Rodent models of anxiety and compulsion: When multiple endpoints add value

Abstract

Anxiety disorders are the most diagnosed mental illnesses and exist independently or as comorbidity with conditions such as autism spectrum disorder, major depressive disorder, and/or substance use disorder. The acute treatment of moderate to severe anxiety includes medications, such as benzodiazepines, whereas for long-term treatment and compulsive disorders, selective serotonin reuptake inhibitors (SSRIs) are often prescribed. The objective of this investigation was to demonstrate the advantages of conducting a battery of behavioral tests to characterize the anxiolytic, anxiogenic, and/or anti-compulsive properties of drugs. Animal anxiety models are based on the natural tendency of rodents to avoid a potentially dangerous situation (e.g., open, brightly lit, or novel environments). Animal models of compulsive-like behavior are based on natural, repetitive behaviors exhibited by rodents (e.g., digging). Within this investigation, assessments were conducted using the elevated plus maze (EPM), staircase, light/dark box, Nestlet shredding, and marble burying tests in male C57BL/6 J mice. Investigations were conducted following intraperitoneal administration of 10 mg/kg paroxetine, fluoxetine, or atropine; 6 mg/kg diazepam; 0.1 mg/kg WIN55,212–2; or 4 mg/kg yohimbine; these doses did not adversely affect locomotor activity. Results show how, by evaluating multiple endpoints, results can be interpreted in terms of compulsion, anxiety, and in some instances, impulsivity with a greater degree of confidence. For example, atropine decreased marble burying by 63 %, Nestlet shredding by 94 %, and time in the light zone by 63 % compared with controls, demonstrating that effects on marble burying and Nestlet shredding were not due to anti-compulsive effects or anxiolysis. These preliminary investigations support the requirement for conducting testing for multiple endpoints when characterizing the potential anxiety or compulsive effect of a novel drug. Multiple endpoints can be considered within the same animals and may be considered for inclusion within toxicology studies.