Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms.
There is much interest in brain regions that drive nicotine intake in smokers. Interestingly, both the rewarding and aversive effects of nicotine are probably critical for sustaining nicotine addiction. The medial and lateral habenular (LHb) nuclei play important roles in processing aversion, and recent work has focused on the critical involvement of the LHb in encoding and responding to aversive stimuli. Several neurotransmitter systems are implicated in nicotine's actions, but very little is known about how nicotinic acetylcholine receptors (nAChRs) regulate LHb activity. Here we report in brain slices that activation of nAChRs depolarizes LHb cells and robustly increases firing, and also potentiates glutamate release in LHb. These effects were blocked by selective antagonists of α6-containing (α6*) nAChRs, and were absent in α6*-nAChR knockout mice. In addition, nicotine activates GABAergic inputs to LHb via α4β2-nAChRs, at lower concentrations but with more rapid desensitization relative to α6*-nAChRs. These results demonstrate the existence of diverse functional nAChR subtypes at presynaptic and postsynaptic sites in LHb, through which nicotine could facilitate or inhibit LHb neuronal activity and thus contribute to nicotine aversion or reward.
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Wanhong
W
Zuo
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Cheng
C
Xiao
Divisions of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
Ming
M
Gao
Department of Neurology, University of California at San Francisco, CA, USA.
F Woodward
FW
Hopf
Department of Physiology, McGill University, Montréal, Canada.
Krešimir
K
Krnjević
George E. Wahlen Veterans Affairs Medical Center and Departments of Psychiatry and Biology, University of Utah, Salt Lake City, UT, USA.
J Michael
JM
McIntosh
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Rao
R
Fu
Divisions of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
Jie
J
Wu
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Alex
A
Bekker
Department of Anesthesiology, Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Jiang-Hong
JH
Ye
D000818:Animals; D019262:Habenula / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology*
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine