title: Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine.
abstract: Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals.
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Martín F
authors.initials: MF
authors.lastname: Adrover
authors.forename: Jung Hoon
authors.initials: JH
authors.lastname: Shin
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D000075402:Channelrhodopsins; D000229:Dependovirus / Q000235:genetics; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008636:Mesencephalon / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D011810:Quinoxalines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects* / Q000235:genetics
chemical_list: D000075402:Channelrhodopsins; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D017448:Receptors, Dopamine D2; C493215:Slc6a3 protein, mouse; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid
keywords: D2 receptors; co-release; cocaine; dopamine; feedback inhibition; glutamate