[Abstract Title]. - Society for Neuroscience

Poster
258. Molecular and Neurochemical Basis of Nicotine Addiction
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 258.16/AA19
Topic: C.16.k. Nicotine
Support: European consortium BACS FP6-IST-027140
Marie Curie Team of Excellence Fellowship BIND MEXT-CT- 2005-024831
Title: Nicotine control of dopamine signaling in the Ventral Tegmental Area
Authors: *M. GRAUPNER, B. GUTKIN;
ENS, Collège de France, Group for Neural Theory, DEC, Paris, France
Abstract: Midbrain dopaminergic (DA) neurons signal motivational properties of natural
reinforcers and addictive drugs. Nicotine, like other drugs of abuse, boosts DA output from the
ventral tegmental area (VTA). This increase results from direct stimulation of nicotinic
acetylcholine receptors (nAChRs) expressed in the VTA. However, how the DA signal is
constructed in the VTA and how nicotine subverts this signal remains controversial. In
particular, in vivo and in vitro experimental paradigms reach contradictory conclusions about the
key target of nicotine action: direct DA cell stimulation or indirect effects mediated through the
GABAergic interneurons. We address these issues through computational modeling of the VTA
circuitry and nAChR function.
The VTA contains DAergic and GABAergic neurons receiving cholinergic (ACh) and
glutamatergic (Glu) afferent inputs from subcortical and cortical structures. The DA response to
endogenous acetylcholine and exogenous nicotine is mediated by various nAChR subtypes
expressed on three different cell types: (i) on the DA neurons, (ii) on the GABAergic neurons,
and (iii) on presynaptic Glu terminals. We implement this structure in a neuronal network which
accounts for the local VTA connectivity as well as the location of the nAChRs. Based on known
activation and desensitization properties of the nAChR subtypes, we investigate the VTA DA
neuron responses to nicotine.
We show that the apparent data mismatch between in vitro and in vivo recordings can be
reconciled by differences in the afferent input activity. We find that the GABA cells are principle
in causing nicotine dependent DA signals. We pin-point the specific contributions of various
nAChRs to the DA signal. Moreover, we make predictions about how Glu and ACh input to the
VTA is translated into DA neuron activity and how such processing is altered in the presence of
nicotine. We furthermore investigate the specific contributions of various input pathways to the
firing modes of the VTA DA neurons thought to be important for reward signaling: the regular