Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

Abstract

Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of β2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in the absence of the US, mice received doses of i.p. nicotine (0, 0.0032, 0.01, 0.032, 0.1 mg/kg) or a selective β2 subunit containing nAChR (β2*nAChR) antagonist dihydro-beta-erythroidine (0, 0.1, 0.3, 1.0, 3.0 mg/kg DHβE). There was a dose-dependent effect of nicotine revealing that only low doses (0.01, 0.032 mg/kg) increased CER suppression ratios (SR) in these mice. DHβE also dose-dependently increased SR at the 3 mg/kg dose. In ethological measures of fear−/anxiety-like behavior, these doses of nicotine and DHβE significantly reduced digging behavior in a marble burying task and 0.3 mg/kg DHβE promoted open-arm activity in the elevated plus maze. Doses of nicotine and DHβE that altered affective behavior had no effect on locomotor activity. Similar to previous reports with anxiolytic drugs, low dose nicotine and DHβE reversed SR in a CER assay, decreased digging in a marble burying assay and increased open arm activity in the elevated plus maze. This study provides evidence that inactivation of β2*nAChRs reduces fear-like and anxiety-like behavior in rodents and suggests that smokers may be motivated to smoke in part to desensitize their β2*nAChRs. These data further identify β2*nAChR antagonism as a potential therapeutic strategy for relief of negative affect and anxiety.

A positive relationship between harm avoidance and brain nicotinic acetylcholine receptor availability

“…While we are not aware of brain imaging studies linking HA with nAChR availability, a prior behavioral genetics study found links between single nucleotide polymorphisms within the nAChR α4 subunit gene (CHRNA4) and HA (Roe et al, 2009), providing additional evidence for the mediation of HA by the cholinergic system. Furthermore, the findings here are consistent with prior research which demonstrates that the cholinergic system is linked with potentiation of a broad range of adaptive behaviors to environmental stimuli (Picciotto et al, 2012), which includes nAChR mediation of fear-like responses (Davis and Gould, 2007; Anderson and Brunzell, 2012), and also includes influences on attention, food intake, and affect.…”

“…In one such study, inactivation of β2*-containing nAChRs with a specific receptor antagonist reduced fear-like and anxiety-like behavior in rodents (Anderson and Brunzell, 2012). Similarly, β2*-containing nAChRs have been shown to be critical for the nicotine-induced enhancement of contextual fear conditioning (Wehner et al, 2004; Davis et al, 2007) and to mediate the anxiety-like and affective components of nicotine withdrawal (Jackson et al, 2008).…”

Nicotinic Receptor Contributions to Smoking: Insights from Human Studies and Animal Models

“…The β2*nAChR antagonist, DHβE, and partial agonists varenicline, ABT-089 and sazetidine promote anxiolysis-like behavior in the EPM, marble burying and conditioned inhibition tasks [129–132]. Low dose nicotine mimics anxiolysis-like effects of DHβE, suggesting that desensitization of nAChRs by low doses of nicotine may decrease anxiety [130]. A study using mice lacking nAChR α4 subunits in the VTA showed that these mice failed to benefit from the anxiolytic-like effects of low dose nicotine, suggesting that α4β2*nAChRs in the VTA are required for nicotine-induced anxiolysis in the EPM [91] (but see [133]).…”

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

“…In contrast, acute administration of varenicline at a range of doses (0.01, 0.1, or 1.0 mg/kg) did not ameliorate nicotine withdrawal behaviors in the NIH test (Figure 3b). To evaluate the effects of these drugs in another model of anxiety, we utilized the marble-burying test, which has been shown to be sensitive to both acute and chronic administration of nicotinic compounds in drug-naive animals (Anderson and Brunzell, 2012;Turner et al, 2010Turner et al, , 2011. In this task, we observe that treatment with sazetidine-A (0.1 mg/kg) as well as varenicline (1.0 mg/kg) significantly reduces the number of marbles buried in this task compared with animals undergoing 24 h WD (Figure 3c).…”