ABSTRACT
Title
Regulation of mGlu 5 receptor activity by the endocannabinoid system
Authors
V. De Chiara1,2, S. Rossi1,2, A. Musella1, V. Studer1, C. Motta1,2, G. Bernardi1,2, A. Usiello3,4 , M. Maccarrone2,5, D. Centonze1,2
1Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
2Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy
3Behavioural Neuroscience Laboratory, CEINGE - Biotecnologie Avanzate, Via Comunale Margherita 482, 80145 Naples, Italy
4Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
5Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, 64100 Teramo, Italy
1Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
2Fondazione Santa Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy
3Behavioural Neuroscience Laboratory, CEINGE - Biotecnologie Avanzate, Via Comunale Margherita 482, 80145 Naples, Italy
4Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy
5Dipartimento di Scienze Biomediche, Università degli Studi di Teramo, 64100 Teramo, Italy
Abstract
Synaptic transmission in the striatum is regulated by metabotropic glutamate (mGlu) receptors through pre- and postsynaptic mechanisms. We investigated the involvement of mGlu 1 and 5 receptors in the control of both excitatory and inhibitory transmission in the striatum. The mGlu 1 and 5 receptor agonist 3,5-DHPG failed to affect glutamate transmission, while it caused a biphasic
effect on GABA transmission, characterized by early increase and late decrease in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from striatal principal neurons. Both mGlu 1 and 5 receptors were involved in the early response to 3,5-DHPG, through membrane depolarization of striatal GABAergic interneurons and action potential generation. The 3,5-DHPG-mediated late depression of inhibitory inputs to striatal principal neurons was conversely secondary to mGlu 5 receptor activation and subsequent endocannabinoid (eCB) release. Of the eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have received the most study.
A selective involvement of 2-AG metabolism have been found to be induced by DHPG in the striatum. Furthermore, Elevation of AEA concentrations by pharmacological or genetic inhibition of AEA degradation reduced the levels, metabolism and physiological effects of 2-AG. The stimulation of transient receptor potential vanilloid 1 (TRPV1) channels mimicked the effects of endogenous AEA on 2-AG metabolism through a previously unknown glutathione-dependent pathway. Consistently, the interaction between AEA and 2-AG was lost after pharmacological and genetic inactivation of TRPV1 channels.
In conclusion, we have identified a relationship between eCB system and mGlu receptors of potential relevance for physiological neuronal activity.
effect on GABA transmission, characterized by early increase and late decrease in the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from striatal principal neurons. Both mGlu 1 and 5 receptors were involved in the early response to 3,5-DHPG, through membrane depolarization of striatal GABAergic interneurons and action potential generation. The 3,5-DHPG-mediated late depression of inhibitory inputs to striatal principal neurons was conversely secondary to mGlu 5 receptor activation and subsequent endocannabinoid (eCB) release. Of the eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have received the most study.
A selective involvement of 2-AG metabolism have been found to be induced by DHPG in the striatum. Furthermore, Elevation of AEA concentrations by pharmacological or genetic inhibition of AEA degradation reduced the levels, metabolism and physiological effects of 2-AG. The stimulation of transient receptor potential vanilloid 1 (TRPV1) channels mimicked the effects of endogenous AEA on 2-AG metabolism through a previously unknown glutathione-dependent pathway. Consistently, the interaction between AEA and 2-AG was lost after pharmacological and genetic inactivation of TRPV1 channels.
In conclusion, we have identified a relationship between eCB system and mGlu receptors of potential relevance for physiological neuronal activity.