Neurosteroids, stress and depression: potential therapeutic opportunities

Abstract

Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those neurosteroids that potently modulate the function of GABA(A) receptors. We then discuss evidence indicating a role for GABA and neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes.

Fig. 1

The list outlines potential therapeutic targets for neuroactive steroids. With the exception of Memory Dysfunction, these are targets for steroids that enhance the function of GABA_A Rs. Memory Dysfunction would be a more likely target for steroids that either enhance the function of NMDARs or that inhibit GABA_A Rs.

Fig. 2

The figure lists major sites of action that have been indentified for neurosteroids. Importantly, steroids have some of their most potent and effective actions at GABA_A Rs.

Fig. 3

The diagram depicts key steps and enzymes involved in the synthesis of alloP from cholesterol. Conversion of cholesterol to pregnenolone occurs at the inner mitochondrial membrane.

Fig. 4

The figure shows the core structure of a 3α-hydroxy pregnane neurosteroid. In alloP, the hydrogen at C5 is in the α-conformation, while in pregnanolone, the hydrogen is in the β-configuration. Synthetic neuroactive steroids have modifications of this core structure. Key elements for enhancement of GABA_A Rs include the pregnane nucleus, the presence of a 3α-hydrogen bond donor and a 17β-hydrogen bond acceptor.

Fig. 5

The traces depict the effects of a representative BDZ (lorazepam), barbiturate (pentobarbital) and neurosteroid (alloP) on GABAergic inhibitory postsynaptic currents (IPSCs) recorded from cultured hippocampal neurons.

Fig. 6

The diagram lists potential therapeutic strategies for altering the function of neurosteroids.