Date Published: August 15, 2013
Publisher: Public Library of Science
Author(s): Michael Graupner, Reinoud Maex, Boris Gutkin, Karl J. Friston
Abstract: Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.
Partial Text: The ventral tegmental area (VTA) is a key dopaminergic structure for signaling reward and motivation as well as for the acquisition of drug-reinforced behavior , . Nicotine (Nic) stimulates nicotinic acetylcholine receptors (nAChRs) in the VTA  boosting dopamine (DA) output to its targets such as the nucleus accumbens  and thereby playing a cititcal role in the mediation of nicotine reward and dependence –. Yet, despite a wealth of data on the outcome of nicotine action, the precise mechanisms by which nicotine usurps control over DA signaling remain debated.
Our minimal local circuit model of the VTA reflects the glutamatergic (Glu) and cholinergic (ACh) afferents to the DA and GABA cells in the VTA, as well as local inhibition of DA cells by GABA neurons (see Fig. 1A). Importantly we explicitly model the subtype-specific activation and desensitization of α4β2 and α7 nAChRs since these subtypes have been shown to be predominant in mediating nicotine effects in the VTA , , . Further evidence supports the critical role of α4-containing nAChRs for Nic action in the VTA , . Based on available data we model the α7 nAChRs as placed at presynaptic Glu terminals where they affect Glu input strength . We model the α4β2 nAChR as placed somatically on both the DA and the GABA neurons. The relative α4β2 nAChR expression level (DA/GABA proportional density) is controlled in our model by a fraction parameter r which allows us to shift continuously the balance of α4β2 nAChR-mediated effects from GABA cells () to DA cells (; Fig. 1A). Overall, the model augments the mean-field firing-rate description of the relevant neuronal populations with subtype specific receptor currents in order to study neuronal activity in response to endogenous (ACh) and exogenous (Nic) ligands acting on nAChRs (see Models).
The major goal of this study was to determine the dominant pathway of action for nicotine in the ventral tegmental area. In order to do so we have developed a novel mesoscopic computational modeling approach extending a population activity representation of the VTA DA and GABA neurons to describe nAChR responses. This allowed us to clarify the interplay of the pharmacodynamics of nicotine and the dopaminergic signal constructed in the VTA. Our analysis of the model showed that in vitro and in vivo data can be reconciled by taking into account the difference in the afferent input strengths to the VTA in the two experimental settings: low for in vitro and high for in vivo. The differential activation and desensitization kinetics of α7- and α4β2 nAChRs combined with different afferent input levels can explain the mechanism of nicotine action.
In order to examine the mechanisms of nicotine action, we built a neural population model of the ventral tegmental area microcircuit using the mean-field approach . Our minimal local circuit model of the VTA incorporates the glutamatergic (Glu) and cholinergic (ACh) afferents to the DA and GABA cells in the VTA, as well as local inhibition of DA cells by GABA neurons (Fig. 1A). The activation and desensitization of the nAChRs in response to Nic and ACh were described by a simple 4-state model adapted from ,  (Fig. 1B,C; see Text S2.).