An inhibitory brainstem input to dopamine neurons encodes nicotine aversion

Details

• Alternative Title:
  Neuron
• Personal Author:
  Liu, Christine ; Tose, Amanda J ; Verharen, Jeroen PH ; Zhu, Yichen ; Tang, Lilly W ; de Jong, Johannes W ; Du, Jessica X ; Beier, Kevin T ; Lammel, Stephan
• Description:
  Nicotine stimulates the dopamine (DA) system, which is essential for its rewarding effect. Nicotine is also aversive at high doses; yet, our knowledge about nicotine's dose-dependent effects on DA circuits remains limited. Here, we demonstrate that high doses of nicotine, which induce aversion-related behavior in mice, cause biphasic inhibitory and excitatory responses in VTA DA neurons that can be dissociated by distinct projections to lateral and medial nucleus accumben subregions, respectively. Guided by computational modeling, we performed a pharmacological investigation to establish that inhibitory effects of aversive nicotine involve desensitization of α4β2 and activation of α7 nicotinic acetylcholine receptors. We identify α7-dependent activation of upstream GABA neurons in the laterodorsal tegmentum (LDT) as a key regulator of heterogeneous DA release following aversive nicotine. Finally, inhibition of LDT GABA terminals in VTA prevents nicotine aversion. Together, our findings provide a mechanistic circuit-level understanding of nicotine's dose-dependent effects on reward and aversion.
• Subjects:
  Alpha7 Nicotinic Acetylcholine Receptor Animals Dopamine Dopaminergic Neurons Gamma-Aminobutyric Acid Mice Nicotine Receptors, Nicotinic Ventral Tegmental Area
• Keywords:
  Alzheimer's Disease Alzheimer's Disease Sequencing Project Antiviral Agents Herpes Simplex Human Papillomavirus Torque Teno Viruses Whole Exome Sequencing Whole Genome Sequencing
• Source:
  Neuron. 110(18):3018-3035.e7
• Pubmed ID:
  35921846
• Pubmed Central ID:
  PMC9509462
• Document Type:
  Journal Article
• Funding:
  R01 DA042889/DA/NIDA NIH HHSUnited States/ ; S10 RR026866/RR/NCRR NIH HHSUnited States/ ; U01 IP000035/IP/NCIRD CDC HHSUnited States/ ; HHMI/Howard Hughes Medical InstituteUnited States/
• Volume:
  110
• Issue:
  18
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:85146771154607aebd9899925762fc226679f2955b7446e00a122fa645b30d39e5073a20296e3d9b6a557a0e3ed5a4e1459b418280bb318ec45c73b1a0e411a1
• Download URL:
  https://stacks.cdc.gov/view/cdc/121562/cdc_121562_DS1.pdf
• File Type:
  [PDF - 3.56 MB ]