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.
Highlights
Human and animal studies indicate that nicotine exerts its psychoactive effects by binding to nicotinic acetylcholine receptors in the brain [1,2]. nAChRs comprised of the b2 subunit (b2*nAChRs; *denotes assembly with other subunits) have high binding affinity for nicotine and the endogenous neurotransmitter, acetylcholine (ACh) [3,4,5,6]. b2*nAChRs are enriched on neurons in limbic system brain areas that regulate both affect and reward [3,6,7,8,9,10,11,12,13,14,15,16] suggesting that these nAChR subtypes may serve a dual role in supporting reward-like behavior and relieving negative affect. nAChRs are ion channels that can be activated as well as desensitized by nicotine [17,18,19,20]
Administration of nicotine resulted in a dosedependent increase in suppression ratio (F4,9 = 3.101, p,0.05) for mice exposed to the 0.3 mA unconditioned stimulus (US)
Mice treated with these low doses of nicotine buried fewer marbles compared to when they were treated with saline in an ethological marble burying task, and previous studies show that low doses of nicotine decrease anxiety-like behavior as measured by increases in open arm activity in an elevated plus maze [27,51]
Summary
Human and animal studies indicate that nicotine exerts its psychoactive effects by binding to nicotinic acetylcholine receptors (nAChRs) in the brain [1,2]. nAChRs comprised of the b2 subunit (b2*nAChRs; *denotes assembly with other subunits) have high binding affinity for nicotine and the endogenous neurotransmitter, acetylcholine (ACh) [3,4,5,6]. b2*nAChRs are enriched on neurons in limbic system brain areas that regulate both affect and reward [3,6,7,8,9,10,11,12,13,14,15,16] suggesting that these nAChR subtypes may serve a dual role in supporting reward-like behavior and relieving negative affect. nAChRs are ion channels that can be activated as well as desensitized (inactivated) by nicotine [17,18,19,20]. A preponderance of the evidence suggests that activation of b2*nAChRs supports nicotine conditioned place preference and nicotine self-administration, models of nicotine reward and reinforcement [21,22,23,24,25,26,27,28,29,30,31,32] (but see [33]) These studies used a conditioned emotional response (CER) assay, a marble burying task and an elevated plus maze experiment to test the hypothesis that inactivation of b2*nAChRs attenuates fear and anxiety-like behavior in mice. As a follow-up to experiments that evaluated affective-like phenotype, a locomotor activity assay using a beam-break apparatus confirmed that doses of nicotine and DHbE in these experiments did not affect locomotor activity
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