title: Glutamate spillover drives endocannabinoid production and inhibits GABAergic transmission in the Substantia Nigra pars compacta.
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: 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.
authors: Peter S
authors: PS
authors: Freestone
authors: Laboratorio di Neurologia Sperimentale, Fondazione Santa Lucia IRCCS, Rome, Italy.
authors: Ezia
authors: E
authors: Guatteo
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.
authors: Fabiana
authors: F
authors: Piscitelli
authors: Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Pozzuoli, Italy.
authors: Vincenzo
authors: V
authors: di Marzo
authors: Department of Physiology and Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, New Zealand.
authors: Janusz
authors: J
authors: Lipski
authors: 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.
authors: Nicola B
authors: NB
authors: Mercuri
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D002491:Central Nervous System Agents / Q000494:pharmacology; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D063388:Endocannabinoids / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D013378:Substantia Nigra / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D001572:Benzofurans; D063387:Cannabinoid Receptor Antagonists; D002491:Central Nervous System Agents; D015259:Dopamine Agents; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018094:Receptors, Metabotropic Glutamate; D013873:Thionucleotides; C474941:arachidonyl dopamine; C104077:metabotropic glutamate receptor type 1; D006153:Guanosine Diphosphate; D018698:Glutamic Acid; D007980:Levodopa; C023427:guanosine 5'-O-(2-thiodiphosphate); C110158:LY 320135; D000077285:Rimonabant; D002118:Calcium; D004298:Dopamine
keywords: Cannabinoids; Dopaminergic; Electrophysiology; Parkinson's disease; Synaptic transmission