Ketamine's rapid and sustained antidepressant and anxiolytic effects depend on neuronal activity in the infralimbic prefrontal cortex (IL-PFC). Inactivating the IL-PFC in rodents completely blocked the behavioral effects of systemic ketamine, while direct microinfusion of ketamine into the IL-PFC reproduced those effects. Optogenetic stimulation of the IL-PFC alone also produced rapid, long-lasting antidepressant and anxiolytic effects, which were linked to increased number and function of spine synapses in layer V pyramidal neurons. The findings demonstrate that activating the IL-PFC is sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to those from systemic ketamine.
A single dose of ketamine produces antidepressant-like effects in rats only when the brain's own opioid system is active in the medial prefrontal cortex (mPFC). Blocking opioid receptors with naltrexone—either throughout the body or directly in the mPFC—eliminates ketamine's behavioral effects. Ketamine rapidly increases levels of the opioid β-endorphin and expression of the μ-opioid receptor gene in the mPFC, and boosts production of β-endorphin's precursor in the hypothalamus. Neutralizing β-endorphin in the mPFC with a specific antibody also abolishes ketamine's behavioral and molecular effects, demonstrating that β-endorphin and opioid receptor activation in the mPFC are necessary for ketamine's antidepressant-like actions.
Ketamine, an NMDA receptor antagonist, rapidly relieves symptoms of depression within hours. While neuroplasticity in the medial prefrontal cortex (mPFC) is known to be critical for these effects, the downstream brain circuits involved were unclear. Using optogenetic and chemogenetic techniques in rodent models, researchers identified two distinct pathways. Activation of mPFC projections to the basolateral amygdala (BLA) and then to the ventral hippocampus mediated ketamine's effects on passive coping behavior, but not on anxiety or reward-seeking. In contrast, mPFC projections to the bed nucleus of stria terminalis (BNST) were necessary and sufficient for effects on anxiety-like and reward-seeking behaviors, but not passive coping. This suggests separate downstream circuits produce different antidepressant-like behavioral responses.
Ketamine's rapid antidepressant effects depend on GluN2B-containing NMDA receptors on somatostatin-expressing (Sst) interneurons in the medial prefrontal cortex (mPFC). In mice, a single subanesthetic dose of ketamine reduced NMDA-induced burst firing of Sst-interneurons, decreased inhibitory transmission, and increased excitatory transmission in layer V pyramidal neurons, reversing behavioral deficits caused by chronic unpredictable stress. These effects were absent in mice lacking GluN2B from Sst-interneurons. The findings identify Sst-interneurons as the initial cellular trigger for ketamine's synaptic and behavioral actions, supporting the disinhibition hypothesis whereby ketamine disinhibits pyramidal neurons via GluN2B-NMDARs on Sst-interneurons, activating mTOR signaling and enhancing synaptic function.