Rapid-acting antidepressant drugs modulate affective bias in rats

Hinchcliffe, J. K. et al. (2024) Rapid-acting antidepressant drugs modulate affective bias in rats. Science Translational Medicine, 16(729), eadi2403. (doi: 10.1126/scitranslmed.adi2403) (PMID:38198569) (PMCID:PMC7615567)

Abstract

How rapid-acting antidepressants (RAADs), such as ketamine, induce immediate and sustained improvements in mood in patients with major depressive disorder (MDD) is poorly understood. A core feature of MDD is the prevalence of cognitive processing biases associated with negative affective states, and the alleviation of negative affective biases may be an index of response to drug treatment. Here, we used an affective bias behavioral test in rats, based on an associative learning task, to investigate the effects of RAADs. To generate an affective bias, animals learned to associate two different digging substrates with a food reward in the presence or absence of an affective state manipulation. A choice between the two reward-associated digging substrates was used to quantify the affective bias generated. Acute treatment with the RAADs ketamine, scopolamine, or psilocybin selectively attenuated a negative affective bias in the affective bias test. Low, but not high, doses of ketamine and psilocybin reversed the valence of the negative affective bias 24 hours after RAAD treatment. Only treatment with psilocybin, but not ketamine or scopolamine, led to a positive affective bias that was dependent on new learning and memory formation. The relearning effects of ketamine were dependent on protein synthesis localized to the rat medial prefrontal cortex and could be modulated by cue reactivation, consistent with experience-dependent neural plasticity. These findings suggest a neuropsychological mechanism that may explain both the acute and sustained effects of RAADs, potentially linking their effects on neural plasticity with affective bias modulation in a rodent model.

• Item Type: Articles
• Additional Information: Funding: This research was funded in whole or in part by the UKri (BBSrc grants BB/V015028/1 and BB/n015762/1 and Mrc grant Mr/l011212/1 to e.S.J.r.). This funding included industrial partnership award grants in collaboration with Boehringer ingelheim (B.H. and r.a) and coMpaSS pathways plc (G.G., c.W.T., a.S., and S.H.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stuart, Dr Sarah
• Authors: Hinchcliffe, J. K., Stuart, S. A., Wood, C. M., Bartlett, J., Kamenish, K., Arban, R., Thomas, C. W., Selimbeyoglu, A., Hurley, S., Hengerer, B., Gilmour, G., and Robinson, E. J.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Science Translational Medicine
• Publisher: American Association for the Advancement of Science
• ISSN: 1946-6234
• ISSN (Online): 1946-6242
• Copyright Holders: Copyright © 2024 The Authors
• First Published: First published in Science Translational Medicine 16(729): eadi2403
• Publisher Policy: Reproduced in accordance with the publisher copyright policy
• Data DOI: 10.17605/OSF.IO/625SF