Endocannabinoids release

Kreitzer AC, Malenka RC (2005) Dopamine modulation of state-dependent endocannabinoid release and long-term depression in the striatum. J Neurosci 25(45) 10537—45 Kreitzer AC, Regehr WG (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto purkinje cells. Neuron 29 717-27 Kreitzer AC, Carter AG, Regehr WG (2002) Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 34 787-96... 

Robbe D, Kopf M, Remaury A, Bockaert J, Manzoni OJ (2002) Endogenous cannabinoids mediate long-term synaptic depression in the nucleus accumbens. Proc Natl Acad Sci USA 99 8384-8 Ronesi J, Gerdeman GL, Lovinger DM (2004) Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport. J Neurosci 24(7) 1673-9... 

Ronesi J, Gerdeman GL, Lovinger DM. 2004. Disruption of endocannabinoid release and striatal long-term depression by postsynaptic blockade of endocannabinoid membrane transport. J Neurosci 24 1673-1679. 

Clearly there is now incontrovertible evidence for the existence of a mammalian endocannabinoid system that consists of at least two types of cannabinoid receptor, CBi and CB2, and of endogenous agonists (endocannabinoids) for these receptors. Agonists that activate both these receptor types with similar potency or that show marked selectivity for one or other receptor type have been discovered, as have potent CBi- and CB2-selective cannabinoid receptor antagonists. Quantitative and sensitive in vitro and in vivo bioassays for these ligands are also available, and these have played a crucial role in determining the CBi and CB2 receptor affinities and intrinsic activities of a number of cannabinoids. There is good evidence that the endocannabinoid system can become Ionically active and that this is due in some instances to endocannabinoid release and in other instances to the ability of cannabinoid receptors to exist in a constitutively activity state, not only when over-... 

Misner and Sullivan 1999), other brain areas in which neurotransmission appears to be modulated by endocannabinoid release include basal forebrain (Harkany et al. 2003 Steffens et al. 2003), striatum (Gerdeman et al. 2002), and cerebellum (Breivogel et al. 2004 Kreitzer et al. 2002 Maejima et al. 2001b). 

Gerdeman GL, Ronesi J, Lovinger DM (2002) Postsynaptic endocannabinoid release is critical to long-term depression in the striatum. Nat Neurosci 5 446-451... 

Endocannabinoid activation of CBi receptors is likely to be involved in the induction, but not in the maintenance of long-term synaptic plasticity because CBl antagonists impair long-term depression only when applied either prior to, or within 5 to 10 min of LTD induction (Chevaleyre and Castillo 2003 Ronesi et al. 2004) (Fig. 2A). The difference between short- and long-term synaptic effects of endocannabinoids may be due to the duration (or type) of endocannabinoid release, and sustained (for several minutes) activation of presynaptic CB i receptors (note DSI has a shorter time course). The mechanisms by which CBi activation induces long-term changes remain to be resolved, but the induction is unlikely to be solely due to CBi activation (Ronesi et al. 2004). 

The endocannabinoid system contributes to the control of hypothalamic regulatory mechanisms. We do not know (yet) in which part of the hypothalamus the endocannabinoids are synthesized, but it is possible that cannabinoid receptors, present in the hypothalamus, are activated by AEA or other endocannabinoids released/synthesized quite far away. There is also the possibility that endocannabinoids act on presynaptic membranes to modulate die release of various neurotransmitters. Also of interest is the hypothesis that endocannabinoids may participate in hormone-cytokine networks that regulate reproduction, as this opens new perspectives for the development of novel medicines for human infertility. Acknowledgements. 

The interest in the vasodilator action of endocannahinoids was further stimulated by a report in 1996 that the mesenteric vasodilation attributable to an endothelium-derived hyperpolarizing factor (EDHF) is sensitive to inhibition by SR141716 (Randall et al. 1996). The corollary of this finding was that EDHF might be an endocannabinoid released from the vascular endothelium and acting at... 

FIGURE 3.1 Cross talk between endocannabinoid and endovanilloid system. A hypothetical illustration of the cross talk between the VRl ion channel receptor and G-protein-coupled CB,R at the cellular and molecular level. Endocannabinoids released as byproducts of phospholipid metabolism are able to activate both receptors. 

Details of endocannabinoid-mediated retrograde suppression of synaphc transmission (DSI and DSE) were further inveshgated by a number of investigators. Kreitzer and Regehr (2001b) examined DSI in the rat cerebellum and reported that it is mediated by endocannabinoids as in the case of DSI in the hippocampus and of DSE in the cerebellum. Endocannabinoid-mediated DSI in the cerebellum was also reported by Diana et al. (2002). Kreitzer et al. (2002) recently demonstrated that endocannabinoids released from cerebellar Purkinje cell dendrites suppress the spontaneous bring of nearby intemeurons. 

Ohno-Shosaku, Tsubokawa, et al. (2002) demonstrated that not only DSI but also DSE can be induced in the rat and mouse hippocampus. DSE in the hippocampus was mediated by the presynaphc CBj receptor and endocannabinoids released from depolarized postsynaphc neurons. They compared DSE and DSI in slices from the same animals and found that DSE was much less... 

In summary, it appears as though endocannabinoids are active at both excitatory and inhibitory synapses through either depolarization of the postsynaptic cell membrane or through activation of G-protein-coupled receptors on the postsynaptic cell. While increased postsynaptic Ca + levels appear necessary to observe endocannabinoid release in the former instance, it also appears that another form of Ca + independent endocannabinoid release is present in the CNS. The G-protein-coupled release of endocannabinoid will no doubt remain of significant interest to future research because of the potentially pivotal role that a variety of neurotransmitter systems may play in the regulation of endocannabinoid signaling in the CNS. 

Di, S., Malcher-Lopes, R., Halmos, K. and Tasker, J. (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus a fast feedback mechanism, J Neurosci, 23 4850-7. 

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