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Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta.
Neuropharmacology. 2014 Apr; 79:467-75.N

Abstract

Endocannabinoids (eCBs) modulate synaptic transmission in the brain, but little is known of their regulatory role in nigral dopaminergic neurons, and whether transmission to these neurons is tonically inhibited by eCBs as seen in some other brain regions. Using whole-cell recording in midbrain slices, we observed potentiation of evoked IPSCs (eIPSCs) in these neurons after blocking CB1 receptors with rimonabant or LY-320,135, indicating the presence of an eCB tone reducing inhibitory synaptic transmission. Increased postsynaptic calcium buffering and block of mGluR1 or postsynaptic G-protein coupled receptors prevented this potentiation. Increasing spillover of endogenous glutamate by inhibiting uptake attenuated eIPSC amplitude, while enhancing the potentiation by rimonabant. Group I mGluR activation transiently inhibited eIPSCs, which could be prevented by GDP-β-S, increased calcium buffering or rimonabant. We explored the possibility that the dopamine-derived eCB N-arachidonoyl dopamine (NADA) is involved. The eCB tone was abolished by preventing dopamine synthesis, and enhanced by l-DOPA. It was not detected in adjacent non-dopaminergic neurons. Preventing 2-AG synthesis did not affect the tone, while inhibition of NADA production abolished it. Quantification of ventral midbrain NADA suggested a basal level that increased following prolonged depolarization or mGluR activation. Since block of the tone was not always accompanied by attenuation of depolarization-induced suppression of inhibition (DSI) and vice versa, our results indicate DSI and the eCB tone are mediated by distinct eCBs. This study provides evidence that dopamine modulates the activity of SNc neurons not only by conventional dopamine receptors, but also by CB1 receptors, potentially via NADA.

Authors+Show Affiliations

Department of Physiology and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand; Laboratorio di Neurologia Sperimentale, Fondazione Santa Lucia IRCCS, Rome, Italy.Laboratorio di Neurologia Sperimentale, Fondazione Santa Lucia IRCCS, Rome, Italy.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.Department of Physiology and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.Laboratorio di Neurologia Sperimentale, Fondazione Santa Lucia IRCCS, Rome, Italy; Dipartimento di Medicina dei Sistemi, Universitá di Tor Vergata, Rome, Italy. Electronic address: mercurin@med.uniroma2.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24334069

Citation

Freestone, Peter S., et al. "Glutamate Spillover Drives Endocannabinoid Production and Inhibits GABAergic Transmission in the Substantia Nigra Pars Compacta." Neuropharmacology, vol. 79, 2014, pp. 467-75.
Freestone PS, Guatteo E, Piscitelli F, et al. Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta. Neuropharmacology. 2014;79:467-75.
Freestone, P. S., Guatteo, E., Piscitelli, F., di Marzo, V., Lipski, J., & Mercuri, N. B. (2014). Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta. Neuropharmacology, 79, 467-75. https://doi.org/10.1016/j.neuropharm.2013.12.007
Freestone PS, et al. Glutamate Spillover Drives Endocannabinoid Production and Inhibits GABAergic Transmission in the Substantia Nigra Pars Compacta. Neuropharmacology. 2014;79:467-75. PubMed PMID: 24334069.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta. AU - Freestone,Peter S, AU - Guatteo,Ezia, AU - Piscitelli,Fabiana, AU - di Marzo,Vincenzo, AU - Lipski,Janusz, AU - Mercuri,Nicola B, Y1 - 2013/12/12/ PY - 2013/08/20/received PY - 2013/11/19/revised PY - 2013/12/03/accepted PY - 2013/12/17/entrez PY - 2013/12/18/pubmed PY - 2014/12/15/medline KW - Cannabinoids KW - Dopaminergic KW - Electrophysiology KW - Parkinson's disease KW - Synaptic transmission SP - 467 EP - 75 JF - Neuropharmacology JO - Neuropharmacology VL - 79 N2 - Endocannabinoids (eCBs) modulate synaptic transmission in the brain, but little is known of their regulatory role in nigral dopaminergic neurons, and whether transmission to these neurons is tonically inhibited by eCBs as seen in some other brain regions. Using whole-cell recording in midbrain slices, we observed potentiation of evoked IPSCs (eIPSCs) in these neurons after blocking CB1 receptors with rimonabant or LY-320,135, indicating the presence of an eCB tone reducing inhibitory synaptic transmission. Increased postsynaptic calcium buffering and block of mGluR1 or postsynaptic G-protein coupled receptors prevented this potentiation. Increasing spillover of endogenous glutamate by inhibiting uptake attenuated eIPSC amplitude, while enhancing the potentiation by rimonabant. Group I mGluR activation transiently inhibited eIPSCs, which could be prevented by GDP-β-S, increased calcium buffering or rimonabant. We explored the possibility that the dopamine-derived eCB N-arachidonoyl dopamine (NADA) is involved. The eCB tone was abolished by preventing dopamine synthesis, and enhanced by l-DOPA. It was not detected in adjacent non-dopaminergic neurons. Preventing 2-AG synthesis did not affect the tone, while inhibition of NADA production abolished it. Quantification of ventral midbrain NADA suggested a basal level that increased following prolonged depolarization or mGluR activation. Since block of the tone was not always accompanied by attenuation of depolarization-induced suppression of inhibition (DSI) and vice versa, our results indicate DSI and the eCB tone are mediated by distinct eCBs. This study provides evidence that dopamine modulates the activity of SNc neurons not only by conventional dopamine receptors, but also by CB1 receptors, potentially via NADA. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/24334069/Glutamate_spillover_drives_endocannabinoid_production_and_inhibits_GABAergic_transmission_in_the_Substantia_Nigra_pars_compacta_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(13)00579-0 DB - PRIME DP - Unbound Medicine ER -