title: Bidirectional regulation of dopamine D2 and neurotensin NTS1 receptors in dopamine neurons.
abstract: Several lines of evidence suggest a close association between dopamine (DA) and neurotensin (NT) systems in the CNS. Indeed, in the rodent brain, abundant NT-containing fibres are found in DA-rich areas such as the ventral tegmental area and substantia nigra. Moreover, it has been shown in vivo that NT, acting through its high-affinity receptor (NTS1), reduces the physiological and behavioural effects of DA D2 receptor (D2R) activation, a critical autoreceptor feedback system regulating DA neurotransmission. However, the mechanism of this interaction is still elusive. The aim of our study was thus to reproduce in vitro the interaction between D2R and NTS1, and then to characterize the mechanisms implicated. We used a primary culture model of DA neurons prepared from transgenic mice expressing green fluorescent protein under the control of the tyrosine hydroxylase promoter. In these cultures, DA neurons endogenously express both D2R and NTS1. Using electrophysiological recordings, we show that activation of D2R directly inhibits the firing rate of DA neurons. In addition, we find that NT, acting through a NTS1-like receptor, is able to reduce D2R autoreceptor function independently of its ability to enhance DA neuron firing, and that this interaction occurs through a protein kinase C- and Ca(2+)-dependent mechanism. Furthermore, prior activation of D2R reduces the ability of NTS1 to induce intracellular Ca(2+) mobilization. Our findings provide evidence for bidirectional interaction between D2R and NTS1 in DA neurons, a regulatory mechanism that could play a key role in the control of the activity of these neurons.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Groupe de Recherche sur le Système Nerveux Central, Centre de Recherche Fernand Seguin, Université de Montréal, Montréal, Québec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Jomphe
authors.forename: P-L
authors.initials: PL
authors.lastname: Lemelin
authors.forename: H
authors.initials: H
authors.lastname: Okano
authors.forename: K
authors.initials: K
authors.lastname: Kobayashi
authors.forename: L-E
authors.initials: LE
authors.lastname: Trudeau
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009496:Neurotensin / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D011493:Protein Kinase C / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013469:Sulpiride / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D002614:Chelating Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010446:Peptide Fragments; D011720:Pyrazoles; D011804:Quinolines; D017448:Receptors, Dopamine D2; D018028:Receptors, Neurotensin; C072093:protein kinase C (19-36); C079087:SR 48692; D049452:Green Fluorescent Proteins; D019257:Quinpirole; D009496:Neurotensin; D004533:Egtazic Acid; D013469:Sulpiride; D014446:Tyrosine 3-Monooxygenase; D011493:Protein Kinase C; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium