Effects of GABA, Sex, and Stress on Reward Learning in Current and Remitted Major Depression

Background Neurocognitive factors including aberrant reward learning, blunted gamma-aminobutyric acid (GABA), and potentiated stress sensitivity have been linked to anhedonia, a hallmark depressive symptom, possibly in a sex-dependent manner. However, past research has not investigated the putative associations among these factors nor the extent to which they represent trait- or state-based vulnerabilities for depression. Methods Young adults with current major depressive disorder, (MDD; N=44), remitted MDD (rMDD; N=42), and healthy control participants (HC; N=44), stratified by sex, underwent magnetic resonance spectroscopy to assess GABA+ (macromolecular contaminated), and then a reward learning task before and after acute stress. We assessed changes in reward learning after stress and associations with GABA+. Results Results revealed blunted baseline reward learning in participants with rMDD versus current MDD and HC, but surprisingly, no differences between current MDD and HC. Reward learning was reduced following acute stress regardless of depressive history. GABA+ in the rostral anterior cingulate cortex, but not dorsolateral prefrontal cortex, was associated with reduced baseline reward learning in female participants, while GABA+ did not predict stress-related changes in reward learning. Conclusions To our knowledge, this study is the first to investigate associations among GABA, sex, reward learning, and stress reactivity in current versus past depression. Hypothesized depression-related differences in reward learning did not emerge, precluding claims about state versus trait vulnerabilities. However, our finding that blunted GABA was associated with greater reward learning in female participants provides novel insights into sex-selective associations between the frontal GABAergic inhibitory system and reward processing.