Persistent behavioural phenotypes in the deer mouse and its response to serotonergic and dopaminergic intervention

MSc (Pharmacology), North-West University, Potchefstroom CampusObsessive compulsive disorder (OCD)1 is a debilitating psychiatric disorder that presents with intrusive thoughts (obsessions) and repetitive ritualistic behaviour (compulsions) as main symptoms. Selective reuptake inhibitors (SSRIs)2 is regarded as first line intervention for OCD patients; however, only 40 - 60% of patients respond favourably to treatment. Moreover second-line interventions, which include switching to another SSRI or augmenting SSRI therapy with a low-dose antipsychotic, also demonstrates suboptimal response. Recent psychological investigations have revealed different phenotypes of OCD, i.e. contamination/ washing; C/W)3 and safety/checking; S/C4, to be associated with unique dopaminergic constructs. Briefly, contrary to what was reported of individuals with S/C OCD, patients with C/W OCD seem to demonstrate more impulsive behaviour as well marked reductions in dopaminergic reward anticipation during tests of incentive-related action-outcome control. In this regard, adequate phasic striatal dopaminergic release prior and during presentation of a reward, is necessary for effective reward consolidation, while the opposite, i.e. inhibition of dopamine release, is needed to consolidate feedback learning from negative outcomes. However, irrespective of rewarding or punishing processing, simultaneous stimulation of the serotonergic pathways of the cortico-striatal-thalamic-cortical (CSTC)5 circuitry is also needed to code an adequate feedback memory. Therefore, that C/W and S/C OCD seem to present with different neurological responses during reward processing, may provide valuable insight into what may possibly be unique neurobiological processes underlying its respective phenotypic presentations. It follows that while most SSRI-refractory cases of OCD are treated with anti-dopaminergic interventions, it should be considered that some individuals with treatment-refractory OCD may indeed benefit from interventions aimed at restoring the deficits in dopaminergic signalling we mention here. This idea forms the foundation of the current study. Deer mice of both sexes that are housed in captivity naturally develop three forms of phenotypically heterogeneous but equally compulsive-like behaviours, i.e. high motor stereotypy, large nest building (LNB)6, and high marble burying behaviour (HMB)1. These traits generally develop in different subjects and are variably expressed across the deer mouse population. Of more importance for the present work is that high motor stereotypy and LNB is sensitive to chronic high dose SSRI intervention, while HMB remains refractory. As such, and taking into account that HMB is just as persistent and repetitive as LNB, we hypothesized that whereas LNB may be founded in a neurobiological construct closely related to the classic picture of hyposerotonergic, but overly normal dopaminergic functioning in OCD2, viz. potentially resembling S/C3 OCD, HMB may be a treatment resistant OC4 phenotype of which the underlying mechanisms should be further studied in terms of its dopaminergic construct. More specifically, we hypothesized that HMB, but not LNB will respond to a combination of a SSRI (escitalopram) and a dopaminergic potentiator, i.e. the monoamine oxidase type B inhibitor, rasagiline. In fact, this concept has not yet been studied in either preclinical or clinical investigations. As HMB is expressed in 11% of the deer mice only, a total number of 160 animals of both sexes (10 weeks of age at the onset of experimentation) first underwent screening for marble burying activity (3 x 30min trials over 3 consecutive days). Those individuals not identified as HMB were then further analysed for nesting building behaviour (7 consecutive days x 24h trials). Importantly, only animals presenting with HMB or LNB were selected for further treatment studies. The remainder of the subjects were either included in studies not related to this investigation, or euthanized. Treatment groups consisted of 1) water (control), 2) escitalopram (50 mg/kg/day), 3) rasagiline (5 mg/kg/day), or 4) a combination of escitalopram and rasagiline (n = 6 for all groups). All drugs were administered in the drinking water for 28 days. After treatment, the behavioural analyses were repeated as described above. Following statistical analyses of the data generated, our results revealed 1) that HMB and LNB respond uniquely to dopaminergic potentiation, where 2) marble-directed behaviour (MDB)5 as observed in the marble burying test is ameliorated by escitalopram and a combination of escitalopram and rasagiline, while only demonstrating modest response to rasagiline alone, and 3) LNB is sensitive to escitalopram alone only, while being exacerbated over time, irrespective of the administration of rasagiline alone or in combination with escitalopram. We also demonstrate the importance of appraising marble burying behaviour with marble-directed behaviour in mind, instead of focusing on the number of marbles buried, only. Our data seems therefore supportive of the hypothesis that LNB and HMB1 are founded in unique neurobiological constructs as described by the inherent dopaminergic dysfunction underlying such behaviour. That HMB, but not LNB responded to dopaminergic intervention, putatively indicate that an improvement in reward feedback processing is associated with an improvement in compulsive-like burying behaviour. Although HMB also responded to escitalopram monotherapy, this response was suboptimal in the absence of rasagiline. Taken together, the data presented in this dissertation provide a valuable and potentially important window on the neurobiological processes underlying symptom heterogeneous OCD. That HMB may be associated with deficits in reward related feedback, albeit being just as persistent and repetitive as SSRI-sensitive LNB, provides the necessary and much needed proof-of-concept to extend this work in clinical samples. Indeed, while OCD2 may be appraised and diagnosed as a single condition, its treatment will possibly require an understanding of the unique perturbations in neurocognitive processes that promulgates the different symptomological clusters.Master

A critical inquiry into marble-burying as a preclinical screening paradigm of relevance for anxiety and obsessive-compulsive disorder: mapping the way forward

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 dat

Large nest building and high marble-burying: two compulsive-like phenotypes expressed by deer mice (Peromyscus maniculatus bairdii) and their unique response to serotoninergic and dopamine modulating intervention

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 disorder