Rapid Antidepressant Action and Restoration of Excitatory Synaptic Strength After Chronic Stress by Negative Modulators of Alpha5-Containing GABAA Receptors

Selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological treatment for depression, but SSRIs are effective in only half of the patients and typically take several weeks to relieve symptoms. The NMDA receptor antagonist ketamine exerts a rapid antidepressant action, but has troubling side effects. We hypothesized that negative allosteric modulators of GABA(A) receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABA(A) receptors containing alpha 5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the alpha 5-selective negative modulator L-655,708 reversed the alterations in hedonic behavior in the sucrose preference and social interaction tests produced by two different chronic stress paradigms in rats within 24 h of systemic administration. Similar effects were observed with another alpha 5-selective negative modulator, MRK-016. L-655,708 had no effect on hedonic or open-field behavior in unstressed animals. Within 24 h, L-655,708 injection also restored the strength of pathologically weakened excitatory synaptic transmission at the stress-sensitive temporoammonic-CA1 synapse, measured electrophysiologically, and increased levels of the GluA1 subunit of the AMPA receptor, measured with western blotting. We suggest that the ability of L-655,708 to restore excitatory synaptic strength rapidly may underlie its ability to restore stress-induced behavioral alterations rapidly, supporting evidence that dysfunction of multiple excitatory synapses in cortico-mesolimbic reward pathways contributes, in part, to the genesis of depression. Negative allosteric modulators of alpha 5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.