Stefania Tolu

Institut Pasteur, Lutetia Parisorum, Île-de-France, France

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Publications (3)25.18 Total impact

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    ABSTRACT: Midbrain dopamine (DA) neurons play a central role in a wide range of behaviors, from attentionand motivation to motor control and reinforcement. The release of DA is modulated by a number of factors, and its deregulation hasbeen implicated in multiple psychiatric disorders, such as addiction. In particular, nicotinicacetylcholine receptors (nAChRs) are key modulators of DA cells. Nicotine, themain addictive component in tobacco, strongly interacts with these receptors in the midbrain DAsystems, resulting in reinforcing effects that are at the core of tobacco addiction. nAChRs are virtually expressed on every cell of the DA system, both at pre-, post- and extra-synaptic locations. The complexissue of interpreting the role of the large portfolio of different nAChR subtypes expressed on ventral tegmental area(VTA) and substantia nigra pars compacta (SNc) neurons, and especially their role in defining functional DAergic subpopulations, is far from being solved. In this review we will try to provide the reader withan integrative view of the nicotinic modulation of DA neurons and its influence at the cellular,systemic and behavioral levels (exploratory behavior), as well as its implication in the reinforcingeffects of nicotine.
    Neuroscience 05/2014; · 3.12 Impact Factor
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    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.Molecular Psychiatry advance online publication, 3 July 2012; doi:10.1038/mp.2012.83.
    Molecular Psychiatry 07/2012; · 15.15 Impact Factor
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    ABSTRACT: The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novel in vivo paradigms were developed to match this aim. Although the beta2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different alpha subunit partners of beta2 (i.e., alpha4 and alpha6), the homo-pentameric alpha7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7-52.6 microg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the beta2, alpha4, alpha6 and alpha7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VEC mice). We show that WT mice, beta2-VEC mice with the beta2 subunit re-expressed exclusively in the VTA, alpha4-VEC mice with selective alpha4 re-expression in the VTA, alpha6-VEC mice with selective alpha6 re-expression in the VTA, and alpha7-KO mice promptly self-administer nicotine intravenously, whereas beta2-KO, beta2-VEC in the substantia nigra, alpha4-KO and alpha6-KO mice do not respond to nicotine. We thus define the necessary and sufficient role of alpha4beta2- and alpha6beta2-subunit containing nicotinic receptors (alpha4beta2*- and alpha6beta2*-nAChRs), but not alpha7*-nAChRs, present in cell bodies of the VTA, and their axons, for systemic nicotine reinforcement in drug-naive mice.
    Journal of Neuroscience 01/2008; 28(47):12318-12327. · 6.91 Impact Factor

Publication Stats

155 Citations
25.18 Total Impact Points

Institutions

  • 2012
    • Institut Pasteur
      Lutetia Parisorum, Île-de-France, France
    • Institut des Systèmes Complexes, Paris Île-de-France
      Lutetia Parisorum, Île-de-France, France