title: Mesolimbic dopamine neurons in the brain reward circuit mediate susceptibility to social defeat and antidepressant action.
abstract: We previously reported that the activity of mesolimbic dopamine neurons of the ventral tegmental area (VTA) is a key determinant of behavioral susceptibility vs resilience to chronic social defeat stress. However, this was based solely on ex vivo measurements, and the in vivo firing properties of VTA dopamine neurons in susceptible and resilient mice, as well as the effects of antidepressant treatments, remain completely unknown. Here, we show that chronic (10 d) social defeat stress significantly increased the in vivo spontaneous firing rates and bursting events in susceptible mice but not in the resilient subgroup. Both the firing rates and bursting events were significantly negatively correlated with social avoidance behavior, a key behavioral abnormality induced by chronic social defeat stress. Moreover, the increased firing rates, bursting events, and avoidance behavior in susceptible mice were completely reversed by chronic (2 week), but not acute (single dose), treatments with the antidepressant medication fluoxetine (20 mg/kg). Chronic social defeat stress increased hyperpolarization-activated cation current (I(h)) in VTA dopamine neurons, an effect that was also normalized by chronic treatment with fluoxetine. As well, local infusion of I(h) inhibitors ZD7288 (0.1 μg) or DK-AH 269 (0.6 μg) into the VTA exerted antidepressant-like behavioral effects. Together, these data suggest that the firing patterns of mesolimbic dopamine neurons in vivo mediate an individual's responses to chronic stress and antidepressant action.
authors.affiliation: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, USA.
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Cao
authors.forename: Herbert E
authors.initials: HE
authors.lastname: Covington
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Friedman
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wilkinson
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Walsh
authors.forename: Donald C
authors.initials: DC
authors.lastname: Cooper
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use*; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000473:pathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004298:Dopamine / Q000378:metabolism*; D004558:Electric Stimulation / Q000379:methods; D005473:Fluoxetine / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009434:Neural Pathways / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques / Q000379:methods; D011743:Pyrimidines / Q000494:pharmacology; D012201:Reward; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017557:Ventral Tegmental Area / Q000473:pathology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001552:Benzazepines; D002316:Cardiotonic Agents; D011743:Pyrimidines; D005473:Fluoxetine; C082246:ICI D2788; C087873:DK-AH 268; D004298:Dopamine