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. 2021 May;11(5):a039610. doi: 10.1101/cshperspect.a039610

Mechanisms of Nicotine Addiction

Marina R Picciotto 1, Paul J Kenny 2
PMCID: PMC8091956  PMID: 32341069

Abstract

Tobacco smoking results in more than five million deaths each year and accounts for ∼90% of all deaths from lung cancer.3 Nicotine, the major reinforcing component of tobacco smoke, acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are allosterically regulated, ligand-gated ion channels consisting of five membrane-spanning subunits. Twelve mammalian α subunits (α2–α10) and three β subunits (β2–β4) have been cloned. The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits (denoted as α4β2* nAChRs). The α4β2* nAChRs mediate many behaviors related to nicotine addiction and are the primary targets for currently approved smoking cessation agents. Considering the large number of nAChR subunits in the brain, it is likely that nAChRs containing subunits in addition to α4 and β2 also play a role in tobacco smoking. Indeed, genetic variation in the CHRNA5–CHRNA3–CHRNB4 gene cluster, encoding the α5, α3, and β4 nAChR subunits, respectively, has been shown to increase vulnerability to tobacco dependence and smoking-associated diseases including lung cancer. Moreover, mice, in which expression of α5 or β4 subunits has been genetically modified, have profoundly altered patterns of nicotine consumption. In addition to the reinforcing properties of nicotine, the effects of nicotine on appetite, attention, and mood are also thought to contribute to establishment and maintenance of the tobacco smoking habit. Here, we review recent insights into the behavioral actions of nicotine, and the nAChR subtypes involved, which likely contribute to the development of tobacco dependence in smokers.

NICOTINIC RECEPTOR SUBTYPES INVOLVED IN CONTROL OF THE MESOLIMBIC SYSTEM AND NICOTINE REINFORCEMENT

The mesolimbic dopamine (DA) system is a central mediator of drug reward and reinforcement (Koob 1992). Lesions of the ventral tegmental area (VTA) and its primary projection area, the nucleus accumbens (NAc), greatly attenuate nicotine self-administration and the psychostimulant properties of nicotine (its ability to increase locomotion [Clarke et al. 1988; Corrigall et al. 1992, 1994]). A great deal of progress has been made in identifying the nicotinic acetylcholine receptor (nAChR) subtypes expressed in both the dopaminergic and GABAergic neurons of the VTA and on neuronal terminals in the NAc (Klink et al. 2001; Zoli et al. 2002). DA neurons express heteromeric nAChRs containing the α4, α5, α6, β2, and β3 subunits in various combinations, with the predominant subtypes being α4/β2/α5 and α4/α6/β2/β3. The α6 subunit appears to be selectively expressed in DA neurons (Le Novere et al. 1996; Drenan et al. 2008b), although there may be some effect of α6-containing receptors on GABA transmission in the VTA (Yang et al. 2011). Gain-of-function studies of the α6 subunit, coupled with α4 subunit knockout show that the predominant receptor mediating DA release from VTA neurons are of the α4/α6/β2* subtype (Engle et al. 2013). In addition, α7 homomeric nAChRs are expressed in DA neurons (Klink et al. 2001), as well as on neuronal terminals on afferents to the VTA (Mansvelder et al. 2002; Wooltorton et al. 2003).

Electrophysiological studies have shown that nAChRs containing the β2 subunit are essential for the ability of nicotine to depolarize DA cell bodies in the VTA and to increase their firing rate (Picciotto et al. 1998; Zhou et al. 2001). Although the predominant inward currents due to nicotine in these neurons involve β2* nAChRs, nicotine can also modulate the presynaptic input to DA neurons from GABAergic and glutamatergic terminals impinging on them. In a slice preparation, nicotine can potentiate glutamate input to DA neurons through α7 nAChRs, resulting in long-term potentiation of those inputs (Mansvelder and McGehee 2000). In addition, nicotine can desensitize β2* nAChRs on GABAergic inputs to DA neurons, resulting in a shift from mixed excitation and inhibition of DA neurons by nicotine, to a more unmixed stimulation of nAChRs on presynaptic glutamatergic terminals (Mansvelder et al. 2002; Wooltorton et al. 2003).

Evidence from mouse genetic models with knockout or mutations of nAChR subunits suggests that the postsynaptic depolarization of DA neurons is essential for behaviors related to nicotine reward and reinforcement such as nicotine place preference and self-administration. Knockout of the β2 subunit abolishes nicotine-mediated DA release (Picciotto et al. 1998; Grady et al. 2001), nicotine-induced locomotor activation (King et al. 2004), nicotine self-administration (Picciotto et al. 1998; Maskos et al. 2005), and nicotine place preference (Walters et al. 2006; Brunzell et al. 2009; Mineur et al. 2009a). Similarly, knockout of the α4 subunit abolishes intracerebroventricular (i.c.v.) self-administration of nicotine, consistent with evidence that α4/β2* nAChRs are required for depolarization of DA neurons in the VTA (Exley et al. 2011; McGranahan et al. 2011). Conversely, knockin of a hypersensitive α4 subunit shifts the dose–response curve for nicotine-induced increases in DA neuron firing to the left, and results in nicotine place preference at very low doses of the drug (Tapper et al. 2004). Similarly, expression of a hypersensitive α6 subunit in a bacterial artificial chromosome (BAC) transgenic mouse line potentiates nicotine-induced burst firing in DA neurons, and potentiates nicotine place preference at low doses of nicotine (Drenan et al. 2008a, 2010).

A series of studies have provided further support for the involvement of α6* nAChRs in nicotine self-administration. Mice lacking the α6 subunit do not acquire nicotine self-administration (Pons et al. 2008). Similarly, conotoxins selective for α6/β2* nAChRs disrupt nicotine self-administration in the rat when infused into the VTA (Gotti et al. 2010) and following self-administration training, these conotoxins decrease the motivation to lever press for nicotine on a progressive ratio schedule (Brunzell et al. 2010). In contrast, in mice with constitutive knockout of the α6 subunit, intra-VTA self-administration of nicotine is not disrupted, whereas α4* nAChRs are necessary and sufficient for both intra-VTA self-administration, as well as nicotine-induced increases in firing of DA neurons (Exley et al. 2011; McGranahan et al. 2011). However, α4 and α6 subunits are both required for the ability of nicotine to gate DA transmission in the NAc, suggesting that nAChRs in NAc may be more important in motivation to self-administer nicotine (Brunzell et al. 2010; Exley et al. 2011) and that this may affect acquisition of self-administration behavior (Pons et al. 2008; Gotti et al. 2010), as well as nicotine-dependent locomotor activation (Gotti et al. 2010).

Despite its contribution to nicotine-dependent plasticity in the VTA, knockout of the α7 subunit in mice does not affect nicotine place preference (Walters et al. 2006) or acquisition of nicotine self-administration (Pons et al. 2008). However, antagonizing α7 type nAChRs in the NAc or anterior cingulate cortex in the rat increases the motivation to self-administer nicotine, whereas infusion of a selective α7 agonist decreases motivation, as measured using a progressive ratio schedule (Brunzell and McIntosh 2012). α7-type nAChRs may modulate, rather than mediate, nicotine reinforcement and therefore the effect of α7 knockout may be more subtle than knockout of β2* nAChRs.

An important role for nAChRs in the VTA in nicotine reinforcement has been shown using both molecular genetic and pharmacological techniques. Selective viral reexpression of β2* (Maskos et al. 2005; Pons et al. 2008) or α4* nAChRs in the VTA is sufficient to support both intra-VTA (Maskos et al. 2005) and systemic nicotine self-administration (Pons et al. 2008), identifying the nAChR subtypes necessary for nicotine reinforcement, as well as showing the importance of nAChRs within the VTA itself for this behavior. This is consistent with previous studies suggesting that nAChRs within the VTA are critical for nicotine reward, because local infusion of a nicotinic agonist into the VTA, but not the NAc, is sufficient for nicotine place preference in the rat (Museo and Wise 1994).

Thus, molecular genetic studies support the idea that α4/α6/β2* nAChRs on DA neurons in the VTA are essential for nicotine reinforcement. These experiments in mice are supported by pharmacological studies in rats, and provide a consistent molecular subtype and neuroanatomical locus for the rewarding and reinforcing effects of nicotine.

NICOTINIC RECEPTORS AND CIRCUITS INVOLVED IN AVERSION AND NICOTINE WITHDRAWAL: FOCUS ON THE HABENULA-INTERPEDUNCULAR PATHWAY

The habenula is a diencephalic structure located on the dorsomedial surface of the caudal thalamus that is segregated into medial (MHb) and lateral (LHb) domains (Lecourtier and Kelly 2007; Hikosaka 2010). The MHb and LHb are anatomically, chemically, and functionally distinct subnuclei, each with different complements of afferent and efferent connections. LHb receives afferent inputs from, and projects extensively to, midbrain and hindbrain sites. In particular, the LHb projects densely to the rostromedial tegmental nucleus (RMTg) (Jhou et al. 2009), and has a well-established inhibitory effect on the firing of midbrain DA neurons (Lecourtier and Kelly 2007; Matsumoto and Hikosaka 2009; Hikosaka 2010; Bromberg-Martin and Hikosaka 2011). LHb neurons are excited by omission of anticipated rewards or exposure to aversive stimuli (Lecourtier and Kelly 2007; Matsumoto and Hikosaka 2009; Hikosaka 2010; Bromberg-Martin and Hikosaka 2011). This has prompted considerable interest in the role for LHb neurons in encoding negative motivational states. Unlike LHb, the MHb projects almost exclusively to the interpeduncular nucleus (IPN) via the fasciculus retroflexus (Fr) (Lecourtier and Kelly 2007; Hikosaka 2010). MHb is comprised of neurons that produce the neurotransmitters acetylcholine (ACh) or substance P (Cuello et al. 1978; Eckenrode et al. 1987), and a small population that produce the cytokine interleukin-18 (IL-18) (Sugama et al. 2002). However, it is believed that most MHb neurons also produce and corelease glutamate, with this excitatory neurotransmitter considered the major functional transmitter at the MHb-IPN synapse (Mata et al. 1977; Vincent et al. 1980; Girod et al. 2000; Ren et al., 2011). The MHb contains some of the highest densities of nicotine-binding sites in brain (Mugnaini et al. 2002). In particular, the highest densities of α5, α3, and α4 nAChR subunits expression in brain are detected in MHb and/or IPN (De Biasi and Salas 2008). Indeed, approximately 90%–100% of MHb neurons express α3, α4, α5, β2, and β4 nAChR subunits (Sheffield et al. 2000), and it is hypothesized that ∼20% of functional nAChRs in rat MHb neurons that project to IPN contain α5 subunits (Grady et al. 2009). Electrophysiological studies have shown that, whereas α3 and β4 nAChR subunit levels are strong throughout the ventral MHb, α6, β2, β3, and α4 subunits are selectively found in some, but not all of these neurons (Shih et al. 2014).

The fact that the MHb-IPN pathway is enriched in α5, α3, and β4 nAChR subunits is of particular interest in the context of recent human genetics findings. It has been shown that allelic variation in the α5/α3/β4 nAChR subunit gene cluster located in chromosome region 15q25 significantly increases risk of tobacco addiction (Saccone et al. 2007; Berrettini et al. 2008; Lips et al. 2010). For example, a single-nucleotide polymorphism (SNP) in CHRNA5 (rs16969968), which is very common in those of European descent (minor allele frequency = 0.42), increases the risk of tobacco dependence by ∼30% in individuals carrying a single copy of the variant, and more than doubles the risk in those carrying two risk alleles (Bierut et al. 2008; Wang et al. 2009); this finding has been consistently replicated (Berrettini et al. 2008; Bierut et al. 2008; Grucza et al. 2008; Stevens et al. 2008). The rs16969968 risk variant is associated with heavy smoking (Berrettini et al. 2008; Bierut et al. 2008; Grucza et al. 2008; Stevens et al. 2008), early onset of smoking behavior (Weiss et al. 2008), and with a “pleasurable buzz” from tobacco (Sherva et al. 2008). In addition, the same genetic variability in CHRNA5 is also a major risk factor for lung cancer and chronic obstructive pulmonary disease (COPD) in smokers (Amos et al. 2008; Hung et al. 2008; Wang et al. 2010), likely reflecting higher levels of tobacco dependence in individuals carrying risk alleles and consequently greater exposure to carcinogens and toxins contained in tobacco smoke (Le Marchand et al. 2008; Thorgeirsson et al. 2008). In addition to the rs16969968 SNP in CHRNA5, there is also increased risk of tobacco dependence in individuals carrying the rs6495308, rs578776, or rs1051730 SNPs in CHRNA3 (Berrettini et al. 2008; Saccone et al. 2009), and rs1948 in CHRNB4 (Schlaepfer et al. 2008).

The above findings suggest that nAChRs containing α5, α3, and/or α4 nAChR subunits, densely expressed in the MHb-IPN pathway, regulate addiction-related actions of nicotine. Consistent with an important role for α5* nAChRs in regulating nicotine intake, it was recently shown that mice with null mutation in this subunit intravenously self-administered far more nicotine than their wild-type littermates (Fowler et al. 2011). Interestingly, the knockout mice consumed more nicotine only when higher unit doses of the drug were available (Fowler et al. 2011). By using Fos immunoreactivity as a measure of neuronal activation, it was shown that the MHb-IPN pathway of the knockout mice was far less sensitive to nicotine-induced activation than wild-type mice (Fowler et al. 2011). Interestingly, chronic nicotine exposure increases action potential firing and nicotine sensitivity of MHb and IPN neurons (Arvin et al. 2019). Chemical inactivation of the MHb or the IPN using the local anesthetic lidocaine, or disruption of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic transmission in these sites using the competitive antagonist LY2358959, increased nicotine self-administration behavior in rats in a manner similar to the α5 nAChR subunit knockout mice (Fowler et al. 2011). Virus-mediated reexpression of the α5 nAChR subunit in the MHb-IPN pathway of knockout mice abolished the increased nicotine intake seen at higher doses of nicotine (Fowler et al. 2011). Conversely, RNA interference-mediated knockdown of α5 nAChR subunits in the MHb-IPN pathway in rats resulted in increased nicotine intake at higher unit doses of the drug, very similar to the same behavioral profile detected in the knockout mice (Fowler et al. 2011). Finally, knockdown of α5 nAChR subunits in the MHb-IPN pathway in rats decreased their sensitivity to the reward-inhibiting (i.e., aversive) actions of higher nicotine doses compared with control rats, as measured by nicotine-induced elevations of intracranial self-stimulation (ICSS) reward thresholds (Fowler et al. 2011). Taken together, these findings suggest that nicotine activates the MHb-IPN pathway through stimulatory effects on α5* nAChRs. Nicotine-induced activation of the MHb-IPN pathway results in a negative motivational signal that serves to limit further nicotine intake. Hence, disruption of α5* nAChR signaling diminishes the stimulatory effects of nicotine on MHb-IPN activity, and thereby permits consumption of greater quantities of nicotine.

In addition to α5* nAChRs, evidence suggests that β4* nAChRs in the MHb-IPN pathway also play an important role in regulating nicotine consumption. Specifically, overexpression of β4* nAChRs in mice using BAC transgenic technology resulted in greatly diminished sensitivity to the reinforcing properties of orally consumed nicotine solutions and far less consumption of the drug than wild-type mice (Frahm et al. 2011). This finding suggests that, similar to α5* nAChRs, β4* nAChRs in the MHb-IPN pathway also regulate sensitivity to the aversive effects of nicotine that control the quantities of the drug consumed.

Dependence on tobacco smoking depends not only on the balance between the rewarding and aversive action of nicotine described above, but also on escape from the aversive consequences of nicotine withdrawal (Doherty et al. 1995; Kenny and Markou 2001). Indeed, withdrawal duration and severity predict relapse in abstinent human smokers (Piasecki et al. 1998, 2000, 2003). The nicotine withdrawal syndrome in abstinent smokers is comprised of “physical” or somatic components, and “affective” components. The most common somatic symptoms include bradycardia, gastrointestinal discomfort, and increased appetite. Affective symptoms primarily include depressed mood including anhedonia, dysphoria, anxiety, irritability, difficulty concentrating, and craving (Parrott 1993; Doherty et al. 1995; Kenny and Markou 2001). Similar to α5 subunits, α2 subunits are highly enriched in the IPN (Grady et al. 2009). α5 and α2 subunit knockout mice that were dependent on nicotine (delivered through subcutaneously implanted osmotic minipumps) did not show somatic signs of nicotine withdrawal when withdrawal was precipitated with the nAChR antagonist mecamylamine (Salas et al. 2009). Moreover, direct infusion of mecamylamine into the IPN, but not the VTA, of nicotine-dependent wild-type mice precipitated the expression of somatic withdrawal signs (Salas et al. 2009). This suggests that α5* and α2* nAChRs in the MHb-IPN pathway, and perhaps other nAChR subtypes enriched in this pathway, regulate the expression of somatic signs of nicotine withdrawal. However, little is known concerning the role for nAChRs in the MHb-IPN tract in regulating affective aspects of nicotine withdrawal, and in particular withdrawal-associated reward deficits that may motivate relapse during periods of abstinence in human smokers.

The above findings support a key role for α5 and β4, and perhaps also α2 and α3 nAChRs, which are enriched in the MHb-IPN pathway in regulating nicotine reinforcement and the expression of the nicotine withdrawal syndrome in nicotine-dependent rodents. As such, nAChRs containing these subunits may be important targets for the development of novel therapeutics for smoking cessation.

In addition to the MHb-IPN pathway, α5, α3, and β4 nAChR subunits are densely expressed in the nucleus of the solitary tract (NTS) in the hindbrain. The role of the NTS in regulating nicotine intake was recently explored. It was shown that nicotine induces robust and dose-dependent increases in Fos immunoreactivity in NTS neurons, with this effect restricted almost neurons that express the neuropeptide glucagon-like peptide-1 (GLP-1) (Tuesta et al. 2017). Using a line of Chrna5-tdTomato reporter mice, GLP-1 neurons were shown to express α5 nAChR subunits (Tuesta et al. 2017), suggesting that the stimulatory effects of nicotine on GLP-1 neurons is mediated at least in part by α5* nAChRs. Systemic delivery of the GLP-1 receptor agonist exendin-4 (Ex4), or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin (to inhibit GLP-1 breakdown) decreased responding for nicotine infusions but not food rewards in mice (Tuesta et al. 2017). Chemogenetic activation of GLP-1 neurons in the NTS similarly decreased nicotine intake in mice (Tuesta et al. 2017). Conversely, nicotine but not food intake was increased in GLP-1 receptor knockout mice (Tuesta et al. 2017). Notably, some of the highest densities of GLP-1 receptor binding sites in the brain are detected in the IPN (Göke et al. 1995). This suggests that GLP-1 released from NTS neurons may regulate activity of the MHb-IPN pathway to control nicotine intake. Consistent with this possibility, GLP-1-immunoreactive fibers can be detected in the IPN of mice (Tuesta et al. 2017). Furthermore, when channelrhodopsin-2 is expressed in GLP-1 neurons in the NTS, optical stimulation of GLP-1 terminals increased the frequency but not the amplitude of postsynaptic currents (oEPSCs) in IPN neurons (Tuesta et al. 2017). The IPN receives massive cholinergic innervation from MHb (Ren et al. 2011), with MHb cholinergic neurons coreleasing glutamate and providing the major source of glutamatergic input to the IPN (Ren et al. 2011). The GLP-1 agonist Ex-4 enhanced EPSCs in IPN neurons optically evoked from the terminals of MHb cholinergic neurons. These findings suggest that GLP-1, released from NTS inputs to IPN, stimulates the terminals of MHb cholinergic neurons to enhance excitatory transmission onto IPN neurons to inhibit nicotine intake. Consistent with this hypothesis, RNA interference-mediated knockdown of GLP-1 receptor transcripts in MHb neurons increased nicotine intake in rats, particularly when higher unit doses were available (Tuesta et al. 2017). This effect is similar to the increased nicotine intake seen in rats after knockdown of Chrna5 transcripts in the MHb (Fowler et al. 2011). Infusion of the GLP-1 receptor antagonist exendin-(9-39)-amide (Ex-9) into the IPN similarly increased nicotine intake in rats (Tuesta et al. 2017). Conversely, infusion of Ex-4 into the IPN decreased nicotine intake in rats (Tuesta et al. 2017). Taken together, these findings suggest that nicotine stimulates GLP-1 neurons in NTS via a5* nAChRs, which in turn enhances the activity of the MHb-IPN pathway to inhibit nicotine intake.

GLP-1 receptors are Gs-coupled G-protein-coupled receptors that enhance the production of cAMP. In pancreatic β cells, GLP-1-stimulated increases in cAMP results in phosphorylation and nuclear translocation of β-catenin, which dimerizes with the transcription factor transcription factor 7-like 2 (TCF7L2). TCF7L2 is considered a core component of the GLP-1 signaling cascade (Yi et al. 2005; Liu and Habener 2008; Vazquez-Roque et al. 2011; Chiang et al. 2012; Shao et al. 2013). Notably, TCF7L2 is highly enriched in MHb neurons (Duncan et al. 2019). Using a line of Tcf7l2 mutant (Tcf7l2mut) rats in which the DNA-binding domain of TCF7L2 was deleted using zinc finger nucleases it was shown that nicotine self-administration behavior is markedly enhanced by TCF7L2 deficiency (Duncan et al. 2019). Inhibition of TCF7L2 activity in the MHb, accomplished in mice by CRISPR-Cas9 cleavage of Tcf7l2 DNA or in rats by local delivery of short interfering RNAs to knock down Tcf7l2 transcripts, dramatically increases nicotine intake (Duncan et al. 2019). As described above, nAChRs in the MHb play a critical role in regulating nicotine intake (Fowler et al. 2011). Using whole-cell recordings to assess pharmacologically isolated nAChR currents in MHb slices, it was shown that the amplitude of nicotine-evoked nAChR currents were similar in wild-type and TCF7L2-deficent rats (Duncan et al. 2019). However, unlike nAChRs in the MHb of wild-type rats, nAChRs failed to recover from nicotine-induced desensitization in TCF7L2-deficent rats (Duncan et al. 2019). Taken together, these observations suggest TCF7L2 acts downstream from GLP-1 receptor-mediated transmission to regulate the function of habenular nAChRs and thereby control nicotine intake.

NICOTINIC INVOLVEMENT IN BEHAVIORS RELATED TO ONGOING SMOKING: EFFECTS OF NICOTINE ON DEPRESSION, APPETITE, AND ATTENTION

Nicotine reinforcement and avoidance of the aversive effects of nicotine withdrawal are clearly fundamental for ongoing smoking, but a number of other factors are also likely to contribute to smoking behavior in humans. nAChRs are expressed throughout the brain on both excitatory and inhibitory neurons, with the ability to increase inhibition of circuits when excitation is high and to increase excitation when circuits are less active (Picciotto 2003). The result of this circuit-level integration is that nicotine can modulate behavioral function bidirectionally, acting as a stimulant and increasing anxiety under some conditions and decreasing activity and anxiety in others (Picciotto 2003).

Some individuals report that they smoke to improve attention (Rusted and Warburton 1992; Warburton et al. 1992), and the ability of smoking to improve attentional function in individuals with schizophrenia (George et al. 2002) is likely to contribute to their extremely high rates of smoking. Similarly, a large proportion of smokers report that they smoke to control symptoms of anxiety and depression (Picciotto et al. 2002), and the rate of smoking in individuals with affective disorders is more than double the rate in the general population (Kalman et al. 2005). The idea that some individuals smoke to self-medicate psychiatric symptoms is thought to underlie the high rate of smoking in individuals with psychiatric illness, and some estimates suggest that ∼44% of cigarettes are sold to individuals with a current psychiatric condition (Lasser et al. 2000).

Effects of nAChRs on Anxiety- and Depression-Like Behaviors

Studies in mouse genetic models have helped identify the nAChR subtypes involved in a number of behavioral effects of nicotine that may affect human smoking. Nicotine is known to have both anxiolytic and anxiogenic effects in rodents (File et al. 2000), and these effects are likely to depend on different nAChR subtypes. For example, chronic administration of nicotine increased anxiety-like behavior in female, but not male, mice (Caldarone et al. 2008), whereas knockout mice lacking the β4 subunit show less anxiety-like behaviors at baseline (Salas et al. 2003) and no difference in anxiety-like behaviors were seen at baseline or following nicotine administration in mice lacking the β2 subunit (Caldarone et al. 2008). Similarly, female, but not male, knockout mice lacking the α5 subunit showed reduced anxiety-like behavior, and this may be related to progesterone effects on α5 subunit expression (Gangitano et al. 2009). These data suggest that stimulation of α5β4* nAChRs is important for the anxiogenic effects of nicotine.

The effects of nicotine on depression-like behavior are also complex. Studies in the Flinders-sensitive line of rats have shown that acute nicotine administration is antidepressant-like in the forced swim test and that this effect can be blocked by the nicotinic antagonist mecamylamine, suggesting that activation of nAChRs decreases depression-like behavior in this model (Tizabi et al. 2000). In contrast, the nicotinic antagonist mecamylamine has antidepressant-like effects in mice (Caldarone et al. 2004; Rabenstein et al. 2006; Andreasen et al. 2009), and is effective as an add-on medication in depressed human subjects who are nonresponsive to a selective serotonin reuptake inhibitor (SSRI) (George et al. 2008). Similarly, nicotinic partial agonists, that would be expected to decrease activity of acetylcholine at endogenous nAChRs when cholinergic tone is high but increase activity of nAChRs when cholinergic tone is low, are effective in mouse models of antidepressant efficacy (Mineur et al. 2007, 2009b, 2011a; Rollema et al. 2009; Caldarone et al. 2011) and in human smokers (Philip et al. 2009). These data suggest that inhibition of nAChRs in some neuronal subtypes or brain areas and activation in others may contribute to an antidepressant-like effect of nicotinic drugs, so the cycles of nAChR activation and desensitization experienced by smokers may result in fluctuations in depressive symptoms throughout the day. Both the antagonist mecamylamine (Rabenstein et al. 2006) and the partial agonist sazetidine (Caldarone et al. 2011), as well as the classical antidepressant amitriptyline (Caldarone et al. 2004), are ineffective in mice lacking the β2 subunit and these knockout mice show decreased depression-like behavior at baseline, suggesting that β2* nAChRs are critical for the antidepressant-like effects of nicotinic drugs. However, mice lacking the α7 subunit are also resistant to the antidepressant-like effects of mecamylamine (Rabenstein et al. 2006), and the effects of the partial agonist sazetidine could be blocked with mecamylamine (Caldarone et al. 2011), suggesting that other nAChR subtypes may also contribute to the antidepressant-like effects of nicotinic drugs, and that activation as well as inhibition of nAChRs can show antidepressant-like effects.

Local knockdown studies have implicated different nAChR subtypes in stress-induced behaviors relevant to human anxiety and depression. Increasing acetylcholine signaling in the hippocampus via local knockdown of acetylcholine esterase (AChE) results in increased avoidance of anxiogenic environments, increased immobility in response to inescapable stress, and decreased threshold for social defeat (Mineur et al. 2013). This mirrors the increased depressive symptoms observed in human subjects administered an AChE antagonist (Risch et al. 1981) and supports the idea that the elevated ACh levels observed in human subjects who are actively depressed contributes to the disorder (Saricicek et al. 2012; Hannestad et al. 2013). Local knockdown of the α7 nAChR subunit in the hippocampus greatly attenuated the anxiogenic and social interaction phenotypes induced by AChE blockade (Mineur et al. 2018a), whereas 5HT1a serotonin receptors in hippocampus are required for antidepressant-like effects of nicotinic compounds (Mineur et al. 2015), suggesting that ACh–serotonin interactions can contribute to dysphoric effects of ACh signaling mediated through this structure.

Although up-regulation of ACh signaling induces anxiogenic and social interaction deficits via nAChRs in the hippocampus, nAChR subtypes regulate baseline activity of the basolateral amygdala (BLA), and decreasing their activity can induce resilience to stress, even in animals with no manipulation of ACh activity. Infusion of the broad nAChR antagonist mecamylamine into the BLA decreases stress-induced immobility, and similarly, knockdown of either α7 or β2 nAChR subunits in BLA decreases cFos immunoreactivity in the structure and attenuates avoidance of anxiogenic stimuli, immobility in response to inescapable stress, and avoidance after social defeat (Mineur et al. 2016). Expression of β2* nAChRs in the BLA is necessary for the antidepressant-like effects of the noradrenergic agonist guanfacine, suggesting that ACh–norepinephrine interactions are important for regulation of BLA activity and associated stress-induced behaviors (Mineur et al. 2018b).

The observation that increased ACh signaling can lead to symptoms of depression and anxiety in human subjects and mouse models is at odds with the idea that nicotine can be rewarding in smokers and vapers, and that ACh signaling is most associated with increased attention and learning (see below). One possibility is that whereas optimal levels of ACh contribute to encoding of both rewarding and aversive stimuli, suprathreshold increases in ACh signaling, mediated by chronic stress or other stimuli that can lead to depression, favor encoding of aversive stimuli and lead to the type of negative encoding bias observed in human subjects with anxiety and depressive disorders (Mineur and Picciotto 2019).

Effects of nAChRs on Behaviors Related to Attention

In addition to effects on anxiety and depression, nicotine and nicotinic drugs can improve attention in control subjects (Rusted and Warburton 1992) and individuals with schizophrenia (Sacco et al. 2004). Interestingly, after control subjects quit smoking and transition past the acute withdrawal period, their working memory function improves compared with when they were smoking (George et al. 2002). In contrast, individuals with schizophrenia show impaired performance once they quit smoking (George et al. 2002). Genetic and functional studies have implicated α7 nAChRs in prepulse inhibition, a physiological marker associated with schizophrenia (Leonard et al. 2000; Freedman et al. 2003). Mice lacking the α7 subunit have been shown to have impaired trace eye-blink conditioning (Brown et al. 2010). These data suggest that optimal nAChR stimulation is achieved at baseline in control subjects or wild-type mice with normal α7 nAChR levels, whereas nicotine from tobacco smoke can further improve attention in individuals with schizophrenia.

Studies using knockout mice with lentiviral-mediated reexpression have shown that β2* nAChRs in the prelimbic medial prefrontal cortex (mPFC) are important for normal performance of the 5-choice serial reaction time task measuring visual attention. Similarly, rapid acetylcholine transients in the mPFC are correlated with attention to brief cues, and mice lacking the β2, but not the α7, subunit show impaired performance in an attentional task (Parikh et al. 2007, 2008). Studies in rodents have also implicated nAChRs on glutamatergic thalamocortical neurons impinging on layer 5 pyramidal neurons in the prefrontal cortex as an important site for nAChR control of attention (Lambe et al. 2005; Bailey et al. 2010). Overall, it appears that nAChRs in thalamo-cortico-thalamic loops are important for regulating glutamate release in this circuit, and for mediating the effects of acetylcholine on attentional function (Heath and Picciotto 2009).

In addition to effects of nicotine on attentional function in adulthood, many studies have shown a role for nAChRs in maturation of circuits important for attention during development (reviewed in Heath and Picciotto 2009). Mice administered nicotine during the adolescent period show deficits in the 5-choice serial reaction time task that are associated with decreased expression of mGluR2 receptors, and that are rescued by administration of mGluR2 agonists (Counotte et al. 2011). Similarly, α5/β2* nAChRs on layer 6 cortical glutamatergic projection neurons to the thalamus are essential in maturation of this circuit and for normal adult performance in passive avoidance, a somatosensory aversive learning task (King et al. 2003; Heath et al. 2010). Electrophysiological studies have shown that currents mediated through α5/β2* nAChRs are maximal in the early postnatal period (Kassam et al. 2008). Nicotine administration during this same period alters performance in the passive avoidance task in normal mice as well as in mice with expression of β2* nAChRs exclusively in corticothalamic neurons (Heath et al. 2010), suggesting that disrupting normal acetylcholine signaling through these nAChRs during a critical period has lasting effects on the function of the corticothalamic circuit in passive avoidance behavior. Interestingly, modulation of nicotinic function through the lynx1 protein is also important for regulating the critical period for activity-dependent visual system development (Morishita et al. 2010).

Effects of nAChRs on Food Intake

The anorexic effects of smoking have been well-documented in human subjects, and the principal reason cited by female teenagers for why they smoke is weight control (Voorhees et al. 2002). On average, smokers weigh ∼5 kg less than nonsmokers and have significantly lower body mass index than nonsmokers (Albanes et al. 1987). Similarly, nicotine decreases feeding in animal models (Grunberg et al. 1987), suggesting that the nicotine in tobacco is important for the effects of smoking on appetite. Whereas β2α4α6* nAChRs are critical for nicotine reward and reinforcement, β4* nAChRs on proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are necessary for the appetite-suppressing effects of nicotine (Mineur et al. 2011b). There are a number of nAChR subtypes expressed in the hypothalamus (Jo et al. 2002, 2005), and nicotine can stimulate the firing of both POMC neurons that signal satiety, and neuropeptide Y (NPY) neurons that stimulate food seeking (Parikh et al. 2007, 2008). Recent studies show that both POMC and NPY neurons express almost all nAChR subunits and that deletion of the β4 nAChR subunit from either subtype is sufficient to attenuate nicotinic-induced decreases in food intake (Calarco et al. 2018). Interestingly, in a slice preparation, the effects of nicotine on firing of POMC neurons persist longer than firing of NPY neurons (Parikh et al. 2007, 2008), showing that at the circuit level, stimulation of nAChRs shifts the balance toward neuronal patterns that signal satiety (Calarco and Picciotto 2020).

Although β4* nAChRs on POMC neurons can signal satiety, nAChRs in the mesolimbic DA system may be more important for the motivation to work for food. The DA system is important for the hedonic value of both drugs of abuse, like nicotine, and palatable foods (Kenny 2011). Food or sugar intake can increase acetylcholine release in the VTA (Hajnal et al. 1998; Rada et al. 2000), and withdrawal from binge eating increases acetylcholine release in the NAc (Avena et al. 2008). Interestingly, blocking α7 nicotinic AChRs in the VTA can decrease food seeking (Schilström et al. 1998). In contrast, previous nicotine exposure increases the motivation of mice to work for food, and this is caused by non-β2* nAChRs (Brunzell et al. 2006). Taken together, these data show that, in addition to its effects on satiety mediated through POMC neuron signaling, acetylcholine in the mesolimbic system is also likely to effect motivation to seek palatable foods and to modulate their hedonic value through distinct nAChR subtypes.

CONCLUSIONS

The high-affinity α4β2* nAChRs play a key role in the behavioral actions of nicotine that contribute to the development of tobacco dependence, including its effects on brain circuitries involved in reinforcement, mood, attention, and food consumption. Recent evidence has shed important light on other nAChR subunits that may also be incorporated into the α4β2* nAChRs that regulate these processes. For example, incorporation of α6 and β3 nAChR subunits in α4β2* nAChRs in the mesoaccumbens pathway gives rise to an nAChR subtype (α4α6β2β3*) that appears to play a particularly important role in nicotine reinforcement. In addition, nAChR subtypes containing α5, α3, and/or β4 nAChR subunits have been implicated in regulating the aversive properties of nicotine that control the quantities of the drug consumed and in the development of tobacco dependence. In addition, β4* nAChRs also play an important role in appetite regulation, particularly the inhibitory effects of nicotine on appetite that underlie the anorectic effects of tobacco smoke. A more refined understanding of the precise contribution of discrete nAChR subtypes to these addiction-relevant properties of nicotine may reveal important new targets for the development of novel therapeutics for tobacco dependence. Moreover, such novel therapeutics could also have usage for the treatment of mood and attention disorders and the control of body weight.

ACKNOWLEDGMENTS

The authors were supported by Grants DA14241, MH076881 (M.R.P.), and DA020686 (P.J.K.) from the National Institutes of Health.

3

This is an update to a previous article published in Cold Spring Harbor Perspectives in Medicine [Picciotto and Kenny (2013). Cold Spring Harb Perspect Med 3: a012112. doi:10.1101/cshperspect.a012112].

Editors: R. Christopher Pierce, Ellen M. Unterwald, and Paul J. Kenny

Additional Perspectives on Addiction available at www.perspectivesinmedicine.org

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