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

Abstract

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 α5 subunits, which are enriched in the hippocampus and prefrontal cortex. Here, we show that the α5-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 α5-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 stressinduced 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 α5 subunit-containing GABA A receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.

Mechanisms of ketamine action as an antidepressant

“…In rats, ketamine administration at sub-anesthetic doses results in a significant increase in extracellular glutamate levels 35 and an increase in glutamate cycling 44 in the prefrontal cortex. Further supporting this hypothesis, administration of partial inverse agonists at the benzodiazepine binding site of alpha5-containing GABA A receptors, which are selectively expressed in the forebrain, including prefrontal cortex and hippocampus, promote coherent network activity via disinhibition of excitatory neurotransmission 45 and exert rapid antidepressant actions in several animal tests 46–48 . Notably, ketamine 13 , similar to negative allosteric modulators of alpha5-containing GABA A receptors 47 , enhance gamma band electroencephalography power, which is hypothesized to be directly related to cortical disinhibition 49–52 , further supporting the role of cortical disinhibition in the rapid antidepressant actions of these drugs.…”

Cell Type-Specific Gene Expression of Alpha 5 Subunit-Containing Gamma-Aminobutyric Acid Subtype A Receptors in Human and Mouse Frontal Cortex

“…This can be achieved by enhancing GABAergic signaling through α5-GABA A Rs. Indeed, selectively modulating α5-GABA A Rs with α5-selective PAM and NAM compounds induces antidepressant-like effects in rodents [18, 28]. Although the reason for converging effects from opposite modulatory mechanisms is not yet understood, it has been suggested that SST cell regulation of cortical microcircuit activity by α5-GABA A R potentiation follows an inverted U curve to promote therapeutic efficacy, or alternatively that short-term inhibition leads to recurrent potentiation through cortical feedback loops, similar to recent findings on the mechanisms of rapid-acting antidepressants [19].…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…1), presumably through a disinhibition of excitatory glutamatergic neurotransmission [161]. Specifically, administration of GABA-NAMs that are selective for receptors containing alpha5 subunits, such as L-655,781 or MRK-016, reversed social interaction and sucrose preference deficits following several chronic stress paradigms 24 h after administration in rats [162]. The effects of a single injection were long-lasting since decreases in behavioral despair in the forced-swim test and restoration of sucrose preference deficits could be seen up to 7 days post-treatment [163].…”

“…Chronic stress-induced decreases in hippocampal GluA1 expression are also rapidly reversed following a single dose of a selective GluN2B antagonist [90] or an alpha5-selective GABA-NAM [162]. An increase in AMPAR expression in specific synapses is likely to be indicative of a potentiation of AMPAR-mediated synaptic transmission following administration of rapid-acting antidepressants.…”