L-655, 708 Exerts Rapidly-Acting Antidepressant Efficacy in Rat Models of Depression

Abstract

The considerable morbidity and mortality associated with depression, combined with its extensive prevalence, makes optimally treating depression a key objective of mental health research. Currently, the first line of pharmacological treatment for depression are selective serotonin reuptake inhibitors (SSRIs). While SSRIs are effective tools in the treatment of depression, their value is substantially diminished by a delay of weeks to months before providing relief of the symptoms depression. Furthermore, SSRIs are only effective in one-half to two-thirds of patients. Investigation into alternative pharmacological treatments that could exert rapid antidepressant effects led to the discovery of ketamine, a non-competitive NMDA receptor antagonist. Unfortunately, ketamine is severely limited in its therapeutic value by its addictive and dissociative properties. Ketamine has been shown to increase excitatory neurotransmission in the hippocampus resulting in a long term enhancement of excitatory synaptic strength, an effect theorized to underlie its antidepressant efficacy. Another way to increase excitatory neurotransmission, is through the attenuation of GABAergic synaptic inhibition using compounds such as the α5 selective, GABAA receptor partial inverse agonist, L-655, 708. In this thesis, I have demonstrated that a single injection of L-655, 708 rapidly reversed a stress-induced impairment of sucrose preference and social interaction in a rat model of stress-induced depression. Associated with this reversal, L-655, 708 rapidly restored the strength of pathologically weakened AMPAR-mediated, but not NMDAR-mediated neurotransmission at temproammonic-CA1 synapses, measured electrophysiologically. Additionally, L-655, 708 rapidly increased S831 phosphorylation at these synapses. This finding indicated that an enhancement of AMPA receptor function may underlie the electrophysiological findings. Based on our previously proposed, excitatory synapse hypothesis of depression, we theorize that ability of L-655, 708 to restore excitatory synaptic strength underlies its efficacy as an antidepressant. Finally, L-655, 708 appears to be non-anxiogenic, as measured by open-field testing. Before now the antidepressant efficacy of compounds like L-655, 708 have never been investigated. We conclude that L-655, 708 may be a novel, effective, rapidly acting, and clinically viable treatment for depression.