Attenuation of Compulsive-Like Behavior Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Non-Induced Compulsive-Like Mice

Abstract

Nicotinic α4β2 receptors are the most abundant subtypes of nicotinic acetylcholine receptors (nAChRs) expressed in brain regions implicated in obsessive compulsive disorder (OCD). These receptors are known to modify normal and addictive behaviors by modulating neuronal excitability. Desformylflustrabromine (dFBr) is a novel, positive allosteric modulator (PAM) of high acetylcholine sensitivity (HS) and low acetylcholine sensitivity (LS) α4β2 nAChRs. The present study tested the hypothesis that positive allosteric modulation of α4β2 receptors by dFBr will attenuate compulsive-like behavior in a non-induced compulsive-like mouse model. Male mice (Mus musculus) selected for compulsive-like nesting behavior (NB; 48 animals; 12 per group) received acute (once) and chronic (every day for 32 days) subcutaneous injection of dFBr at 2, 4 and 6 mg/kg doses. Saline was used as a control (0 mg/kg). Compulsive-like NB was assessed after 1, 2, 3, 4, 5 and 24 h, while compulsive-like marble burying (MB) and anxiety-like open field (OF) behaviors were performed 2 h after dFBr administration. In the acute administration protocol, dFBr dose dependently attenuated NB and MB. Rapid effects (1-2 h after drug administration) of dFBr on MB and NB were observed for the chronic administration which was in congruence with the acute study. Chronic administration also revealed sustained suppression of NB by dFBr following 5 weeks of treatment. In both the acute and chronic regimen dFBr did not modulate OF behaviors. This research demonstrates the novel role of positive allosteric modulation of α4β2 nicotinic receptors by dFBr as a translational potential for OCD.

Keywords: desformylflustrabromine (dFBr); non-induced compulsive-like mice; obsessive compulsive disorder; positive allosteric modulator; α4β2 nicotinic receptors.

Figure 1

Schedules for behavioral assessments following Desformylflustrabromine (dFBr) administration. Top panel-Acute Study: mice in all experimental groups (0, 2, 4 and 6 mg/kg) received subcutaneous administration of vehicle or dFBr on days 1, 3 and 5. On day 1, immediately after injections all mice were subjected to nest-building and data were collected 1, 2, 3, 4, 5 and 24 h after injection (nest building testing schedule). On day 3 and 5 all mice were subjected to marble burying (MB) and open field (OF) behaviors, respectively, 2 h after vehicle or dFBr injections. On days 2 and 4 mice were not given injections and were not tested. Lower panel-Chronic study: for the chronic study mice from all groups (0, 2, 4 and 6 mg/kg) received daily single subcutaneous injections of vehicle or dFBr for 32 days. On day 30, immediately after injection all mice were subjected to nest-building and data were collected after 1, 2, 3, 4, 5 and 24 h after injection (nest building testing schedule). On day 31 and 32 all mice were subjected to MB and OF behaviors, respectively, 2 h after vehicle or dFBr injections.

Figure 2

Dose-dependent effect of dFBr on compulsive-like NB behavior in compulsive-like BIG mice (n = 12 in each group) from 1–5 h of (A) acute and (B) chronic dFBr administration. Data are expressed as the mean ± standard error of the mean (SEM) for the amount of cotton used in grams. Statistical significance is considered as *p < 0.05, **p < 0.01 ***p < 0.001. All comparisons are with respect to control (saline).

Figure 3

Dose-dependent effects of dFBr on overall compulsive-like NB behavior in compulsive-like BIG mice (n = 12 in each group) 0–24 h after (A) acute and (B) chronic dFBr administration. Data are expressed as the mean ± SEM for the amount of cotton used in grams. Statistical significance is considered as *p < 0.05 and ***p < 0.001. All comparisons are with respect to control (saline).

Figure 4

Dose-dependent effect of dFBr on compulsive-like MB behavior in compulsive-like BIG mice (n = 12 in each group) 2 h after (A) acute and (B) chronic dFBr administration. Data are expressed as the mean ± SEM for the number of marbles that are 2/3 buried. Statistical significance is considered as **p < 0.01 and ***p < 0.001. All comparisons are with respect to control (saline).

Figure 5

Effect of dFBr on OF locomotory activity in (A) acute administration and (B) chronic administration. Anxiety-like time in center in OF in (C) acute administration and (D) chronic administration in compulsive-like BIG mice (n = 12 in each group). Data are expressed as the mean ± SEM for the total distance traveled in the OF. No statistical significance was found.