title: Rewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons.
abstract: Ventral tegmental area (VTA) neurons play roles in reward and aversion. The VTA has three major neuronal phenotypes: dopaminergic, GABAergic, and glutamatergic. VTA glutamatergic neurons--expressing vesicular glutamate transporter-2 (VGluT2)--project to limbic and cortical regions, but also excite neighboring dopaminergic neurons. Here, we test whether local photoactivation of VTA VGluT2 neurons expressing Channelrhodopsin-2 (ChR2) under the VGluT2 promoter causes place preference and supports operant responding for the stimulation. By using a Cre-dependent viral vector, ChR2 (tethered to mCherry) was expressed in VTA glutamatergic neurons of VGluT2::Cre mice. The mCherry distribution was evaluated by immunolabeling. By confocal microscopy, we detected expression of mCherry in VTA cell bodies and local processes. In contrast, VGluT2 expression was restricted to varicosities, some of them coexpressing mCherry. By electron microscopy, we determined that mCherry-VGluT2 varicosities correspond to axon terminals, forming asymmetric synapses on neighboring dopaminergic neurons. These findings indicate that ChR2 was present in terminals containing glutamatergic synaptic vesicles and involved in local synaptic connections. Photoactivation of VTA slices from ChR2-expressing mice induced AMPA/NMDA receptor-dependent firing of dopaminergic neurons projecting to the nucleus accumbens. VTA photoactivation of ChR2-expressing mice reinforced instrumental behavior and established place preferences. VTA injections of AMPA or NMDA receptor antagonists blocked optical self-stimulation and place preference. These findings suggest a role in reward function for VTA glutamatergic neurons through local excitatory synapses on mesoaccumbens dopaminergic neurons.
authors.affiliation: Neuronal Networks Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.affiliation: Neuronal Networks Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Jia
authors.initials: J
authors.lastname: Qi
authors.affiliation: Neuronal Networks Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Shiliang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Neuronal Networks Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224.
authors.forename: Huikun
authors.identifier: http://orcid.org/0000-0001-8556-3504
authors.initials: H
authors.lastname: Wang
authors.affiliation: Neuronal Networks Section, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland 21224 mmorales@intra.nida.nih.gov.
authors.forename: Marisela
authors.initials: M
authors.lastname: Morales
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000075402:Channelrhodopsins; D002772:Cholera Toxin / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005971:Glutamates / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D010775:Photic Stimulation; D012201:Reward; D012646:Self Administration; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D017557:Ventral Tegmental Area / Q000166:cytology* / Q000187:drug effects; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D014795:Visual Pathways / Q000502:physiology
chemical_list: D000075402:Channelrhodopsins; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; C493477:Slc17a6 protein, mouse; D050599:Vesicular Glutamate Transport Protein 2; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002772:Cholera Toxin; D004298:Dopamine
keywords: VGluT2; VTA; addiction; aversion; dopamine; reward