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Title: Endogenous Cholinergic Inputs and Local Circuit Mechanisms Govern the Phasic Mesolimbic Dopamine Response to Nicotine}
Article:
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.
Introduction:
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[1],[2]. Nicotine( Nic) stimulates nicotinic acetylcholine receptors( nAChRs) in the VTA[3] boosting dopamine( DA) output to its targets such as the nucleus accumbens[4] and thereby playing a cititcal role in the mediation of nicotine reward and dependence[5]–[7]. 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. Release of endogenous acetylcholine( ACh) from cholinergic projections[8] causes activation of nAChRs in the VTA[9]. The rapid breakdown of ACh by acetylcholinesterase precludes significant nAChR desensitization[9],[10]. Exogenous nicotine is not hydrolyzed[11] and thus activates and subsequently desensitizes nAChRs within seconds to minutes[10],[12]. The various subtypes of nAChRs exhibit markedly different activation/desensitization kinetics and distinct affinities for ACh and Nic, as well as different expression targets[7],[13]. The low-affinity α7 subunit-containing nAChRs desensitize rapidly( ∼ms)[14] and are found in the VTA presynaptically on the glutamatergic terminals[15]. The high-affinity α4β2 subunit-containing nAChRs desensitize relatively slowly( ∼sec) and are located postsynaptically on the DA and GABAergic cells[13]. Studies on knockout mice suggest that the α4β2 nAChRs mediate most of the Nic-evoked currents and the acute reinforcing effects of nicotine[16], while α7 nAChRs appear to contribute to the fine-tuning of the DA response to nicotine[17]. A major outstanding question is whether nicotine acts directly on the DA neurons through the activation of α4β2 nAChRs or affects the local GABA interneurons and thereby the inhibition of DA neurons. In vitro data suggest that the increased activity of DA neurons is due to nicotine desensitizing the α4β2 nAChRs, decreasing the endogenous cholinergic drive to GABA neurons and resulting in disinhibition of DA cells[18],[19]. In vivo studies emphasize the role of nicotine-evoked direct activation of β2-containing nAChRs expressed on the DA neurons[17]. We set out to clarify the mechanisms linking the nicotine-triggered nAChR activation/desensitization and nicotine control of DA signaling. In order to do so we built a neuronal network model that includes the afferent and local VTA connectivity as well as the location and activation/desensitization properties of the different nAChR subtypes. Our results show that each of the two mechanisms, direct excitation and disinhibition, requires distinct conditions for afferent input strengths and cellular properties in order to account for the nicotine-evoked DA boost. We develop a series of experimental protocols to disambiguate the disinhibition vs. the direct stimulation pathways and reveal that the endogenous cholinergic input rate dictates the DA response to nicotine for both.
Discussion:
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. However, available experimental data have not allowed to pinpoint whether α4β2 nAChRs on VTA DA( direct stimulation) or GABA cells( disinhibition) are the dominant site of nicotine action in vivo. Using the model, we demonstrate that both disinhibition and direct stimulation of DA cells can potentially be at the origin of the experimentally observed nicotine-induced boost of DA activity in agreement with the recent suggestion that both receptor activation and desensitization play a role in nicotine influence[34]. Critically we identify that the endogenous cholinergic input rate has to be low for direct stimulation, whereas high cholinergic inputs are crucial in the disinhibition case, in order to observe a DA activity increase. These results emerge directly from known activation and desensitization properties of α4β2 nAChRs. Several experimental results support the critical role of the GABAergic cells for the action of nicotine. Most of the cholinergic axon terminals in the VTA synapse on the non-DA neurons[35]. The α4-containing nAChRs expressed on the VTA GABAergic neurons upregulate in response to chronic nicotine, potentially boosting the nicotine control of their activity[28],[36]. The activation of VTA GABA neurons is necessary for the reinforcing actions of Nic[37]. A wide class of addictive drugs, including opioids, cannabinoids, γ-hydroxy butyrate( GHB), benzodiazepines, lead to inhibition of GABA neurons in the VTA and thereby disinhibition of DA neurons( e. g,[38], see[39] for an overview). Furthermore, the GABA antagonist bicuculline is self-administered by mice[40],[41]. Taken together these facts support the hypothesis that reduced GABAergic input to DA cells can initiate addictive behaviors. The hyperexcitability of the VTA in response to nicotine[42] could be related to the higher abundance of GABAergic cells in the VTA as compared to the SN( GABA to DA ratio about 1/4 in the VTA[43]; and 1/19 in the substantia nigra[44]). We would like to point out that the disinhibition scenario emphasizes the role of local circuitry organization as opposed to the single cell mechanism associated with direct stimulation of DA cells. It may also be that disinhibtion is primarily due to nicotine-induced inhibition of GABA activity of extrinisic rather than local GABA neurons. Candidates include GABAergic projections onto DA neurons that arise in the ventral palladium or the rostromedial tegmental nucleus[45],[46]. Our model makes several testable predictions for the case that the reinforcing properties of nicotine are mediated by inhibition of the GABA cells. Notably, the DA activity response to Nic is a mirror-image of the GABAergic firing response( Fig. 4D, F). Moreover, the DA response to Nic is biphasic: the longer boost is preceded by a short-lasting inhibtion due to the fast activation of α4β2 nAChRs( Fig. 4D, and 5B). Some DA neuron recordings appear to support this observation[47]. We further predict that the DA boost should saturate at relatively low Nic levels( ∼500 nM) in case of disinhibition( Fig. 5F). Higher nicotine levels do not evoke further increases of DA activity since the maximal desensitization of α4β2 nAChR is already attained at low nicotine. This result implies that Nic elicits maximal α4β2 nAChR-mediated increase of DA activity at nicotine concentrations attained in the blood of smokers[11],[31]. We confirm previous findings suggesting that physiologically relevant doses of nicotine do not significantly desensitize α7-containing nACh receptors[48]. We extend this statement and propose that physiological concentrations of nicotine do not significantly activate α7-containing nAChRs. We consider it therefore unlikely that increased glutamatergic drive to DA cells in response to nicotine augments their activity. It should however be noted that the mean-field approach presented here does not resolve the different firing modes of DA cells, i. e., bursting and regular firing. α7-containing nAChs could play a role in nicotine induced bursting[49],[50]. The tonic inhibitory input from GABAergic cells may be setting the overall level of excitability of DA cells by controling the mean membrane potential. When the DA cells are disinhibited through desensitization of α4β2 nAChRs, the α7 nAChR activation could induce burst firing on top of the elevated membrane potential. Hence GABA cells would gate the DA burst firing, as suggested in a biophysically detailed model by Komendantov et al.[51]. Furthermore, bursting induced by α7 nAChR activation could be crucial for the induction of long-term potentiation of Glu synapses onto DA cells[18],[52]. These topics remain subject of active investigations. We note that we focus only on feedforward afferent input( glutamatergic and cholinergic) and a simplified local circuitry of the VTA. While we leave aside the possible involvement of other neuronal structures[46],[53], we find that our setup is sufficient to account for a wide range of data on nicotine/DA interactions. Furthermore, we chose to not address the potential heterogeneity of the VTA itself[35],[54],[55]. However, our proposed circuitry can be seen either as a global description of the VTA or as a model of a local computational unit within the VTA. Whether the experimentally observed diversity of DA cell behavior could be explained by the coexistent presence of direct stimulation and disinhibition subcircuits or whether recurrent inhibition has to be taken into account remains an area for future studies. However, already in our model the activities of the DA and GABAergic cells show a variety of temporal profiles depending on the α4β2 nAChR expression and the cholinergic input rate. Data and theory suggest that dopamine levels modulate synaptic plasticity and learning[56],[57]. Our results together with this fact lead us to speculate that if salient characteristics of environmental cues are reflected in the overall cholinergic tone[58], the nicotine induced increase of phasic DA may explain the strong associations formed between these cues and the habit of smoking[59],[60]. Our results provide a clear paradigm for understanding the interactions between endogenous acetylcholine input and the mechanism by which exogenous nicotine may provoke DA changes: differential control over the local VTA mechanisms by endogenous ACh input rates. Endogenous ACh inputs determine whether Nic evokes a positive DA response or a DA depression for either scenarios discussed here, i. e., direct stimulation and disinhibition. For example, nicotine-evoked DA increases and high ACh input imply disinhibition, while DA increases and low ACh implicate direct stimulation. Furthermore, taking diural rhythms of cholinergic signaling into account, the VTA may give rise to different DA outputs at different times of the day, e. g., the morning cigarette may deploy different mechanisms than an evening cigarette. In turn this state-dependency of nicotine-induced reinforcement could imply that the therapeutic strategies for smoking cessation may need to be tailored for a variety of cognitive states in order to act on specific targets within the predominant pathway of nicotine action.
Nicotine is the major addictive substance in tobacco smoke . Nicotine exerts its control over neural circuits through nicotinic acetylcholine receptors that normally respond to endogenous acetylcholine . Activation of dopamine neurons in the mesolimbic dopaminergic circuits , which signal motivational properties of actions and stimuli , is at the heart of mediating nicotine reward and dependence . However , major questions have remained unsettled over the precise mechanisms by which nicotine usurps dopaminergic signaling: through receptor activation on dopamine neurons or through receptor desensitization on local inhibitory interneurons . Here we reconcile this debate by showing that both mechanisms are possible . Most notably we present a novel hypothesis suggesting that the mechanisms for nicotine action are state-dependent; they are controlled by the rate of the endogenous cholinergic input to the dopaminergic circuits .