The recent FDA approval of the neurosteroid, brexanolone (allopregnanolone), as a treatment for women with postpartum depression, and successful trials of a related neuroactive steroid, SGE-217, for men and women with major depressive disorder offer the hope of a new era in treating mood and anxiety disorders based on the potential of neurosteroids as modulators of brain function. This review considers potential mechanisms contributing to antidepressant and anxiolytic effects of allopregnanolone and other GABAergic neurosteroids focusing on their actions as positive allosteric modulators of GABAA receptors. We also consider their roles as endogenous "stress" modulators and possible additional mechanisms contributing to their therapeutic effects. We argue that further understanding of the molecular, cellular, network and psychiatric effects of neurosteroids offers the hope of further advances in the treatment of mood and anxiety disorders.

Human studies examining the effects of the dissociative anesthetic ketamine as a model for psychosis and as a rapidly acting antidepressant have spurred great interest in understanding ketamine's actions at molecular, cellular, and network levels. Although ketamine has unequivocal uncompetitive inhibitory effects onN-methyl-d-aspartate receptors (NMDARs) and may preferentially alter the function of NMDARs on interneurons, recent work has questioned whether block of NMDARs is critical for its mood enhancing actions. In this viewpoint, we examine the evolving literature on ketamine supporting NMDARs as important triggers for certain psychiatric effects and the possibility that the antidepressant trigger is unrelated to NMDARs. The rapidly evolving story of ketamine offers great hope for untangling and treating the biology of both depressive and psychotic illnesses.

Zinc has complex effects on NMDA receptors (NMDARs) and may be an endogenous modulator of synaptic plasticity. In the CA1 region of rat hippocampal slices, we observed that low micromolar concentrations of zinc depress NMDAR synaptic responses by 40–50% and inhibit long-term depression (LTD) but not long-term potentiation (LTP). A combination of zinc plus ifenprodil, an inhibitor of NR1/NR2B receptors, produced no greater inhibition of synaptic NMDARs than either agent alone, suggesting overlapping effects on NMDARs. Similar to low micromolar zinc, ifenprodil inhibited LTD but not LTP. In contrast, low concentrations of 2-amino-5-phosphonovalerate (APV) did not block either LTP or LTD despite producing >50% inhibition of synaptic NMDARs. NVP-AAM077 ([(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydro-quinoxalin-5-yl)-methyl]phosphonic acid), an antagonist with relative NR1/NR2A selectivity at low concentrations, also inhibited synaptic NMDARs by ∼50% at 0.05 μmbut failed to completely block either LTP or LTD. These results suggest that LTD induction depends on specific NMDARs with sensitivity to low micromolar zinc and ifenprodil, but LTP is less dependent on specific NMDAR subtypes. Because high-affinity sites of NR2A are likely occupied by ambient zinc, we also examined effects of extracellular zinc chelators. Zinc chelation blocked LTP but had no effect on LTD. This LTP inhibition was overcome by APV and NVP-AAM077 but not ifenprodil, suggesting that zinc chelation unmasks tonic NR1/NR2A activation that negatively modulates LTP.