Oxytocin improves probabilistic reversal learning but not effortful motivation in Brown Norway rats

Abstract

Deficits in cognition and motivation are common and debilitating aspects of psychiatric disorders, yet still go largely untreated. The neuropeptide oxytocin (OT) is a potential novel therapeutic for deficits in social cognition and motivation in psychiatric patients. However, the effects of OT on clinically relevant domains of non-social cognition and motivation remain under studied. The present study investigated the effects of acute and chronic (21-day) administration of subcutaneous OT (0.04, 0.2, and 1 mg/kg) in cross-species translatable operant paradigms of reward learning and effortful motivation in male and female Brown Norway (BN) rats (n=8-10/group). Reward learning was assessed using the probabilistic reversal learning task (PRLT) and effortful motivation was measured using the progressive ratio breakpoint task (PRBT). As predicted, BN rats exhibited baseline deficits in the detection of reversals of reward contingency in the PRLT relative to Long Evans (LE) rats. The two strains performed equally in the PRBT. Thirty minutes after a single OT injection (1 mg/kg), measures of both initial probabilistic learning (trials to first criterion) and subsequent reversal learning (contingency switches) were significantly improved to levels comparable with LE rats. The OT effect on switches persisted in male, but not female, BN rats 30 minutes, 24 hours, and 6 days after long-term OT administration, suggesting the induction of neuroplastic changes. OT did not affect effortful motivation at any time-point. The beneficial effects of OT on reward learning in the absence of increased effortful motivation support the development of OT as a novel therapeutic to improve cognitive functioning.

The role of oxytocin in delay of gratification and flexibility in non-social decision making

“…Variation in the data due to Order of substance administration in the low WMC group was accounted for by a Substance × Order interaction, beta = 0.069, t (66) = 2.28, p = 0.025. These findings are in line with previous animal findings ( Roberts et al, 2019 ) and suggest that oxytocin improves reversal learning as a function of baseline WMC, consistent with the baseline-dependent impacts of other pharmacological interventions (including dopamine agonists and antagonists) on reversal learning ( Cools et al, 2009 ; Kandroodi et al, 2020 ; Kimberg et al, 1997 ; Soutschek et al, 2020b ; van der Schaaf et al, 2014 ).…”

“…Alternatively, reversal learning also crucially depends on orbitofrontal cortex ( Schoenbaum et al, 2007 ), which too is susceptible to oxytocin manipulations ( Preckel et al, 2015 ). While the underlying neural mechanisms require further investigation, our results are in line with recent animal findings suggesting significant improvement in the probabilistic reversal learning task after oxytocin administration in rodents ( Roberts et al, 2019 ) and provide first evidence in humans for a causal role of oxytocin for the flexible updating of cue-outcome associations. Furthermore, the result is in line with the allostatic theory ( Quintana and Guastella, 2020 ) that predicts improved reversal learning under oxytocin.…”

“…We hypothesized that intranasal oxytocin (relative to placebo) increases the preference for delayed rewards in intertemporal choice, in line with previous findings from animal research and clinical studies suggesting reduced craving and impulsiveness under oxytocin ( Hansson et al, 2018 ; Hurlemann et al, 2019 ; Miller et al, 2016 ). For reversal learning, we hypothesized that oxytocin improves cognitive flexibility, as suggested by animal findings ( Roberts et al, 2019 ). Finally, we hypothesized that oxytocin increases advantageous inequity aversion ( Pornpattananangkul et al, 2017 ).…”

Comparison of conventional and rapid-acting antidepressants in a rodent probabilistic reversal learning task

“…Both ketamine and scopolamine impaired RL, PFS and motivation. Both drugs have sedative effects at higher doses, a potential cause of their motivational impairments, although it has been observed that motivation and RL are dissociable within the PRLT (Roberts et al, 2019). Rychlik et al (2017) argued that attenuating animals' sensitivity to misleading negative feedback may be a mechanism for ketamine's therapeutic action.…”

The oxytocin system and early‐life experience‐dependent plastic changes

“…[27][28][29] Oxytocin also has been shown to play a role in learning and memory including reversal learning. 30 All of these oxytocin actions of increasing social behaviours, modulating stress-related responses, inducing negative metabolic states and exerting neuroprotection, have been suggested to contribute to active coping towards various environmental challenges. 20 In addition to acute actions, oxytocin has been shown to be involved in neurogenesis and neurotropic actions.…”