TY - JOUR T1 - Dopamine D<sub>4</sub> Receptor Excitation of Lateral Habenula Neurons via Multiple Cellular Mechanisms JF - The Journal of Neuroscience JO - J. Neurosci. SP - 16853 LP - 16864 DO - 10.1523/JNEUROSCI.1844-13.2013 VL - 33 IS - 43 AU - Cameron H. Good AU - Huikun Wang AU - Yuan-Hao Chen AU - Carlos A. Mejias-Aponte AU - Alexander F. Hoffman AU - Carl R. Lupica Y1 - 2013/10/23 UR - http://www.jneurosci.org/content/33/43/16853.abstract N2 - 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 (IDAi) and increases spontaneous firing in 32% of LHb neurons. IDAi was also observed upon application of amphetamine or the DA uptake blockers cocaine or GBR12935, indicating involvement of endogenous DA. IDAi was blocked by D4 receptor (D4R) antagonists (L745,870 or L741,742), and mimicked by a selective D4R agonist (A412997). IDAi 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. IDAi 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 IDAi 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. ER -