title: 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 GABAA receptors would exert similar effects on brain activity as ketamine, but would not exert as many side effects if targeted only to GABAA 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 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 α5 subunit-containing GABAA receptors represent a promising novel class of fast-acting and clinically viable antidepressant compounds.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Molecular Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fischell
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Membrane Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Van Dyke
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Neuroscience, University of Maryland School of Medicine, Baltimore, MD, USA.|Program in Membrane Biology, University of Maryland School of Medicine, Baltimore, MD, USA.|Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Kvarta
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Tara A
authors.initials: TA
authors.lastname: LeGates
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000503:physiopathology; D002908:Chronic Disease; D019422:Dietary Sucrose / Q000008:administration & dosage; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D012149:Restraint, Physical; D012919:Social Behavior; D013315:Stress, Psychological / Q000188:drug therapy* / Q000503:physiopathology; D013569:Synapses / Q000187:drug effects* / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D046509:Tissue Culture Techniques; D014227:Triazines / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D019422:Dietary Sucrose; D018757:GABA Modulators; D007093:Imidazoles; D007555:Isoxazoles; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D014227:Triazines; C511535:Gabra5 protein, rat; C105490:L 655,708; C494554:MRK 016