Neuropsychopharmacology
March 5, 2015
Sarah A. Stuart, Paul Butler, Marcus R. Munafò et al.
73 citations
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.
Science Translational Medicine
January 10, 2024
Katie Kamenish, Roberto Arban, Aslihan Selimbeyoglu et al.
26 citations
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.
bioRxiv (Cold Spring Harbor Laboratory)
November 1, 2025
Dasha Anderson, Justyna Hinchcliffe, Megan Jackson et al.
1 citation
preprint
Antidepressant doses used in conventional rodent models of depression often exceed those used in clinical practice by 1.5 to 25 times, potentially engaging mechanisms irrelevant to human therapeutic effects. A review of forced swim test studies found median doses of 10 mg/kg across antidepressants, while the more recently developed affective bias test showed doses closer to clinical levels. In a separate analysis of 232 ketamine and 202 fluoxetine rodent studies, median doses were also 10 mg/kg, exceeding animal equivalent doses by 1.6–6.5 times. This mismatch may explain why positive preclinical results often fail to translate into clinical efficacy.
bioRxiv (Cold Spring Harbor Laboratory)
March 4, 2026
Matthew D. B. Claydon, Justyna K. Hinchcliffe, Julia M. Bartlett et al.
Psilocybin, the active compound in magic mushrooms, produces rapid and lasting antidepressant effects in people with major depressive disorder, but the underlying brain mechanisms are not fully understood. In rats, psilocin (the active metabolite of psilocybin) alters negative affective biases—a key feature of depression—by acting on a specific circuit in the medial prefrontal cortex. It suppresses excitatory signals to cortico-amygdala projection neurons while enhancing excitatory transmission to other targets, effects dependent on 5HT1A and 5HT2A receptors. These changes persist for at least 24 hours and shift from suppressed excitation to enhanced inhibition in those same cells. Chemogenetically inhibiting these neurons reproduced psilocybin's effects on affective biases and reward memories, identifying this circuit as a key substrate for its antidepressant actions.
bioRxiv (Cold Spring Harbor Laboratory)
January 15, 2026
Justyna K. Hinchcliffe, Christopher W. Thomas, Gary Gilmour et al.
Psilocybin, a serotonergic psychedelic, can rapidly and lastingly reverse impaired reward processing in a rat model of depression. In rats with chronic interferon-alpha-induced depression, a single dose of psilocybin (0.3 mg/kg) restored reward-induced behavioral biases within 24 hours, and the effect persisted for at least 7 days. This suggests that restoring blunted reward processing may contribute to psilocybin's sustained antidepressant effects.