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

Abstract

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.

Bidirectional Behavioral Selection in Mice: A Novel Pre-clinical Approach to Examining Compulsivity

“…Excessive nest-building and marble burying in the compulsivelike HA mouse strains can also form disparate compulsive-like traits (145) that can be utilized to better understand disparate compulsive traits in patient subgroups. Moreover, the degree of nest-building in the HA strains always exhibits consistent and positive correlation with marble burying providing a basis for comparison of behavioral traits through sex, treatment and physiological differences (140)(141)(142)(143)(144)(145)279).…”

“…It is interesting to note that such burying attributes often correlate to anxiety-like and not compulsive-like responses. On the contrary, compulsive burying in the HA strains comprise of aggravated and stereotypic digging of the marbles averaging 18-20 marbles (140)(141)(142)(143)(144)(145)279). Upon completion of digging, mice often appear agitated with rapid locomotor movements and perform frenzy investigation of the apparatus.…”

“…The presence of non-compulsive-like LA and control strains further strengthens the phenotypic rigor in terms of establishing a behavioral gradient across strains to better understand the behavioral anomaly expressed as a function of genetic selection and variation. Further, nest-building and marble burying behaviors are malleable to genetic (181,182), pharmacological (140,142,145,279) and environmental (181,182) manipulations serving as important tools for dissecting neural substrates mediating functional outcomes. Nest-building behavior draws a parallel with hoarding in human patients as reported earlier, while marble burying can recapitulate failure of task completion that falls in the realm of compulsive checking as seen in many OCD patient subsets (241).…”

“…In fact, OCD patients with comorbid bipolar disorders become easily addicted to caffeine indicating possible interactions between caffeine and OCD traits (342)(343)(344)(345). Acute exposure to a high dose of caffeine reduces both nestbuilding and marble burying behavior in the compulsive-like HA strains (279). On the contrary, a chronic exposure of a high dose of caffeine increases nest-building behavior without influencing marble burying indicating trait and drug response heterogeneity (279).…”

“…Acute exposure to a high dose of caffeine reduces both nest-building and marble burying behavior in the compulsive-like HA strains ( 279 ). On the contrary, a chronic exposure of a high dose of caffeine increases nest-building behavior without influencing marble burying indicating trait and drug response heterogeneity ( 279 ).…”