Chronic unpredictable stress in male rodents reduces GABAergic proteins and the frequency of inhibitory postsynaptic currents in layer V pyramidal neurons of the medial prefrontal cortex, accompanied by depression-like behaviors. A single dose of ketamine reverses these stress-induced deficits in GABA markers and depressive-like behaviors. The findings indicate that impairments of GABAergic synapses are key determinants of depressive behavior and that ketamine restores both GABA inhibitory and glutamate neurotransmission.
Stress-related disorders like depression and anxiety affect nearly 20% of people in the United States. Traditional antidepressants such as selective serotonin reuptake inhibitors and monoamine oxidase inhibitors have drawbacks, including a delayed therapeutic response and low efficacy. Ketamine works rapidly and helps treatment-resistant patients, but its use is limited by temporary dissociative and psychotomimetic side effects and potential for abuse. Rodent stress models produce behavioral, molecular, and cellular changes in brain regions like the prefrontal cortex and hippocampus that resemble those in depression. Rapid-acting antidepressants like ketamine can reverse these stress-induced changes. This review examines how these agents counteract stress and explores their molecular, cellular, and circuit-level targets.
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.
Activating Drd1 dopamine receptor expressing pyramidal cells in the medial prefrontal cortex (mPFC) produces rapid and long-lasting antidepressant and anxiolytic responses in mice, whereas stimulating Drd2 expressing pyramidal cells does not affect anxiety-like or depression-like measures. Disrupting Drd1 activity also blocks the rapid antidepressant effects of ketamine. Stimulation of mPFC Drd1 terminals in the basolateral amygdala recapitulates the antidepressant effects of somatic stimulation. These findings identify specific cellular targets in the mPFC and downstream circuitry involved in rapid antidepressant responses.