α6-Containing Nicotinic Acetylcholine Receptors Dominate the Nicotine Control of Dopamine Neurotransmission in Nucleus Accumbens

Abstract

Modulation of striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Nicotine, by desensitizing b2 subunit-containing (b2*) nicotinic acetylcholine receptors (nAChRs) on striatal DA axons, significantly enhances how DA is released by reward-related burst activity compared to nonreward-related tonic activity. This action provides a synaptic mechanism for nicotine to facilitate the DA-dependent reinforcement. The subfamily of b2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of a6b2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real-time using fast-scan cyclic voltammetry at carbon-fiber microelectrodes in mouse striatal slices. The a6-specific antagonist a-conotoxin-MII suppressed DA release evoked by single and low-frequency action potentials and concurrently enhanced release by high-frequency bursts in a manner similar to the b2*-selective antagonist dihydro-b-erythroidine (DHbE) in NAc, but less so in CPu. The greater role for a6*-nAChRs in NAc was not due to any confounding regional difference in ACh tone since elevated ACh levels (after the acetylcholinesterase inhibitor ambenonium) had similar outcomes in NAc and CPu. Rather, there appear to be underlying differences in nAChR subtype function in NAc and CPu. In summary, we reveal that a6b2*-nAChRs dominate the effects of nicotine on DA release in NAc, whereas in CPu their role is minor alongside other b2*-nAChRs (eg a4*), These data offer new insights to suggest striatal a6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation

“…Nicotinic acetylcholine receptors can facilitate low probability dopamine release, but suppress dopamine release from high-frequency stimulation (mimicking burst firing) (Exley and Cragg, 2008b;Sulzer et al, 2016;Threlfell and Cragg, 2011). Indeed, although disrupting nAChR signaling can suppress the tonic dopamine measured by microdialysis (Lim et al, 2014), the higher resolution afforded by FSCV shows that it can actually augment high-frequency phasic release under some conditions (Exley et al, 2008a;Rice and Cragg, 2004), an effect we demonstrate here in awakebehaving animals with dopamine activity generated by unexpected reward or reward cue presentation. Interestingly, nAChR agonists can also augment high-frequency phasic dopamine release ex vivo (Rice and Cragg, 2004;Zhang and Sulzer, 2004), but they do so through rapidly desensitizing the nAChRs, mimicking an antagonist-like effect (Lim et al, 2014;Zhang and Sulzer, 2004).…”

“…Data from ex vivo studies, demonstrating that cholinergic receptor activity can modulate dopamine signaling via direct action at dopamine terminals (Exley et al, 2008a;Exley and Cragg, 2008b;Threlfell et al, 2012), provide a parsimonious mechanism for the results here. Activating presynaptic nAChRs on dopamine terminals with endogenous acetylcholine can trigger dopamine release (Cachope et al, 2012;Threlfell et al, 2012), but ex vivo studies have demonstrated that this modulation depends on the activity level of dopamine cells (Zhang and Sulzer, 2004;Zhang et al, 2009).…”

“…Tonically-active, cholinergic interneurons provide the primary source of acetylcholine acting at these receptors (Bolam et al, 1984). Nicotinic acetylcholine receptors (nAChR) on striatal dopamine terminals (Jones et al, 2001) are known to be particularly relevant to the regulation of striatal dopamine signaling (Cachope et al, 2012;Exley et al, 2008a;Threlfell et al, 2012). Muscarinic acetylcholine receptor (mAChR) activity also contributes to dopamine modulation both via regulation of endogenous activity at nAChRs on dopamine terminals (Threlfell et al, 2010) and through activation of mAChRs on dopamine terminals (Foster et al, 2014;Shin et al, 2015).…”

Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions

“…186,187 It is possible that some regulatory variants within the CHRNA6-CHRNB3 gene cluster are associated with upregulation and others with downregulation of the subunits.…”

Elucidation of Molecular Impediments in the α6 Subunit for in Vitro Expression of Functional α6β4* Nicotinic Acetylcholine Receptors

“…Extensive investigations have identified the ␣6␤2␤3 and ␣6␣4␤2␤3 subtypes localized on dopaminergic neurons in the substantia nigra and ventral tegmental area as key modulators of dopamine release in striatum and nucleus accumbens (7)(8)(9)(10)(11)(12)(13)(14)(15)(16), making the receptors interesting in connection with Parkinson disease and nicotine addiction (4,6,17). Although not having been subjected to the same meticulous exploration as ␣6␤2* receptors, ␣6␤4* nAChRs have recently been reported to regulate norepinephrine release in mouse hippocampus (18), to play a major role for exocytosis in human adrenal gland chro-* This work was supported by the Lundbeck Foundation, The Aase and Ejner maffin cells (19), and to be expressed in rat dorsal root ganglia (20).…”