α6-Containing nicotinic acetylcholine receptors in midbrain dopamine neurons are poised to govern dopamine-mediated behaviors and synaptic plasticity

Abstract

Acetylcholine acts through nicotinic and muscarinic acetylcholine (ACh) receptors in ventral midbrain and striatal areas to influence dopamine (DA) transmission. This cholinergic control of DA transmission is important for processes such as attention and motivated behavior, and is manipulated by nicotine in tobacco products. Identifying and characterizing the key ACh receptors involved in cholinergic control of DA transmission could lead to small molecule therapeutics for treating disorders involving attention, addiction, Parkinson’s disease, and schizophrenia. α6-containing nicotinic acetylcholine receptors (nAChRs) are highly and specifically expressed in midbrain DA neurons, making them an attractive drug target. Here, we used genetic, pharmacological, behavioral, and biophysical approaches to study this nAChR subtype. For many experiments, we used mice expressing mutant α6 nAChRs (“α6L9S” mice) that increase the sensitivity of these receptors to agonists such as ACh and nicotine. Taking advantage of a simple behavioral phenotype exhibited by α6L9S mice, we compared the ability of full versus partial α6* nAChR agonists to activate α6* nAChRs in vivo. Using local infusions of both agonists and antagonists into brain, we demonstrate that neurons and nAChRs in the midbrain are sufficient to account for this behavioral response. To complement these behavioral studies, we studied the ability of in vivo α6* nAChR activation to support plasticity changes in midbrain DA neurons that are relevant to behavioral sensitization and addiction. By coupling local infusion of drugs and brain slice patch clamp electrophysiology, we show that activating α6* nAChRs in midbrain DA areas is sufficient to enhance glutamatergic transmission in VTA DA neurons. Together, these results from in vivo studies strongly suggest that α6* nAChRs expressed by VTA DA neurons are positioned to strongly influence both DA-mediated behaviors and the induction of synaptic plasticity by nicotine.

Neural circuits and nicotinic acetylcholine receptors mediate the cholinergic regulation of midbrain dopaminergic neurons and nicotine dependence

“…Thus, α3, α5, α6, and β4 subunits are selectively expressed in SNc DA neurons, while α4, α7, β2, and β3 subunits consist of major nAChR subtypes in both DA and non-DA neurons [40]. The selective expression of α3, α5, α6, and β3 subunits in midbrain DA neurons has also been supported by many other studies [41][42][43][44][45].…”

“…α4 and α6 nAChRs In the VTA, the α6 subunit is selectively expressed in DA neurons [41][42][43][44][45]. Exley et al [96] demonstrated that the α4 and α6 subunits play different roles in the reinforcing effect of nicotine.…”

Modulation of ethanol reward sensitivity by nicotinic acetylcholine receptors containing the α6 subunit

“…Of particular interest, nAChRs containing the α6 subunit (α6* nAChR; * denotes that the receptor complex contains additional, non-α6 subunits) are uniquely enriched in catecholinergic neurons, including midbrain DAergic neurons where they are positioned to influence neuronal activity through cholinergic innervation (Berry, Engle, McIntosh, & Drenan, 2015; Champtiaux et al, 2002, 2003; Drenan, Grady, et al, 2008). They also contribute to nicotine dependence-associated behavior, including reward (Gotti et al, 2010; Jackson, McIntosh, Brunzell, Sanjakdar, & Damaj, 2009).…”

Effects of Cyclization on Activity and Stability of α-Conotoxin TxIB

“…α6/α3β2β3 (α6β2*) nAChRs are highly expressed in the region of midbrain dopamine (DA) neurons in the central nervous system, which regulates the release of dopamine [6]. Several previous studies implied that α6β2* nAChRs were closely related to several neuropsychiatric disorders, such as Parkinson's disease and nicotine addiction [7][8][9].…”