title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Alaska FairbanksFairbanks, AK, USA; IDeA Network of Biomedical Research Excellence (INBRE), University of Alaska FairbanksFairbanks, AK, USA.
authors.forename: Swarup
authors.initials: S
authors.lastname: Mitra
authors.affiliation: Department of Chemistry and Biochemistry, University of Alaska Fairbanks Fairbanks, AK, USA.
authors.forename: Mckenzie
authors.initials: M
authors.lastname: Mucha
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences Philadelphia, PA, USA.
authors.forename: Shailesh N
authors.initials: SN
authors.lastname: Khatri
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University Richmond, VA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Glenon
authors.affiliation: Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences Philadelphia, PA, USA.
authors.forename: Marvin K
authors.initials: MK
authors.lastname: Schulte
authors.affiliation: Department of Biology and Wildlife, University of Alaska Fairbanks Fairbanks, AK, USA.
authors.forename: Abel
authors.initials: A
authors.lastname: Bult-Ito
keywords: desformylflustrabromine (dFBr); non-induced compulsive-like mice; obsessive compulsive disorder; positive allosteric modulator; α4β2 nicotinic receptors