Nicotine Persistently Activates Ventral Tegmental Area Dopaminergic Neurons via Nicotinic Acetylcholine Receptors Containing α4 and α6 Subunits

Abstract

Nicotine is reinforcing because it activates dopaminergic (DAergic) neurons within the ventral tegmental area (VTA) of the brain's mesocorticolimbic reward circuitry. This increase in activity can occur for a period of several minutes up to an hour and is thought to be a critical component of nicotine dependence. However, nicotine concentrations that are routinely self-administered by smokers are predicted to desensitize high-affinity ␣4␤2 neuronal nicotinic acetylcholine receptors (nAChRs) in seconds. Thus, how physiologically relevant nicotine concentrations persistently activate VTA DAergic neurons is unknown. Here we show that nicotine can directly and robustly increase the firing frequency of VTA DAergic neurons for several minutes. In mouse midbrain slices, 300 nM nicotine elicited a persistent inward current in VTA DAergic neurons that was blocked by ␣-conotoxin MII[H9A;L15A], a selective antagonist of nAChRs containing the ␣6 subunit. ␣-conotoxin MII[H9A;L15A] also significantly reduced the longlasting increase in DAergic neuronal activity produced by low concentrations of nicotine. In addition, nicotine failed to significantly activate VTA DAergic neurons in mice that did not express either ␣4 or ␣6 nAChR subunits. Conversely, selective activation of nAChRs containing the ␣4 subunit in knock-in mice expressing a hypersensitive version of these receptors yielded a biphasic response to nicotine consisting of an acute desensitizing increase in firing frequency followed by a sustained increase that lasted several minutes and was sensitive to ␣-conotoxin MII[H9A;L15A]. These data indicate that nicotine persistently activates VTA DAergic neurons via nAChRs containing ␣4 and ␣6 subunits.

Role of CB2 Cannabinoid Receptors in the Rewarding, Reinforcing, and Physical Effects of Nicotine

“…Intra-VTA infusion of nicotine receptor antagonists blocked the effect of systemic nicotine injections on DA release in NAcc (Nisell et al, 1994) and disrupt nicotine self-administration (Corrigall et al, 1994). Several evidences suggested that nicotine receptors containing the a3-and a4-nAChRs are involved in the reinforcement effects of nicotine (Glick et al, 2011;Liu et al, 2012;Pons et al, 2008). Considering the key role of nAChRs mediating the rewarding effects of nicotine, it is tempting to speculate that the lack of nicotine reinforcement properties observed in CB2KO may be related to functional alterations occurring in nAChRs.…”

“…This drug exerts its reinforcement properties through the activation of nAChRs (Stolerman and Jarvis, 1995) expressed at high levels in the mesolimbic reward DA system (Champtiaux et al, 2003;Jones and Wonnacott, 2004;Pidoplichko et al, 1997). The activation of nAChRs by nicotine increases DA release and TH expression in VTA (Liu et al, 2012;Rahman et al, 2003). These molecular changes in DA signaling are crucial for the development of nicotine dependence (David et al, 2006;Ferrari et al, 2002;Ikemoto et al, 2006;Laviolette and van der Kooy, 2004;Rahman et al, 2003).…”

Insights into the Neurobiology of the Nicotinic Cholinergic System and Nicotine Addiction from Mice Expressing Nicotinic Receptors Harboring Gain-of-Function Mutations

“…Zhao-Shea et al (2011) recently used ␣4 L9ЈA mice to map ␣4* nAChR expression within the VTA, reporting that ␣4* nAChRs coassemble with ␣6 subunits preferentially in posterior VTA. As a follow-up, Liu et al (2012) demonstrated that a population of ␣4* nAChRs in VTA DA neurons may be resistant to desensitization by nicotine. These nAChRs probably contain both ␣4 and ␣6 nAChR subunits (Fig.…”

Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats

“…In the mammalian brain, the heteromeric nAChRs consist of a2-6 and b2-4 subunits and the homomeric nAChRs consist of a7 subunits (Dani and Bertrand, 2007;Leslie et al, 2013). Nicotine mediates its rewarding effects at least partly by activating a4/a6/b2*, a3b4*, and a7 nAChRs (Liu et al, 2012;Picciotto and Kenny, 2013;Jackson et al, 2013;Toll et al, 2012;Markou and Paterson, 2001). Cessation of nicotine administration leads to negative affective (dysphoric-and anxiety-like behavior) and somatic withdrawal signs (Epping-Jordan et al, 1998).…”