Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

Abstract

Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABAA receptor (GABAAR). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be “fine‐tuned” by these neurosteroids to influence behaviour. In preclinical studies, these neurosteroids exhibited anxiolytic, anticonvulsant, analgesic and sedative properties and, at relatively high doses, induced a state of general anaesthesia, a profile consistent with their interaction with GABAARs. However, realising the therapeutic potential of either endogenous neurosteroids or synthetic “neuroactive” steroids has proven challenging. Recent approval by the Food and Drug Administration of the use of allopregnanolone (brexanolone) to treat postpartum depression has rekindled enthusiasm for exploring their potential as new medicines. Although neurosteroids are selective for GABAARs, they exhibit little or no selectivity across the many GABAAR subtypes. Nevertheless, a relatively minor population of receptors incorporating the δ‐subunit (δ‐GABAARs) appears to be an important contributor to their behavioural effects. Here, we consider how neurosteroids acting upon GABAARs influence neuronal signalling, as well as how such effects may acutely and persistently influence behaviour, and explore the case for developing selective PAMs of δ‐GABAAR subtypes for the treatment of psychiatric disorders.

Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice

“…In the brain, AlloP exerts rapid actions to downregulate CRF gene expression in the hypothalamus [ 64 ], reduce circulating glucocorticoid production [ 65 , 66 ], and to restore homeostasis as an endogenous modulator of the HPA axis. The protective effects of AlloP over gp120 have not been established but should be investigated given that AlloP is an FDA-approved therapy [ 67 ].…”

Neuroactive steroids: From basic research to clinical use

“…Probably the most studied mechanism of action of neuroactive steroids is the interaction with the GABA A receptor, 6 which has the possibility of influencing a wide number of circuits, functions and behavior. In humans, 7,8 elevated allopregnanolone levels are associated with disorders such as catamenial epilepsy, premenstrual disorder, hepatic encephalopathy, polycystic ovarian syndrome, increased negative mood, disturbed memory and increased food intake in some individuals.…”

“…In humans, 7,8 elevated allopregnanolone levels are associated with disorders such as catamenial epilepsy, premenstrual disorder, hepatic encephalopathy, polycystic ovarian syndrome, increased negative mood, disturbed memory and increased food intake in some individuals. The review by Belelli et al 6 provides a history of the discovery and properties of interactions among neuroactive steroids and GABA A receptor, highlighting the difficulties found in clinical applications. However, in this context, it is important to note that the recent approval by the Food and Drug Administration in the USA for the use of allopregnanolone (brexanolone) when treating postpartum depression has again stimulated enthusiasm for exploring the potential of neuroactive steroids as new therapeutic strategies for treating psychiatric disorders.…”

Comparison of Behavioral Effects of GABAergic Low- and High-Efficacy Neuroactive Steroids in the Zebrafish Larvae Assay

“…We chose to employ a neurosteroid-based agent. Neurosteroids and analogues can have a wide range of GABAergic action and many are known to generate sedation and anesthesia (e.g., refs − ). Neurosteroids and analogues have several advantages over other classes of GABAergic agents.…”