Nicotinic Acetylcholine Receptors in the Ventral Tegmental Area are Important Targets for Nicotine and Ethanol Co-dependence

Abstract

Tobacco and alcohol are the most commonly abused drugs. The nicotine (NIC) in tobacco and the ethanol (EtOH) in alcoholic drinks are responsible for their dependence respectively. The magnitude of tobacco smoking is drastically higher among alcoholics, suggesting a NIC-EtOH co-dependence. However, the mechanisms of NIC-EtOH interaction are not fully known, and the clarification of this action is clinically relevant. The majority of the NIC-EtOH interaction utilizes the ventral tegmental area (VTA) through both dopamine (DA) and non-DA systems. EtOH has been shown to bind directly to some nicotinic acetylcholine receptors (nAChRs) as, of course, does NIC. The non-selective/noncompetitive nAChR antagonist mecamylamine (MEC) has been shown to partially block the DA releasing action of EtOH in the nucleus accumbens (NAc), while both the α4β2 nAChR antagonist dihydro-β-erythroidine (DHβE) and the α7 nAChR antagonist methyllycaconitine (MLA) do not. However, the α6-containing nAChRs (α6*-nAChRs) are responsible for both NIC-induced effects on DA release in the NAc and EtOH-induced GABA release in the VTA, suggesting that the α6*-nAChRs likely play a significant role in NIC-EtOH interactions. In this review, we have summarized current studies that reveal how EtOH reward through VTA nAChRs and what nAChR subtypes play roles in mediation of EtOH's effects in mesolimbic circuits. The accumulating lines of evidence suggest that the nAChRs, especially α6*-nAChRs in the VTA are likely important targets for NIC-EtOH interactions and NIC-EtOH co-dependence.

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

“…However, our results would suggest that there are interneurons regulating DA release in the NAc. It is likely that nAChRs are present on the terminals of these interneurons that then modulate the release of DA from DAergic neurons (Yang et al, 2011;Taylor et al, 2013b). Under this model, activation of the nAChRs on the interneurons would decrease the level of evoked DA release recorded by FSCV.…”

“…However, once the a6 subunit is re-expressed via a lentiviral vector, the mice develop sustained short-term selfadministration behavior (Pons et al, 2008). The VTA has a6*-nAChRs on presynaptic GABA terminals but not on the somata of the DAergic neurons (Yang et al, 2009b;Taylor et al, 2013b). Thus, nicotine can modulate both DA and GABA terminal neurotransmitter release (Yin and French, 2000;Mansvelder et al, 2002), although the majority of endogenous cholinergic inputs into the VTA appear to contact GABA rather than DA neurons (Garzon et al, 1999;Fiorillo and Williams, 2000).…”

“…Often taken in concert (Miller and Gold, 1998), tobacco and alcohol are leading causes of preventable death in the United States (Danaei et al, 2009). Approximately 80% of alcoholics are also smokers (Hendrickson et al, 2013;Taylor et al, 2013b), and heavy smokers are 10 times more likely to be alcoholics (DiFranza and Guerrera, 1990). Although smoking rates in the general population have decreased in recent decades, the use of nicotine has remained high (∼70%-75%) in individuals who regularly use alcohol (Meyerhoff et al, 2006;Hendrickson et al, 2013).…”

“…It has recently been theorized that because of the high percentage of codependence with these drugs, both ethanol and nicotine may act on similar targets in the brain, specifically nicotinic acetylcholine receptors (nAChRs) on presynaptic GABAergic neurons or DAergic terminals (Hendrickson et al, 2013;Taylor et al, 2013b). Ethanol appears to activate DAergic neurons in the VTA through an interaction at nAChRs (Soderpalm et al, 2009).…”

Neuronal nicotinic acetylcholine receptors are important targets for alcohol reward and dependence

“…These lines of evidence suggest that the α6* and β3* nAChRs may modulate alcohol behaviors. Collectively, mounting lines of evidence suggest that various nAChR subtypes are involved in alcohol reward and dependence [33] . Although having very limited investigation, the α6* nAChRs in the VTA have attracted special attention [33] (Figure 1).…”