[Show abstract][Hide abstract] ABSTRACT: Midbrain dopamine (DA) neurons are key players in motivation and reward processing. Increased DA release is thought to be central in the initiation of drug addiction. Whereas dopamine neurons are generally considered to be activated by drugs such as nicotine, we report here that nicotine not only induces excitation of ventral tegmental area (VTA) DA cells but also induces inhibition of a subset of VTA DA neurons that are anatomically segregated in the medial part of the VTA. These opposite responses do not correlate with the inhibition and excitation induced by noxious stimuli. We show that this inhibition requires D2 receptor (D2-R) activation, suggesting that a dopaminergic release is involved in the mechanism. Our findings suggest a principle of concurrent excitation and inhibition of VTA DA cells in response to nicotine. It promotes unexplored roles for DA release in addiction contrasting with the classical views of reinforcement and motivation, and give rise to a new interpretation of the mode of operation of the reward system. M idbrain dopamine (DA) neurons from the ventral tegmental area (VTA) are involved in several brain processes including reinforcement, associative learning, motivation, and are critically involved in the pathophysiology of addiction. Nicotine, the primary addictive component of tobacco, exerts its rein-forcing effects by modifying VTA DA neurons activity through its action on nicotinic acetylcholine receptors (nAChRs) 1–4 and through the subsequent DA release 5 in target areas such as the Nucleus Accumbens (NAc) and the prefrontal cortex (PFC). DA VTA cells can be segregated into different functional subpopulations, according to their spontaneous electrophysiological activity, protein expression, area of axonal projection 6,7
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 11/2008; 28(47):12318-12327. DOI:10.1523/JNEUROSCI.3918-08.2008 · 6.75 Impact Factor