Search

Investigating the motivational triggers underlying naturalistic compulsive-like behavior is generally regarded as challenging. To this extent, the current study aimed to establish a proof-of-concept for future investigation by probing unconditioned and naturalistic operant responses aimed at obtaining nesting material by normal (NNB) and large (LNB) nest building deer mice (Peromyscus maniculatus bairdii). LNB mice and NNB controls were individually placed in cages equipped with a lever-operated nesting material (cotton rope) dispenser and allowed to become accustomed to the response (lever press)-outcome (obtaining cotton rope) contingency over seven nights. Subsequently, the contingency was manipulated by withdrawing the nesting material (experiment 1) or punishing the lever-press response with a mild electrical foot shock (experiment 2). Mice were then treated for 28 days with escitalopram (50 mg/kg/d) and retested. Our results indicate that (1) LNB mice generally made more operant responses compared to NNB controls, (2) withdrawal of nesting material and institution of punishment bolstered responding in LNB but not NNB mice and (3) escitalopram treatment tended to reduce increased responding in LNB mice following experimental manipulation, while normalizing the total number of lever-press counts in the LNB cohort. Therefore, LNB seems to diverge from NNB, not only as a spontaneous phenotype, but also in terms of the motivation to obtain nesting material, despite demotivating feedback. That such differences were abrogated by chronic escitalopram intervention, indicates that the uniquely motivated operant interactions displayed by LNB mice, may be founded upon serotonergic mechanisms, a finding in line with the neurobiological theory of obsessive-compulsive disorder.

This study aimed to further dissect the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavior with respect to two persistent-like behavioral phenotypes viz. large nest building (LNB) and high marble-burying (HMB), which may be relevant to understanding the neurobiology of different symptom dimensions in obsessive-compulsive and related disorders. Since LNB is sensitive to chronic, high dose escitalopram intervention but HMB is not, we assessed whether the two behaviors could be further distinguished based on their response to 4 weeks of uninterrupted serotoninergic intervention (i.e. escitalopram; ESC; 50 mg/kg/day), dopaminergic antagonism, i.e. flupentixol; FLU; 0.9 mg/kg/day), dopaminergic potentiation (i.e. rasagiline; RAS; 5 mg/kg/day), and their respective combinations with escitalopram (ESC/FLU and ESC/RAS). Here we show LNB to be equally responsive to chronic ESC and ESC/FLU. HMB was insensitive to either of these interventions but was responsive to ESC/RAS. Additionally, we report that scoring preoccupied interaction with marbles over several trials is an appropriate measure of compulsive-like behavioral persistence in addition to the standard marble burying test. Taken together, these data provide further evidence that LNB and HMB in deer mice have distinctive neurobiological underpinnings. Thus, the naturally occurring compulsive-like behaviors expressed by deer mice may be useful in providing a platform to test unique treatment targets for different symptom dimensions of OCD and related disorders.

Cognitive flexibility, shown to be impaired in patients presenting with compulsions, is dependent on balanced dopaminergic and serotonergic interaction. Towards the development of a zebrafish (Danio rerio) screening test for anti-compulsive drug action, we manipulated social reward appraisal under different contexts by means of dopaminergic (apomorphine) and serotonergic (escitalopram) intervention. Seven groups of zebrafish (n = 6 per group) were exposed for 24 days (1 h per day) to either control (normal tank water), apomorphine (50 or 100 μg/L), escitalopram (500 or 1000 μg/L) or a combination (A100/E500 or A100/E1000 μg/L). Contextual reward appraisal was assessed over three phases i.e. Phase 1 (contingency association), Phase 2 (dissociative testing), and Phase 3 (re-associative testing). We demonstrate that 1) sight of social conspecifics is an inadequate motivational reinforcer under circumstances of motivational conflict, 2) dopaminergic and serotonergic intervention lessens the importance of an aversive stimulus, increasing the motivational valence of social reward, 3) while serotoninergic intervention maintains reward directed behavior, high-dose dopaminergic intervention bolsters cue-directed responses and 4) high-dose escitalopram reversed apomorphine-induced behavioral inflexibility. The results reported here are supportive of current dopamine-serotonin opponency theories and confirm the zebrafish as a potentially useful species in which to investigate compulsive-like behaviors.

Rodent marble-burying behavior in the marble-burying test (MBT) is employed as a model or measure to study anxiety- and compulsive-like behaviors or anxiolytic and anticompulsive drug action. However, the test responds variably to a range of pharmacological interventions, and little consensus exists regarding specific methodologies for its execution. Regardless, the test is widely applied to investigate the effects of pharmacological, genetic, and behavioral manipulations on purported behaviors related to the said neuropsychiatric constructs. Therefore, in the present review we attempt to expound the collective translational significance of the MBT. We do this by (1) reviewing burying behavior as a natural behavioral phenotype, (2) highlighting key aspects of anxiety and obsessive-compulsive disorder from a translational perspective, (3) reviewing the history and proof of concept of the MBT, (4) critically appraising potential methodological confounds in execution of the MBT, and (5) dissecting responses of the MBT to various pharmacological interventions. We conclude by underlining that the collective translational value of the MBT will be strengthened by contextually valid experimental designs and objective reporting of data.