Stereotypy and spontaneous alternation in deer mice and its response to anti‐adenosinergic intervention

Abstract

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A 2A receptor antagonist at two doses (10 and 20 mg kg −1 day −1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.

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.…”

“…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.…”

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

“…Test cages were cleaned after each screen. Norm-N and Comp-H animals (65 animals in total; 31 Norm-N; 34 Comp-H) were selected based on prior published criteria that account for both the intensity of and time spent expressing stereotypical behaviour during a 12-hour dark cycle (de Brouwer et al , 2021) (Table 1 and Fig. 1).…”

“…Mice were allowed 14 more arm choices over a maximum period of 30 minutes, with a 30-second intertrial interval in the start box separating each choice (Deacon and Rawlins, 2006). Mice that failed to enter any of the transverse arms within 10 minutes after the onset of assessment, or mice that executed less than eight-arm choices within 30 minutes, were excluded from further study and replaced by other animals (de Brouwer et al , 2021). Between assessments, animals were gently relocated to their respective home cages and moved back to the housing room, after which the T-maze was cleaned with 90% ethanol (which was completely evaporated before the next assessment) to prevent any potential olfactory influence on the alternation behaviour of subsequently assessed mice (Gerlai, 1998).…”