Psychopharmacology (2006) 186: 402–413 DOI 10.1007/s00213-005-0254-6 REVIEW Olivier George . Monique Vallée . Michel Le Moal . Willy Mayo Neurosteroids and cholinergic systems: implications for sleep and cognitive processes and potential role of age-related changes Received: 9 June 2005 / Accepted: 7 October 2005 / Published online: 17 January 2006 # Springer-Verlag 2006 Abstract Rationale: The neurosteroids pregnenolone sul- fate (PREGS), dehydroepiandrosterone sulfate (DHEAS) and allopregnanolone (3α,5α THPROG) have been im- plicated as powerful modulators of memory processes and sleep states in young and aged subjects with memory impairment. As these processes depend on the integrity of cholinergic systems, a specific effect of neurosteroids on these systems may account for their effects on sleep and memory. Objective: To review the evidence for a specific and differential effect of neurosteroids on cholinergic systems. Methods: We carried out keyword searches in “Medline” to identify articles concerning (1) the effects of neurosteroids on cholinergic systems, sleep and memory processes, and (2) changes in neurosteroid concentrations during aging. Few results are available for humans. Most data concerned rodents. Results: Peripheral and central administrations of PREGS, DHEAS, and 3α,5α THPROG modulate the basal forebrain and brainstem projection cholinergic neurons but not striatal cholinergic interneu- rons. Local administration of neurosteroids to the basal forebrain and brainstem cholinergic neurons alters sleep and memory in rodents. There are a few conflicting re- ports concerning the effects of aging on neurosteroid concentrations in normal and pathological conditions. Conclusions: The specific modulation of basal forebrain and brainstem cholinergic systems by neurosteroids may account for the effects of these compounds on sleep and memory processes. To improve our understanding of the role of neurosteroids in cholinergic systems during normal and pathological aging, we need to determine whether there is specific regionalization of neurosteroids, and we need to investigate the relationship between neurosteroid concentrations in cholinergic nuclei and age-related sleep and memory impairments. Keywords Acetylcholine . In vivo microdialysis . Learning and memory . Neurotransmitter release . Prefrontal . REM sleep . Steroid Introduction Several studies have suggested that the neurosteroids pregnenolone sulfate (3β-hydroxy-5-pregnen-20-one-3 sul- fate; PREGS), dehydroepiandrosterone sulfate (5-andro- stene-3β-ol-17-one sulfate; DHEAS) and allopregnanolone (3α,5α tetrahydroxyprogesterone; 3α,5α THPROG) may play a critical role in age-related neuropsychiatric disorders in humans and animals, and in the disruption of sleep and memory processes in particular (Vallée et al. 1997, 2001; Maurice 2001; Racchi et al. 2001; Weill-Engerer et al. 2002a; Mayo et al. 2003; Schumacher et al. 2003). There is little direct evidence of a pathophysiological relationship between neurosteroid concentrations in specific cerebral structures and age-related sleep and memory impairments (Vallée et al. 1997; Weill-Engerer et al. 2002b), but many studies have demonstrated that these neurosteroids affect sleep and memory processes in young subjects. Indeed, the peripheral or central administration of PREGS, DHEAS and 3α,5α THPROG induces robust changes in memory performances and sleep states (Flood et al. 1992; Frye 1995; Isaacson et al. 1995; Meziane et al. 1996; Lancel et al. 1997; Darnaudery et al. 1999a,b; Ladurelle et al. 2000; Damianisch et al. 2001; Matthews et al. 2002; Johansson et al. 2002; Turkmen et al. 2004). There are several lines of evidence suggesting that cholinergic systems may mediate these effects. Firstly, the integrity of cholinergic systems is critical for sleep and memory processes (Everitt and Robbins 1997), and these systems are known to degenerate during aging (Bartus et al. 1982; Perry et al. 1999; Sarter and Bruno 2004). Secondly, although little is known about the anatomic distribution of neurosteroid enzymes in discrete cerebral structures in adults, the key regulator of neurosteroid O. George (*) . M. Vallée . M. Le Moal . W. Mayo INSERM, U588, Institut François Magendie, Université de Bordeaux II, 146 rue Léo Saignat, Bordeaux 33077, France e-mail: george@bordeaux.inserm.fr Tel.: +33-5-57573676 Fax: +33-5-57573669