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Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake.

ABSTRACT: Activation of cannabinoid CB1 receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. Here we investigated CB1 receptor regulation of glutamate release and uptake and synaptic transmission in the rat striatum. We show that CB1 receptor activation reduces both the release and uptake of [3H]glutamate in striatal slices. We also demonstrate that both activation of CB1 receptors and inhibition of glutamate uptake reduce corticostriatal synaptic transmission in a mutually occlusive manner and that both forms of depression are dependent on metabotropic glutamate receptor (mGluR) activation. We propose that CB1 receptor activation in the striatum decreases glutamate transporter activity and that the resulting increase in synaptic cleft glutamate concentration causes the activation of presynaptic mGluRs, which then decrease glutamate release.

SUBMITTER: Brown TM

PROVIDER: S-EPMC6741038 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake.

Brown Timothy M TM Brotchie Jonathan M JM Fitzjohn Stephen M SM

The Journal of neuroscience : the official journal of the Society for Neuroscience 20031201 35

Activation of cannabinoid CB1 receptors reduces glutamatergic synaptic transmission in the rodent striatum and is involved in the normal control of motor function by the basal ganglia. Here we investigated CB1 receptor regulation of glutamate release and uptake and synaptic transmission in the rat striatum. We show that CB1 receptor activation reduces both the release and uptake of [3H]glutamate in striatal slices. We also demonstrate that both activation of CB1 receptors and inhibition of gluta ...[more]

PMID: 14657164

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Project description:BackgroundAlzheimer's disease (AD) is the most common form of age-related neurodegenerative diseases. Cerebral deposition of Aβ peptides, especially Aβ42, is considered the major neuropathological hallmark of AD and the putative cause of AD-related neurotoxicity. Aβ peptides are produced by sequential proteolytic processing of APP, with β-secretase (BACE) being the initiating enzyme. Therefore, BACE has been considered an attractive therapeutic target in AD research and several BACE inhibitors have been tested in clinical trials, but so far, all have had negative outcomes or even led to worsening of cognitive function. AD can be triggered by Aβ years before the first symptoms appear and one reason for the failures could be that the clinical trials were initiated too late in the disease process. Another possible explanation could be that BACE inhibition alters physiological APP processing in a manner that impairs synaptic function, causing cognitive deterioration.MethodsThe aim of this study was to investigate if partial BACE inhibition, mimicking the putative protective effect of the Icelandic mutation in the APP gene, could reduce Aβ generation without affecting synaptic transmission. To investigate this, we used an optical electrophysiology platform, in which effects of compounds on synaptic transmission in cultured neurons can be monitored. We employed this method on primary cortical rat neuronal cultures treated with three different BACE inhibitors (BACE inhibitor IV, LY2886721, and lanabecestat) and monitored Aβ secretion into the cell media.ResultsWe found that all three BACE inhibitors tested decreased synaptic transmission at concentrations leading to significantly reduced Aβ secretion. However, low-dose BACE inhibition, resulting in less than a 50% decrease in Aβ secretion, did not affect synaptic transmission for any of the inhibitors tested.ConclusionOur results indicate that Aβ production can be reduced by up to 50%, a level of reduction of relevance to the protective effect of the Icelandic mutation, without causing synaptic dysfunction. We therefore suggest that future clinical trials aimed at prevention of Aβ build-up in the brain should aim for a moderate CNS exposure of BACE inhibitors to avoid side effects on synaptic function.

Project description:Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission.

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Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake.

Publications

Cannabinoids decrease corticostriatal synaptic transmission via an effect on glutamate uptake.

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