Premenstrual Syndromes : PMS and PMDD - Rutuja :: The site ...

EVIDENCE OF ALTERED GABAERGIC
FUNCTION IN PMS/PMDD
Preclinical evidence
As reviewed in Chapter 9, estrogen and progesterone
have numerous effects throughout the CNS, mediating/
modulating reproductive as well as non-reproductive
behaviors. As is true with all steroid hormones, estradiol
and progesterone act through classic genomic
mechanisms, binding to intracellular receptors and
leading to gene transcription and protein synthesis over
the course of several minutes to hours to days (reviewed
by McEwen 3 ). However, it is now well known that
estrogen and progesterone (through its metabolites)
can modulate glial and/or neuronal function within
seconds via membrane-bound ion channels. 2,6,22 It is
this latter action, which is likely to be most relevant to
PMS/PMDD.
While estrogen acts directly on these membrane ion
channels, particularly those of the NMDA receptor
type, 2 the effects of progesterone are primarily, if not
exclusively, mediated via its metabolites 3�-hydroxy-
5�-pregnane-20-one (allopregnanolone; ALLO) and
ALLO’s �-stereoisomer 3�-hydroxy-5�-pregnane-20one
(pregnanolone; PREG) acting as potent GABA A
receptor agonists. 23,24 Several studies indicate that
estrogen binding to NMDA receptors on principal
neurons in the CA1 region of the hippocampus leads to
enhanced voltage-gated Ca 2+ currents 2,25 and increased
dendritic spine formation. Although it is somewhat
controversial whether estrogen treatment in menopausal
women enhances overall cognition, 26 the positive
effects of estrogen on hippocampal-mediated cognitive
function have been well demonstrated in humans, 27,28
non-human primates, 29 and rodents. 30,31 In addition,
estrogen appears to be critical to the maintenance of
cholinergic and catecholaminergic input to the dorsal
lateral prefrontal cortex in young adult monkeys, 32
although the exact mechanism has not been fully elucidated.
Estrogen treatment (ET) increases the gene and
protein expression of the astrocytic enzyme glutamine
synthase, which is important for the conversion of glutamate
to glutamine. 6 As glutamine is the predominant
precursor for glutamate synthesis, estradiol may
enhance overall glutamatergic function and cortical
excitability.
In contrast, ALLO and PREG exert sedative, hypnotic,
and anxiolytic properties by enhancing the duration
and frequency of the opening of GABA A receptor
chloride channels. 22 While the seizure threshold is
lowered in proestrus when estrogen is elevated, animals
are less likely to seizure during periods of high progesterone.
33 Across the estrus and menstrual cycles, ALLO
PATHOPHYSIOLOGY II: NEUROIMAGING, GABA, AND THE MENSTRUAL CYCLE 103
and PREG levels are thought to mirror the rise in plasma
progesterone, which occurs after ovulation. However,
ALLO and PREG are neurosteroids and, as such, can be
produced in glia and some neurons independent of
peripheral progesterone sources. Rodent studies indicate
that when under stress, the brain ratio of ALLO/progesterone
is greater than that of plasma. 23,34 It is thought
that adrenal production of ALLO, which is usually negligible,
rises in concert with cortisol during stress states,
presumably to counteract and/or supplement some of
the stress-related effects of cortisol. 35
Thus, what happens to the GABA A receptor during
the estrus and menstrual cycle, as well as during pregnancy
and lactation, has become the focus of a number
of preclinical and clinical research laboratories.
Ground-breaking work from Smith and colleagues 36,37
shows that acute and prolonged exposure as well as
withdrawal from ALLO results in an increase in � 4
subunit-containing GABA A receptors, which leads to
decreased benzodiazepine sensitivity and enhanced anxiety
behaviors in rodents. In contrast, progesterone and
PREG dampen the accentuation of the acoustic startle
response (ASR) in rodents undergoing corticotropinreleasing
hormone (CRH) infusion into the basal
nucleus of the stria terminalis (BNST), an area of the
brain thought to mediate the effects of anxiety/stress on
the ASR. 38 These data suggest that length of neurosteroid
administration may contribute to varied effects
on GABAergic function. While prolonged exposure
and withdrawal may accentuate anxiety, a brief exposure
to neurosteroids during stress may serve to dampen
anxiety and the stress response. Alternatively, as discussed
by Backstrom and colleagues in Chapter 13,
ALLO may exert a bimodal effect on anxiety/mood/
irritability/aggression, with lower doses that result in
blood levels similar to those seen during the luteal
phase, leading to negative affect in vulnerable individuals,
while higher doses, similar to those seen in late
pregnancy, are noted to improve mood.
Why consider the relationship between
glutamate and GABA?
These profound, and often opposing effects of estrogen
and progesterone highlight the importance of ‘striking
a balance’ in the neuroendocrine milieu in order to
maintain cognitive and neurobehavioral health.
Although this is likely to be true with multiple neurotransmitter
systems, the intimate link between the
glutamatergic and GABAergic systems with respect to
their synthesis and actions in the CNS is unique and
underscores their critical role in balancing neuronal
excitation and inhibition. Furthermore, glutamate and