title: Dopamine D4 receptor excitation of lateral habenula neurons via multiple cellular mechanisms.
abstract: Glutamatergic lateral habenula (LHb) output communicates negative motivational valence to ventral tegmental area (VTA) dopamine (DA) neurons via activation of the rostromedial tegmental nucleus (RMTg). However, the LHb also receives a poorly understood DA input from the VTA, which we hypothesized constitutes an important feedback loop regulating DA responses to stimuli. Using whole-cell electrophysiology in rat brain slices, we find that DA initiates a depolarizing inward current (I(DAi)) and increases spontaneous firing in 32% of LHb neurons. I(DAi) was also observed upon application of amphetamine or the DA uptake blockers cocaine or GBR12935, indicating involvement of endogenous DA. I(DAi) was blocked by D4 receptor (D4R) antagonists (L745,870 or L741,742), and mimicked by a selective D4R agonist (A412997). I(DAi) was associated with increased whole-cell conductance and was blocked by Cs+ or a selective blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, ZD7288. I(DAi) was also associated with a depolarizing shift in half-activation voltage for the hyperpolarization-activated cation current (Ih) mediated by HCN channels. Recordings from LHb neurons containing fluorescent retrograde tracers revealed that I(DAi) was observed only in cells projecting to the RMTg and not the VTA. In parallel with direct depolarization, DA also strongly increased synaptic glutamate release and reduced synaptic GABA release onto LHb cells. These results demonstrate that DA can excite glutamatergic LHb output to RMTg via multiple cellular mechanisms. Since the RMTg strongly inhibits midbrain DA neurons, activation of LHb output to RMTg by DA represents a negative feedback loop that may dampen DA neuron output following activation.
authors.affiliation: Cellular Neurobiology Research Branch, Electrophysiology Research Section, and Integrative Neuroscience Research Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Baltimore, Maryland 21224, and Department of Neurosurgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan, Republic of China.
authors.forename: Cameron H
authors.initials: CH
authors.lastname: Good
authors.forename: Huikun
authors.initials: H
authors.lastname: Wang
authors.forename: Yuan-Hao
authors.initials: YH
authors.lastname: Chen
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Mejias-Aponte
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Carl R
authors.initials: CR
authors.lastname: Lupica
mesh_terms: D000200:Action Potentials; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D002586:Cesium / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D018698:Glutamic Acid / Q000378:metabolism; D019262:Habenula / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D045042:Pedunculopontine Tegmental Nucleus / Q000166:cytology / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050638:Receptors, Dopamine D4 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009435:Synaptic Transmission; D017557:Ventral Tegmental Area / Q000166:cytology / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D010879:Piperazines; D050638:Receptors, Dopamine D4; D002586:Cesium; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D000661:Amphetamine; D003042:Cocaine; D004298:Dopamine