title: Reduction in Ventral Midbrain NMDA Receptors Reveals Two Opposite Modulatory Roles for Glutamate on Reward.
abstract: Glutamate is a major component of the reward circuitry and recent clinical studies suggest that new molecules that would target glutamate neurotransmission are most likely to constitute more effective medications for mood disorders. It is well known that activation of N-methyl-D-aspartate glutamate receptors (NMDARs) initiates dopamine burst firing, a mode associated with reward signaling; but NMDARs also contribute to the maintenance of an inhibitory drive to dopamine neurons. Such opposite modulatory functions imply that different subtypes of NMDARs are expressed on different ventral midbrain (VM) neurons and/or afferent inputs to dopamine neurons. By using the small interfering RNA (siRNA) technique, we studied the effects of VM downregulation of NMDAR subunits GluN1, GluN2A, and GluN2D on reward induced by dorsal raphe electrical stimulation. Reward thresholds were measured before and 24 h after each of three consecutive daily bilateral microinjections of siRNA for the targeted receptor subunit(s) or non-active RNA sequence. After the last measurement, reward thresholds were reassessed following a bilateral microinjection of the preferred GluN2A-NMDA antagonist, (2R,4S)-4-(3-Phosphopropyl)-2-piperidinecarboxylic acid (PPPA). Western-blot analysis showed that siRNAs reduced GluN1- and GluN2A-containing receptors whereas behavioral tests showed that only a reduction in GluN1 produced reward attenuation. Despite NMDAR reduction, reward-enhancing effect of PPPA remained unchanged. We conclude that VM glutamate relays the reward signal initiated by dorsal raphe electrical stimulation by acting on NMDARs devoid of GluN2A/2D subunits and exerts an inhibition on this reward signal by acting on GluN2A-containing NMDARs most likely located on afferent terminals.
authors.affiliation: Département de Neurosciences, Université de Montréal, Montréal, QC, Canada.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Hernandez
authors.affiliation: FRQ-S Research Group in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Khodami-Pour
authors.affiliation: Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lévesque
authors.affiliation: 1] Département de Neurosciences, Université de Montréal, Montréal, QC, Canada [2] FRQ-S Research Group in Behavioral Neurobiology, Department of Psychology, Concordia University, Montréal, QC, Canada.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Rompré
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000378:metabolism*; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012646:Self Administration; D013223:Statistics as Topic
chemical_list: D018683:Excitatory Amino Acid Agents; D005229:Fatty Acids, Monounsaturated; D005456:Fluorescent Dyes; D021122:Protein Subunits; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane