Role of α6 nicotinic receptors in CNS dopaminergic function: relevance to addiction and neurological disorders

Abstract

Although a relative newcomer to the nicotinic acetylcholine receptor (nAChR) family, substantial evidence suggests that α6 containing nAChRs play a key role in CNS function. This subtype is unique in its relatively restricted localization to the visual system and catecholaminergic pathways. These latter include the mesolimbic and nigrostriatal dopaminergic systems, which may account for the involvement of α6 containing nAChRs in the rewarding properties of nicotine and in movement. Here, we review the literature on the role of α6 containing nAChRs with a focus on the striatum and nucleus accumbens. This includes molecular, electrophysiological and behavioral studies in control and lesioned animal models, as well as in different genetic models. Converging evidence suggest that the major α6 containing nAChRs subtypes in the nigrostriatal and mesolimbic dopamine system are the α6β2β3 and α6α4β2β3 nAChR populations. They appear to have a dominant role in regulating dopamine release, with consequent effects on nAChR-modulated dopaminergic functions such as reinforcement and motor behavior. Altogether these data suggest that drugs directed to α6 containing nAChRs may be of benefit for the treatment of addiction and for neurological disorders with locomotor deficits such as Parkinson’s disease.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

“…These channels can exist in either homomeric or heteromeric form, with the a7 subunit composing the most common homomeric nAChR in the CNS, and pentameric mixtures of a (a2-a10) and b (b2-b4) subunits, with a4b2*-nAChRs as the most common heteromeric CNS receptor (Taylor et al, 2013a). Although nAChRs are of a wide variety in the VTA (Wooltorton et al, 2003), heteromeric a6*-nAChRs are highly expressed in the mesolimbic DA system (Champtiaux et al, 2003;Yang et al, 2009bYang et al, , 2011 and a6 is the primary a subunit that plays a prominent role in DA release (Quik et al, 2011), and they are predominantly expressed in catecholaminergic systems (Brunzell, 2012). a6*-nAChR subunits are functional in recombinant systems when paired with b subunits or hybrids of a subunits.…”

Expression of cloned α6* nicotinic acetylcholine receptors

“…It is the subtype controlling dopamine release that is most sensitive to activation by nicotine Kuryatov and Lindstrom, 2011). Loss of a6* AChRs is an early sign of dopaminergic neuron loss in Parkinson's disease (Gotti et al, 2006;Quik et al, 2011;Srinivasan et al, 2014). Both (a6b2)(a4b2)b3 and (a6b2) 2 b3 subtypes of AChRs are vulnerable to nigrostriatal damage in an animal model of Parkinson's disease .…”

Chronic Nicotine Exposure Attenuates Methamphetamine-Induced Dopaminergic Deficits

“…Previous studies have suggested that a4b2 and a6b2 subtypes of nicotinic acetylcholine receptors (nAChRs) contribute to the neuroprotective effects of the stimulant, although other nicotinic subunits also likely contribute (Ryan et al, 2001;Khwaja et al, 2007;Takeuchi et al, 2009;Quik et al, 2011). For example, a4b2 antagonist administration inhibits the protection afforded by nicotine in rotenonetreated mice (Takeuchi et al, 2009).…”