Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol

The term neurosteroid refers to rapid membrane actions of steroid hormones and their derivatives that can modulate physiological functions and behavior via their interactions with ligand-gated ion channels. This chapter will highlight recent advances pertaining to the modulatory effects of a select group of neurosteroids that are primarily potent positive allosteric modulators of γ-aminobutyric acid_A receptors (GABA_ARs). Nanomolar concentrations of neurosteroids, which occur in vivo, potentiate phasic and tonic forms of GABA_AR-mediated inhibition, indicating that both synaptic and extrasynaptic GABA_ARs possess sensitivity to neurosteroids and contribute to the overall ability of neurosteroids to modulate central nervous system excitability. Common effects of alcohol and neurosteroids at GABA_ARs have stimulated research on the ability of neurosteroids to modulate alcohol's acute and chronic effects. Background on neurosteroid pharmacology and biosynthetic enzymes will be provided as it relates to experimental findings. Data will be summarized on alcohol and neurosteroid interactions across neuroanatomical regions and models of intoxication, consumption, dependence, and withdrawal. Evidence supports independent regulation of neurosteroid synthesis between periphery and brain as well as across brain regions following acute alcohol administration and during withdrawal. Local mechanisms for fine-tuning neuronal excitability via manipulation of neurosteroid synthesis exert predicted behavioral and electrophysiological responses on GABA_AR-mediated inhibition. Collectively, targeting neurosteroidogenesis may be a beneficial treatment strategy for alcohol use disorders.