Antidepressant drugs like ketamine and venlafaxine modify emotional biases in rats, but through different brain regions and at different times. In a bowl-digging task, rats learned two equal-value experiences, one under an affective manipulation and one under control conditions; their later choices revealed an affective bias. Ketamine, which acts rapidly, reduced a previously acquired negative bias when given before the preference test, and its effect depended on the medial prefrontal cortex. Venlafaxine, which acts slowly, induced a positive bias when given before learning, and its effect depended on the amygdala. Increasing the number of substrate-reinforcer associations amplified both positive and negative biases. This pattern may explain why venlafaxine has a delayed onset of action while ketamine acts quickly but lacks long-term efficacy.
Negative cognitive biases—where mood colors learning and memory—are a core feature of major depressive disorder, and reversing them may be key to how rapid-acting antidepressants work. In rats, a single dose of ketamine, scopolamine, or psilocybin selectively weakened a negative affective bias induced in an associative learning task. Low doses of ketamine and psilocybin, but not high doses, reversed the valence of the bias 24 hours later. Only psilocybin produced a lasting positive bias that depended on new learning. Ketamine's relearning effects required protein synthesis in the medial prefrontal cortex and could be altered by cue reactivation, pointing to experience-dependent neural plasticity as a shared mechanism for both the rapid and sustained effects of these drugs.