Spontaneous alternation and stereotypical behaviour in deer mice: response to escitalopram and levetiracetam

Abstract

Obsessive-compulsive disorder is varyingly associated with cognitive impairment, that is, deficits in spatial working memory, although it seems unlikely that this is generalised across all domains of functioning. Further, it is unclear whether symptoms will respond to potentially novel, non-serotonergic drugs that have shown promise as so-called cognitive enhancers. Here, we studied low (Norm-N; n = 31) and compulsive-like high (Comp-H; n = 34) stereotypical deer mice (Peromyscus maniculatus bairdii) to establish (1) whether there is a relationship between stereotypical intensity and working memory ability as measured by spontaneous T-maze arm alternation and (2) if and how stereotypy and its association with changes in working memory, would respond to the known anti-compulsive agent, escitalopram, and the proposed cognitive enhancer, levetiracetam. After assessing the stereotypical and alternation behaviour of all animals at baseline, they were divided into three socially housed drug exposure groups, that is, water control (n = 11 per phenotype), escitalopram 50 mg/kg/d (n = 11 per phenotype) and levetiracetam 75 mg/kg/d (Norm-N: n = 9; Comp-H: n = 12). Drugs were administered for 28 days before stereotypy and alternation assessment were repeated. The present data indicate a weak negative relationship between stereotypical intensity and spontaneous alternation. While levetiracetam increased the time spent engaging in normal rodent activity by Comp-H, but not Norm-N animals, neither of the interventions affected the expression of Comp-H behaviour or the alternation behaviour of deer mice. In conclusion, this work points to some degree of cognitive involvement in Comp-H expression, which should be explored to further our understanding of compulsivelike stereotypy.

Behavioral restriction, lorazepam, and escitalopram uniquely influence the expression of naturalistic stereotypy in deer mice: perspectives on anxiety- and compulsive-like behavior

“…To explain, rigid behavioral stereotypies that arise in a less complex environment may be related to a lower degree of functional behavioral organization. Thus, and taking into account earlier work that showed HS deer mice to present with perturbations in cognitive performance also (de Brouwer et al, 2021;de Ridder et al, 2022), it is possible that unique interactions between the standard laboratory environment and distinct neurobiological and genetic influences, might contribute to HS animals presenting with a behavioral phenotype that is representative of a lower degree of behavioral organization, as proposed for ICR mice in earlier work (Würbel and Stauffacher, 1996). Still, HS behavior is remarkably similar in its psychobiological resemblance to compulsive-like processes.…”

“…By regarding the nine highest values (or the three highest values generated per night) as a marker of intensity, a clearer separation between animals that engage in HS, vs. NS behavior is attained, while random variability in the data set is accommodated for. This approach is standard in the present model system (de Brouwer et al, 2021 ; de Ridder et al, 2022 ). These averages were then expressed as percentage scores that reflected their deviation from the 30-min cut-off values for the classification of HS behavior.…”

“…Last, the typical behaviors seen in deer mice, are likely less founded on processes related to gradual behavioral shifts and more on a distinct and innate psychobiological profile in HS, compared to NS mice. For example, associations between HS behavior and changes in cognition were shown in our laboratory, whereby HS behavior was associated with lower alternation scores in a T-maze (de Brouwer et al, 2021 ; de Ridder et al, 2022 ). This association further seems to be founded upon unique neurobiological underpinnings, as reflected by the response of both HS (but not NS) behavior and T-maze alternation to the cognitive enhancer, levetiracetam (de Ridder et al, 2022 ) and the anti-adenosinergic drug, istradefylline (de Brouwer et al, 2021 ).…”

“…For example, associations between HS behavior and changes in cognition were shown in our laboratory, whereby HS behavior was associated with lower alternation scores in a T-maze (de Brouwer et al, 2021 ; de Ridder et al, 2022 ). This association further seems to be founded upon unique neurobiological underpinnings, as reflected by the response of both HS (but not NS) behavior and T-maze alternation to the cognitive enhancer, levetiracetam (de Ridder et al, 2022 ) and the anti-adenosinergic drug, istradefylline (de Brouwer et al, 2021 ). In terms of serotonergic involvement, HS animals show significantly reduced striatal serotonin transporter (SERT) density compared to NS controls (Wolmarans et al, 2013 ), which is supportive of a hyposerotonergic state in this cohort.…”

“…Bridging these concepts is a third possibility. Considering that not all animals in a laboratory-housed setting develop spontaneous stereotypy (Hadley et al, 2006 ; de Ridder et al, 2022 ), it is possible that subjects displaying high stereotypical (HS) behaviors, might present with a lower sensitivity threshold for stereotypy-triggering stimuli, e.g., anxiety (Koolhaas et al, 1999 ). From this perspective, stereotypies might be related to distinct implicit processes in certain animals only.…”