The effects of inhibitors of GABAergic transmission and stress on brain and plasma allopregnanolone concentrations

Abstract

1 This study was undertaken to investigate the relationship between a reduction in brain GABA A receptor function and the cerebro-cortical content of 3a-hydroxy-5a-pregnan-20 one (allopregnanolone, AP), a potent endogenous positive modulator of g-aminobutyric acid (GABA) action at GABA A receptors, with anticon¯ict and anticonvulsant e ects in rodents. 2 An acute depletion of the cerebral content of GABA or an attenuation of GABA A receptor-mediated transmission by systemic injections of isoniazid (375 mg kg 71 , s.c.) or FG 7142 (15 mg kg 71 , i.p.) induced a transient increase in the cerebro-cortical and plasma concentrations of AP in handlinghabituated (not stressed) rats. 3 Two stress paradigms, handling in naive rats and mild foot shock in handling-habituated rats, that reduce central GABAergic tone mimicked the e ects of isoniazid and FG 7142 on cortical AP content; foot shock in handling-habituated rats, but not handling in naive animals, also increased plasma AP. Isoniazid, FG 7142, and foot shock also each increased the concentrations of the AP precursors, pregnenolone and progesterone, in both brain and plasma of handling-habituated rats, whereas handling in naive rats increased the concentrations of these steroids only in brain. 4 Pretreatment of handling-habituated rats with the anxiolytic b-carboline derivative abecarnil, a positive allosteric modulator of GABA A receptors, which per se failed to a ect the AP concentration in brain or plasma, prevented the increase in brain and plasma AP induced by foot shock or isoniazid. 5 In adrenalectomized and castrated rats foot shock or isoniazid failed to increase AP both in brain cortex and plasma. 6 These observations indicate that inhibition of GABAergic transmission, induced by foot shock or pharmacological manipulations, results in an increase in the concentrations of AP in brain and plasma, possibly via a modulation of hypothalamic-pituitary-adrenal (HPA) axis. 7 Given that AP enhances GABA A receptor function with high e cacy and potency, an increase in brain AP concentration may be important in the ®ne tuning of the GABA-mediated inhibitory transmission in the central nervous system.

Neurosteroids in the context of stress: Implications for depressive disorders

“…In keeping with the early observations of Selye (1941Selye ( , 1956) that steroid hormone metabolites could exert central effects within minutes of administration, Purdy and colleagues (Purdy et al, 1991;Barbaccia et al, 1996Barbaccia et al, , 1997 were among the first to demonstrate in rat models that acute stress results in significant increases in both plasma and CNS concentrations of the 3α-hydroxy ring A-reduced steroid metabolites, 3α,5α-THP (allopregnanolone) and 3α,5α-THDOC (allotetrahydroDOC), in physiologic ranges known to enhance GABA receptoractivated Cl-currents (Purdy et al, 1991;Reddy, 2006).…”

“…PMDD women also report more traumatic life stress, including sexual and physical abuse histories (Paddison et al, 1990;Golding & Taylor, 1996Girdler et al, 2003Girdler et al, , 2007. Since allopregnanolone is stress responsive, at least in animal models (Purdy et al, 1991;Barbaccia et al, 1996Barbaccia et al, , 1997, greater allostatic load in PMDD resulting from more severe life stress could contribute to the elevated allopregnanolone concentrations that we have seen in PMDD women (Girdler et al, 2001) and result in the documented alterations in GABA A receptor function in PMDD (Sundstrom et al, 1997a(Sundstrom et al, , 1997b(Sundstrom et al, , 1998, including alterations in the agonism properties of the GABA A receptor as animal models (Smith et al, 2006) and human studies of PMDD suggest (Le Melledo et al, 2000). This could then explain the seemingly paradoxical association between increasing allopregnanolone concentrations in the luteal phase and increased dysphoric mood states in PMDD.…”

Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder

“…Interestingly, GABAergic neurons in the BNST as well as preoptic area and hypothalamus can inhibit outflow from the parvocellular paraventricular nucleus neurons and, thus, reduce adrenocorticotropin hormone (ACTH) secretion (Tringali et al, 2004;Herman et al, 2004). Although estrogen and progesterone have been shown in some studies to enhance and diminish HPA axis activation (Fonseca et al, 2001;Patchev et al, 1994), respectively, ALLO concentrations in plasma and brain increase as a result of stress (Barbaccia et al, 1997(Barbaccia et al, , 2001), perhaps as a compensatory mechanism. Women with PMDD fail to demonstrate the normal increase in ALLO seen in healthy subjects under conditions of stress (Monteleone et al, 2000;Girdler et al, 2001;Droogleever Fortuyn et al, 2004;Lombardi et al, 2004), or during HPA axis activation with ACTH administration (Genazzani et al, 1998;Lombardi et al, 2004).…”

Neuroactive Steroid 3α-Hydroxy-5α-Pregnan-20-One Modulates Electrophysiological and Behavioral Actions of Ethanol

“…3␣,5␣-THP is an endogenous pregnane steroid and potent agonist modulator of the inhibitory neurotransmitter GABA A receptor subtype. 3␣,5␣-THP is increased in brain in many stress paradigms (Purdy et al, 1991;Barbaccia et al, 1996;Barbaccia et al, 1997), as well as during naturally occurring hormonal fluctuations such as the estrus cycle (Ichikawa et al, 1974;Paul and Purdy, 1992;Finn and Gee, 1993) and pregnancy (Concas et al, 1998). A wealth of evidence demonstrates that the anxiolytic, sedative/ hypnotic, and anticonvulsant effects attributed to 3␣,5␣-THP are mediated by enhancement of chloride ion conductance through GABA A receptors in brain (Morrow, 1995).…”