REVIEWSex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators
Introduction
Mood disorders are a common health problem among women, especially during the reproductive years. Women are approximately twice as likely as men to report a lifetime history of major depression or anxiety disorder. Periods of hormonal variability, that is, menarche (Angold et al., 1999), premenstrual periods (Soares et al., 2001), postpartum (Chaudron et al., 2001), and perimenopause (Freeman et al., 2004) have been suggested to increase the risk of mood disorders in certain women. Therefore, it seems likely that sex steroid hormones can provide one possible explanation for the differences in mood disorders observed between the genders.
The sex steroid hormones act directly and indirectly via different neurotransmitter systems in the central nervous system (CNS). One of these systems is the gamma aminobutyric acid A (GABAA) receptor complex, which is the major inhibitory system in the mammalian CNS (Majewska et al., 1986). There is evidence for an interaction between mood effects and GABAA modulatory agents such as benzodiazepines, barbiturates, and alcohol. In addition, several neuroactive metabolites of steroid hormones, such as allopregnanolone and pregnanolone, are also modulators of the GABAA receptor complex; for this reason, they are known as GABA steroids. This review will therefore concentrate on arguments indicating a link between GABA steroids and negative mood effects.
In this context, GABA steroids are defined as steroids produced mainly by the ovary during the menstrual cycle, but also by the adrenals, and by the testes in men. The steroids are transported in the blood from the production unit to the brain. GABA steroids are also produced directly in the brain in both sexes (Celotti et al., 1992). Previous work by our group, among others, has shown that with the exception of oestradiol it is not the classic hormones that achieve many of the CNS effects. Instead, the 3alpha-hydroxy-5alpha/beta metabolites of progesterone (pregnanolone and allopregnanolone), testosterone (3alpha-5alpha-androstan-diol), and desoxycorticosterone (tetra-hydro-desoxycortico-sterone, THDOC) have a direct impact on the GABA system via the GABAA receptor (Majewska et al., 1986, Birzniece et al., 2006). These so-called GABA steroids modulate the brain's largest inhibiting system, the GABA system, by enhancing the effect on the GABAA receptor of GABA itself.
Section snippets
Sex steroid induced negative mood
Three obvious examples where there is evidence for the interaction between mood, steroids, and the CNS are: (i) premenstrual dysphoric disorder (PMDD), (ii) the negative mood symptoms encountered during sequential progestagen addition to oestrogen treatment in postmenopausal women, and (iii) the side effects of oral contraceptives (OCs).
The GABA paradox
It seems plausible to assume that all GABA allosteric modulators have similar behavioural as well as adverse effects. However, there is an obvious contradiction in the effects mediated by GABA active modulators. The positive effects, such as anxiolysis and sedation, are well known; but there is also evidence for the opposite, namely adverse effects, which also seem to be mediated by the GABAA receptor. This paradox of positive as well as adverse effects being mediated by GABA modulators is
GABA steroids and mood
With regard to GABA steroids, allopregnanolone has been found to be the most potent of the progesterone metabolites, followed by pregnanolone (Norberg et al., 1987, Paul and Purdy, 1992, Zhu et al., 2001, Timby et al., 2005). In fertile women, the circulating levels of allopregnanolone and pregnanolone follow that of progesterone, with higher concentrations during the luteal phase than in the follicular phase (Genazzani et al., 1998, Wang et al., 1996, Nyberg et al., 2007). A human post-mortem
A biphasic effect of GABAA modulators
In an attempt to explain the GABA paradox, it has been suggested that in certain individuals several GABAA receptor modulators, including allopregnanolone, have biphasic effects, with low doses or concentrations increasing an adverse, anxiogenic effect, and high doses or concentrations decreasing this effect and having more calming properties. The exact mechanism of this phenomenon is not known, but it is often referred to as a biphasic or bimodal effect. A hypothetical model of the biphasic
Potential mechanisms underlying the GABA-paradox
The results in the literature indicate two potential underlying mechanisms for the GABA-paradox; 1/disinhibition of output neurons or 2/reversal of Cl− current at the α4β2δ GABAA receptor. One of these mechanisms alone could be a possible reason to why allopregnanolone induce adverse mood effects. The shown paradoxical increase in the activity of the amygdala might reflect the disinhibition of the principal neurons of the amygdala via inhibition of inhibitory interneurons. As was shown in fMRI
Conclusions
Why is it that GABAA receptor positive modulators, such as benzodiazepines, barbiturates, alcohol and allopregnanolone show paradoxical effects in some individuals, rather than being anxiolytic and calming? These positive modulators have the opposite effect and instead cause anxiety, depression, and irritability/aggression. Given these findings, it seems plausible to conclude that a subset of individuals is sensitive to low doses or concentrations of GABAA receptor modulators and thus respond
Role of funding source
The funding has been unrestricted research grants from local, national and international souses. No influence on the text has been performed.
Conflict of interest
In this paper there is no involvement of commercial partners or other factors that could cause a conflict of interest. The paper is based on 25 years of research in the field.
Acknowledgements
This work was supported by the Swedish Medical Research Council (proj. 4X-11198), Umeå sjukvård, spjutspetsanslag, Visare Norr Norra Regionen, and by a grant from the EU Regional Funds, Objective 1. The financial support is from research grants and sponsors had no influence on the studies or the text.
References (119)
- et al.
Pharmacokinetics of progesterone and its metabolites allopregnanolone and pregnanolone after oral administration of low-dose progesterone
Maturitas
(2006) - et al.
Relationship between allopregnanolone and negative mood in postmenopausal women taking sequential hormone replacement therapy with vaginal progesterone
Psychoneuroendocrinology
(2005) - et al.
Isoallopregnanolone; an antagonist to the anaesthetic effect of allopregnanolone in male rats
Eur. J. Pharmacol.
(2005) Neurosteroids: a new function in the brain
Biol. Cell
(1991)- et al.
Neurosteroids and reward: allopregnanolone produces a conditioned place aversion in rats
Pharmacol. Biochem. Behav.
(2000) - et al.
The influence of subunit composition on the interaction of neurosteroids with GABA(A) receptors
Neuropharmacology
(2002) - et al.
Neuroactive steroids and inhibitory neurotransmission: mechanisms of action and physiological relevance
Neuroscience
(2006) - et al.
The effects of diazepam (valium) and aggressive disposition on human aggression: an experimental investigation
Addict. Behav.
(2002) - et al.
GABAergic and dopaminergic transmission in the rat cerebral cortex: effect of stress, anxiolytic and anxiogenic drugs
Pharmacol. Ther.
(1990) - et al.
Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems
Brain Res. Rev.
(2006)