Trait specific modulatory effects of caffeine exposure on compulsive-like behaviors in a spontaneous mouse model of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by recurring intrusive thoughts and repetitive compulsive behaviors, ultimately interfering with their quality of life. The complex heterogeneity of symptom dimensions across OCD patient subgroups impedes diagnosis and treatment. The core and comorbid symptomologies of OCD are thought to be modulated by common environmental exposures such as consumption of the psychostimulant caffeine. The effect of caffeine on the expression of obsessions and compulsions are unexplored. The current study utilized mouse strains (HA) with a spontaneous, predictable, and stable compulsive-like phenotype that have face, predictive, and construct validity for OCD. We demonstrate that an acute high dose (25 mg/kg) of caffeine decreased compulsive-like nest-building behavior in the HA strains in the first hour after injection. However, nest-building scores increased in hours 3, 4, and 5 after administration finally decreasing over a 24 h period. In contrast, a high dose of chronic caffeine (25 mg/kg/d) increased nest-building behavior. Interestingly for compulsive-like digging behavior, acute exposure to a high dose of caffeine decreased the number of marbles buried, while chronic exposure had little effect. An acute high dose of caffeine decreased anxiety-like and motor activity in open field behaviors whereas chronic caffeine administration did not have any overall effect on open field activity. The results, therefore, suggest a complex role of caffeine on compulsive-like, anxiety-like, and locomotor behaviors that is dependent on the duration of exposure.

Postpartum Lactation-Mediated Behavioral Outcomes and Drug Responses in a Spontaneous Mouse Model of Obsessive-Compulsive Disorder.

Using a spontaneous mouse model of obsessive-compulsive disorder (OCD), the current study evaluated the influence of postpartum lactation on the expression of compulsive-like behaviors, SSRI effectiveness, and the putative role of oxytocin and dopamine in mediating these lactation specific behavioral outcomes. Compulsive-like lactating mice were less compulsive-like in nest building and marble burying and showed enhanced responsiveness to fluoxetine (50 mg/kg) in comparison to compulsive-like nonlactating and nulliparous females. Lactating mice exhibited more anxiety-like behavior in the open field test compared to the nulliparous females, while chronic fluoxetine reduced anxiety-like behaviors. Blocking the oxytocin receptor with L368-899 (5 mg/kg) in the lactating mice exacerbated the compulsive-like and depression-like behaviors. The dopamine D2 receptor (D2R) agonist bromocriptine (10 mg/kg) suppressed marble burying, nest building, and central entries in the open field, but because it also suppressed overall locomotion in the open field, activation of the D2R receptor may have inhibited overall activity nonspecifically. Lactation- and fluoxetine-mediated behavioral outcomes in compulsive-like mice, therefore, appear to be partly regulated by oxytocinergic mechanisms. Serotonin immunoreactivity and serum levels were higher in lactating compulsive-like mice compared to nonlactating and nulliparous compulsive-like females. Together, these results suggest behavioral modulation, serotonergic alterations, and changes in SSRI effectiveness during lactation in compulsive-like mice. This warrants further investigation of postpartum events in OCD patients.

Attenuation of Compulsive-Like Behavior Through Positive Allosteric Modulation of α4ß2 Nicotinic Acetylcholine Receptors in Non-Induced Compulsive-Like Mice.

Nicotinic α4ß2 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) α4ß2 nAChRs. The present study tested the hypothesis that positive allosteric modulation of α4ß2 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 α4ß2 nicotinic receptors by dFBr as a translational potential for OCD.