Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol

Abstract

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 receptors (GABARs). Nanomolar concentrations of neurosteroids, which occur in vivo, potentiate phasic and tonic forms of GABAR-mediated inhibition, indicating that both synaptic and extrasynaptic GABARs 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 GABARs 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 GABAR-mediated inhibition. Collectively, targeting neurosteroidogenesis may be a beneficial treatment strategy for alcohol use disorders.

Interneuronal δ-GABAA receptors regulate binge drinking and are necessary for the behavioral effects of early withdrawal

“…Relatedly, acute alcohol may increase synthesis and translocation of steroidogenic acute regulatory protein [44][45][46], an integral protein in the rate-limiting step in the steroid synthesis pathway. This may underlie the increase in synthesis and availability of neurosteroids following acute ethanol ( [47]; [22,23,[48][49][50]). With this, acute ethanol may augment δ-mediated tonic inhibition and that chronic ethanol exposure may lead to long-term adaptations in this system.…”

“…Specific to binge drinking, activation of δ-GABA A Rs using THIP has been shown to reduce this pattern of alcohol intake in mice [19][20][21]. The well-established relationship between neurosteroids that modulate δ-GABA A receptor activity and alcohol [22][23][24], also supports a role for δ-GABA A Rs as a neural substrate for the behavioral effects associated with this pattern of alcohol use.…”

The Endocrine System and Alcohol Drinking in Females

“…[16][17][18][19][20][21][22] Finally, steroid hormone derivatives can rapidly alter ion channel function via allosteric interactions with ligand-gated ion channels. [23][24][25][26] For example, the progesterone derivative allopregnanolone and the deoxycorticosterone derivative tetrahydrodeoxycorticosterone (THDOC) are very potent positive allosteric modulators of gamma-aminobutyric acid A (GABA A ) receptors and can rapidly alter neuronal inhibition. Rapid actions at the cell membrane gave rise to the terms "neuroactive steroids" and "neurosteroids" (Refer to the Finn and Jimenez article on neurosteroid networks for more information about neurosteroid synthesis and pathways.)…”

“…Rapid actions at the cell membrane gave rise to the terms "neuroactive steroids" and "neurosteroids" (Refer to the Finn and Jimenez article on neurosteroid networks for more information about neurosteroid synthesis and pathways.) 24 Thus, steroid hormones and their derivatives can influence brain function and behavior through classic genomic actions and rapid membrane effects.…”

“…Studies have examined whether manipulation in levels of the progesterone derivative allopregnanolone, which is a potent, positive allosteric modulator of GABA A receptors, [23][24][25][26] alters alcohol drinking and alcohol's subjective effects. In general, females have higher endogenous allopregnanolone levels than males.…”