.00100.2014.—The endocannabinoid system (ECS) regulates numerous cellular and physiological processes through the activation of receptors targeted by endogenously produced ligands called endocannabinoids. Importantly, this signaling system is known to play an important role in modulating energy balance and glucose homeostasis. For example, current evidence indicates that the ECS becomes overactive during obesity whereby its central and peripheral stimulation drives metabolic processes that mimic the metabolic syndrome. Herein, we examine the role of the ECS in modulating the...

The endocannabinoid system, including its receptors (CB1 and CB2), endogenous ligands (‘endocannabinoids’), synthesising and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. In addition, the endocannabinoids, notably 2-arachidonyl glycerol, are also present in maternal milk. During three distinct developmental stages (i.e. embryonic implantation, prenatal brain development and postnatal suckling), the endocannabinoid system appears to play an essential role for development and survival. Thus, during early pregnancy, successful embryonic passage through the oviduct and implantation into the uterus both require critical enzymatic control of optimal anandamide levels at the appropriate...

The endocannabinoid signaling system is composed of the cannabinoid receptors; their endogenous ligands, the endocannabinoids; the enzymes that produce and inactivate the endocannabinoids; and the endocannabinoid transporters. The endocannabinoids are a new family of lipidic signal mediators, which includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. Endocannabinoids signal through the same cell surface receptors that are targeted by 9 -tetrahydrocannabinol (9 -THC), the active principles of cannabis sativa preparations like hashish and marijuana. The biosynthetic pathways for the synthesis and release of endocannabinoids are still rather uncertain. Unlike neurotransmitter molecules that are typically held in vesicles before synaptic release, endocannabinoids are synthesized...

Abstract The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB(1) receptors by the major pCB, Δ(9)-tetrahydrocannabinol (Δ(9)-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ(9)-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent....

Aims/hypothesis: We examined the presence of functional cannabinoid receptors 1 and 2 (CB1, CB2) in isolated human islets, phenotyped the cells producing cannabinoid receptors and analysed the actions of selective cannabinoid receptor agonists on insulin, glucagon and somatostatin secretion in vitro. We also described the localisation on islet cells of: (1) the endocannabinoid-producing enzymes Nacyl-phosphatidyl ethanolamine-hydrolysing phospholipase D and diacylglycerol lipase; and (2) the endocannabinoiddegrading enzymes fatty acid amidohydrolase and monoacyl glycerol lipase. Methods: Real-time PCR, western blotting and immunocytochemistry were used to analyse the presence of endocannabinoid-related proteins and genes. Static secretion experiments were used to examine the effects of activating CB1 or...

To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural substrate of these actions. We used a recently developed antibody against the CB1 cannabinoid receptor to study this question in hippocampal networks. Interneurons with features typical of basket cells showed a selective, intense staining for CB1 in all hippocampal subfields and layers. Most of them (85.6%) contained cholecystokinin (CCK), which corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron microscopy revealed that CB1-immunoreactive...

Parkinson’s disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure. Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD. The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems. As the cannabinoid...