Co-activation of VTA DA and GABA neurons mediates nicotine reinforcement

Abstract

Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.

Nicotinic receptors mediate stress-nicotine detrimental interplay via dopamine cells’ activity

“…To test this hypothesis, we measured DA neuron responses to intravenous nicotine administration in vivo. In naive mice (NoSD), a single intravenous injection of 30 μg kg − 1 of nicotine, 11,18 enhanced the firing and bursting activities of VTA DA cells (Figure 1d and Supplementary Figure S1b-g). In striking contrast, defeated mice exhibited a virtually abolished response to nicotine evidenced by a lack of significant variation from baseline of firing and bursting patterns of DA neurons ( Figure 1d and Supplementary Figure S1b-g).…”

“…The ability of systemic nicotine to excite VTA DA neurons in naive conditions requires the activation of VTA nAChRs located on both GABA and DA neurons. 11 Therefore, changes in nAChRs expression could explain a blunted nicotine response in SD conditions. Extensive brain mapping of α-bungarotoxin and epibatidine binding sites by autoradiography revealed no global alteration of α7 or β2* nAChRs numbers after SD, respectively (Supplementary Figures S2 and S3).…”

“…Neuronal nicotinic acetylcholine receptors (nAChRs) are key modulators of midbrain dopamine (DA) cell activity. 11 The activation of nAChRs within the ventral tegmental area (VTA) by nicotine encodes tobacco's primary reinforcing properties. 5,[12][13][14] Nicotine, in the absence of tobacco, is sufficient to sustain selfadministration 15 and produce reward in a conditioned place preference paradigm.…”

“…18 VTA nAChRs subtypes are present on GABA and DA neurons, as well as on excitatory inputs, which results in a fine tuning of DA neuronal activity. 11,12 Preclinical and clinical studies implicate both high-and low-affinity nAChRs in stress-induced pathologies. For example, changes in nAChRs availability have been observed in patients suffering from post-traumatic stress disorders or depression.…”

Mechanisms for multiple activity modes of VTA dopamine neurons

“…The VTA GABAergic populations are subject to similar glutamatergic and cholinergic currents as the DAergic populations, and there is an interplay between the DAergic and GABAergic activities. This balance of excitation to inhibition plays a role in the VTA DA neural response to nicotine stimulation [23][24][25].…”