223. Multidomain behavioural profiling in the Flinders Sensitive Line rat and response to escitalopram or a novel butyrylcholinesterase inhibitor: focus on anhedonia

Abstract

Abstract Background Anhedonia is a core symptom of major depressive disorder (MDD) but is challenging to model and to treat. First-line serotonergic antidepressants, e.g., escitalopram (ESC), often show limited efficacy in certain reward-related domains. Anhedonia is multi-dimensional, encompassing motivational drive, consummatory pleasure, and reward learning, yet many preclinical studies assess only consummatory sucrose intake, potentially overlooking critical deficits. The Flinders Sensitive Line (FSL) rat is a validated model of MDD. However, inconsistent findings regarding anhedonia raise questions about whether this model emphasises unique reward-related subdomains. Moreover, anhedonia represents a valuable target for novel antidepressant testing, where the FSL rat may be a valuable translational model. Regulation of reward signalling by butyrylcholinesterase (BChE) via control of bioactive ghrelin represents a novel mechanism influencing these processes. Selective BChE inhibition improves several MDD-relevant behavioural domains in FSL rats through ghrelinergic and dopaminergic pathways, suggesting a reward-specific approach to treating MDD. Considering the multi-dimensional presentation of anhedonia, we investigated whether a typical serotonergic antidepressant like ESC or a novel selective BChE inhibitor (BChEI) would display broad antidepressant-like activity in FSL rats using multidomain behavioural assessment, thus in line with the Research Domain Criteria. Aims & Objectives Define the depressive-like phenotype of the FSL rat, viz., cognitive, anhedonia- and despair-like traits, versus control Flinders Resistant Line (FRL) rats. Assess whether chronic ESC or BChEI treatment can alleviate depressive and anhedonia-like behaviour in FSL rats. Method To establish validity for MDD, FSL rats were subjected to the forced swim test (FST) and novel object recognition test (NORT) as reference behavioural assessments for despair and cognition, respectively. Anhedonia was evaluated across two domains, viz., consummatory reward (sucrose preference test; SPT) and motivational reward learning (conditioned place preference; CPP). Thereafter, behavioural response following chronic ESC (20 mg/kg po x 16 days) or BChEI (30 mg/kg po x 16 days) treatment in FSL rats was assessed. Statistical evaluation included strain comparisons by independent t-tests, with treatment effects analysed using one- or two-way ANOVAs with Bonferroni corrections. Statistical significance was accepted at p < 0.05. Results Vehicle-treated FSL rats demonstrated significantly impaired cognition (NORT) and increased despair (FST) relative to control FRL rats, both reversed by ESC and BChEI. While consummatory reward (SPT) remained intact, FSL rats exhibited a marked deficit in motivational reward learning (CPP), supporting a specific impairment in reward acquisition. Chronic ESC and BChEI treatment produced comparable improvements in CPP performance, restoring motivational reward learning akin to FRL controls. Discussion & Conclusions The value of multidomain reward assessment in preclinical antidepressant research is emphasised. While consummatory reward is preserved in FSL versus FRL rats, motivational and learning-based reward processes are significantly impaired. These findings mirror clinically relevant patterns of anhedonia observed in MDD. The comparable efficacy of ESC and BChEI in reversing CPP deficits highlights the therapeutic responsiveness of consummatory anhedonia, strengthening the translational validity of the FSL model. These data also position the BChE-ghrelin-dopamine pathway as a promising avenue for further mechanistic exploration in MDD research.