Endocannabinoids glutamate release

Yin HH, Lovinger DM (2006) Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling. Proc Natl Acad Sci USA 103(21) 8251-6... 

Because activation of CBj receptors inhibits vesicular glutamate release, there is great interest in finding CB, receptor ligands that exhibit neuroprotective potential, not only by exogenous administration, but also by stimulation of intrinsic pathways leading to elevated synaptic levels of endocannabinoids. The in vivo experiments published so far (Table 14.1) have not given a clear answer. 

The elucidation of synaptic mechanisms involving endocannabinoids has revealed some surprises. Indeed, endocannabinoids are released in the extracellular space from postsynaptic neurons in response to a rise in intracellular Ca. Then, endocannabinoid neurotransmitters travel backward across synapses, and eventually stimulate CBl receptor on the presynaptic neuron. The main effect of endocannabinoids on presynaptic neurons is to decrease the release of either the inhibitory y-aminobutyric acid (GABA) or the excitatory glutamate neurotransmitters, resulting in a control of a broad range of physiological functions including food intake, fear,and anxiety. ... 

Physiological studies have identified both post- and presynaptic roles for ionotropic kainate receptors. Kainate receptors contribute to excitatory post-synaptic currents in many regions of the CNS including hippocampus, cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are codistributed with AMPA and NMDA receptors, but there are also synapses where transmission is mediated exclusively by postsynaptic kainate receptors for example, in the retina at connections made by cones onto off bipolar cells. Extrasynaptically located postsynaptic kainate receptors are most likely activated by spill-over glutamate (Eder et al. 2003). Modulation of transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerve terminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation of kainate receptors. The hyperexcitability evoked by locally applied kainate, which is quite effectively reduced by endocannabinoids, is probably mediated preferentially via an activation of postsynaptic kainate receptors (Marsicano et al. 2003). 

Galante M, Diana MA (2004) Group 1 metabotropic glutamate receptors inhibit GABA release at interneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci 24 4865-4874... 

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