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.
Highlights
Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder (Pittenger et al, 2005)
Some studies have indicated exacerbation of obsessive compulsive disorder (OCD) symptoms induced by nicotine (Abramovitch et al, 2015)
It has been suggested that nicotinic activation of an already hyperactivated fronto-striatal circuit worsens OCD symptoms (Abramovitch et al, 2015)
Summary
Obsessive-compulsive disorder (OCD) is the fourth most common mental disorder (Pittenger et al, 2005). It has a lifetime prevalence of 2.3% and a 12-month prevalence of 1.2% (Ruscio et al, 2010). Patients suffering from OCD suffer from persistent obsessive thoughts causing distress, and perform compulsive repetitive behaviors to alleviate uncomfortable feelings resulting. Recently declassified as an anxiety disorder (American Psychiatric Association, 2015), many clinicians conceptualize OCD as a spectrum of related disorders (OCRD) sharing common clinical features of anxiety/fear and worry (Stein and Lochner, 2006; Storch et al, 2008; Fornaro et al, 2009). A large group of patients remain resistant to treatment either partially or completely (Jenike, 2004; Pittenger et al, 2005)
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