Nicotine Control of Dopamine Signaling in the Ventral Tegmental Area
Year: 2008
Type: article
Abstract: Midbrain dopaminergic (DA) neurons signal motivational properties of natural reinforces 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 changes 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 inter-neurons. We address these issues by building and analysing a computational model of the VTA circuitry and nAChR function, based on known activation and desensitization properties of the nAChR subtypes. 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. Finally, we show that DA neuron response to afferent inputs is altered in the presence of nicotine so as to favor phasic dopaminergic release. These results identify mechanisms by which the VTA mediates the rewarding properties of nicotine that lead to addictive behavior. KEY WORDS dopamine, nicotinic acetylcholine receptors, ventral tegmental area, local circuitry, biophysical model 1
Authors: Michael Graupner, Boris Gutkin
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4299384909