Distinct downstream targets of the medial prefrontal cortex underlie discrete antidepressant responses to ketamine
Ryota Shinohara, Brendan Hare, Rong-Jian Liu, Jin Hua Li, Xiaoyuan Li, Catharine H. Duman, Ralph Dileone, Ronald S. Duman
Proceedings for Annual Meeting of The Japanese Pharmacological Society 2022 DOI: 10.1254/jpssuppl.95.0_1-o-011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study Peer reviewed |
|---|---|
| Population | Rodent models for studying depression |
| Intervention | Ketamine |
| Duration | Period immediately following ketamine administration |
| Topics | Ketamine Esketamine |
| Keywords | Prefrontal cortex Stria terminalis Antidepressant Optogenetics Basolateral amygdala Nmda receptor Hippocampus |
| Key points | Distinct downstream circuits of the medial prefrontal cortex—one involving the basolateral amygdala and ventral hippocampus, another involving the bed nucleus of stria terminalis—mediate separate antidepressant-like behavioral effects of ketamine. |
Abstract
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is the prototype for a potential new generation of glutamate-based antidepressants that rapidly relieve symptoms of depression within hours of treatment. Studies in rodents have demonstrated that neuroplasticity in the medial prefrontal cortex (mPFC) is critical for the antidepressant actions of ketamine. However, effector circuits downstream of the mPFC underlying the rapid antidepressant responses remain unknown. To address this issue, we used optogenetic and chemogenetic circuit mapping in rodent models for studying depression, demonstrating the role of the basolateral amygdala (BLA) and bed nucleus of stria terminalis (BNST) as downstream targets of the mPFC mediating distinct behavioral effects of ketamine. By inhibiting isolated mPFC projections in the period immediately following ketamine administration, we found that mPFC-mediated activation of BLA principal neurons, and subsequent projections to the ventral hippocampus, mediate a subset of ketamine's persistent antidepressant-like effects on passive coping behavior but not on anxiety-like and reward-seeking behaviors. In contrast, mPFC projections to the BNST are necessary and sufficient to produce persistent antidepressant-like effects on anxiety-like and reward-seeking behaviors but not on passive coping behavior. Therefore, our data support a model where distinct downstream circuits of the mPFC contribute to producing separate antidepressant-like behavioral responses.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |