title: Neurotensin inhibits glutamate-mediated synaptic inputs onto ventral tegmental area dopamine neurons through the release of the endocannabinoid 2-AG.
abstract: Neurotensin (NT), a neuropeptide abundant in the ventral midbrain, is known to act as a key regulator of the mesolimbic dopamine (DA) system, originating in the ventral tegmental area (VTA). NT activates metabotropic receptors coupled to Gq heterotrimeric G proteins, a signaling pathway often triggering endocannabinoid (EC) production in the brain. Because ECs act as negative regulators of many glutamate synapses and have also been shown recently to gate LTP induction in the VTA, we examined the hypothesis that NT regulates glutamate-mediated synaptic inputs to VTA DA neurons. We performed whole cell patch-clamp recordings in VTA DA neurons in TH-EGFP transgenic mouse brain slices and found that NT induces a long-lasting decrease of the EPSC amplitude that was mediated by the type 1 NT receptor. An antagonist of the CB1 EC receptor blocked this decrease. This effect of NT was not dependent on intracellular calcium, but required G-protein activation and phospholipase C. Blockade of the CB1 receptor after the induction of EPSC depression reversed synaptic depression, an effect not mimicked by blocking NT receptors, thus suggesting the occurrence of prolonged EC production and release. The EC responsible for synaptic depression was identified as 2-arachidonoylglycerol, the same EC known to gate LTP induction in VTA DA neurons. However, blocking NT receptors during LTP induction did not facilitate LTP induction, suggesting that endogenously released NT is not a major source of EC production during LTP inducing stimulations.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Kortleven
authors.forename: Laura Charlotte
authors.initials: LC
authors.lastname: Bruneau
authors.forename: Louis-Eric
authors.initials: LE
authors.lastname: Trudeau
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D004558:Electric Stimulation; D063388:Endocannabinoids / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000502:physiology*; D005989:Glycerides / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D009496:Neurotensin / Q000378:metabolism / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D018028:Receptors, Neurotensin / Q000187:drug effects / Q000378:metabolism; D013569:Synapses / Q000187:drug effects*; D017557:Ventral Tegmental Area / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D018691:Excitatory Amino Acid Antagonists; D005989:Glycerides; D018028:Receptors, Neurotensin; C493477:Slc17a6 protein, mouse; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D009496:Neurotensin; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate