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Hormones and  Benzodiazepines

PMS, Postpartum Depression, Sedative Withdrawal Believed to Have Common Brain-Receptor Link

By Richard Karel

A study in the April 30, 1998 edition of Nature suggests there may be a fundamental biochemical commonality in the psychological and physical symptoms associated with premenstrual syndrome (PMS), postpartum lability and sudden withdrawal from sedatives such as benzodiazepines and alcohol.

In the article ("GABA Receptor Alpha-4 Subunit Suppression Prevents Withdrawal Properties of an Endogenous Steroid"), Sheryl S. Smith, Ph.D., an associate professor in the department of neurobiology and anatomy at Allegheny University of the Health Sciences in Philadelphia, Pa., and colleagues show how all of the above are related to increased production of the alpha-4 subunit, one of five molecules that make up the brain receptor for gamma-aminobutyric acid (GABA).

GABA is the brain's primary inhibitory neurotransmitter, functioning as an internally produced tranquilizer. But when too much alpha-4 is produced, the receptor's capacity to use GABA is blunted, and a variety of unpleasant results occur, including increased anxiety, an increased tendency toward seizures, and other symptoms of PMS, postpartum lability, and sedative withdrawal.

All of this occurs only at the end of a long, neurochemical cascade, and in this one study using rats, Smith and colleagues follow that cascade to its logical conclusion.

The first link is progesterone, a hormone that exists in high concentrations during pregnancy and prior to the onset of menstruation.

Progesterone, in both men and women, breaks down into allopregnanolone, which enhances the sedative effects of GABA, although precisely how is unknown. But immediately after pregnancy, and right before the onset of menstruation, progesterone levels plunge, leading to a corresponding drop in the metabolite allopregnanolone. Without allopregnanolone to come to the GABA receptor's defence, the alpha-4 molecule gains the upper hand, hindering GABA's efficacy and leading to all the unpleasant symptoms associated with PMS, postpartum mood swings, and acute sedative withdrawal.

Although the research was conducted on rats, its ultimate implications for psychiatry are both clear and tantalizing. It is, after all, the goal of psychiatry to restore normal balance to the brain, and by implication, the psyche. Should it prove feasible to modify neurocellular processes in humans in a manner similar to what Smith and her colleagues did with their rats, it is possible to envision the development of psychiatric drugs that are simultaneously narrow in their targeting of neuroreceptor systems and broad in their capacity to normalize brain function.

"I would hope that at some point in the future, targeting the alpha-4 subunit may prove to be useful for therapeutic intervention in PMS anxiety or other anxiety states," Smith told Psychiatric News. "The use of neuroactive steroids as therapeutic agents is already the goal of several drug companies, both in the U.S. and abroad," she noted, but the technology needs further refinement.

Although the research is most relevant to women, changes in the alpha-4 subunit may occur under stress, leading to "anxiety states" in both men and women, said Smith. Although the research identified allopreg-nanolone as the agent effecting alpha-4 subunit production, the next step will be to determine how allopregnanolone exerts its effects, Smith added.

The current study is "only a part of an explosion of interest in modulation of brain function by neuroactive steroids" such as allopregnanolone, observe Karen Britton, M.D., of the department of psychiatry at the University of California at San Diego, and George Koob, Ph.D., a professor of neuropharmacology at the Scripps Research Institute in La Jolla, Calif., in a commentary accompanying Smith's study. A number of steroids with the potential to "act like neuroactive steroids" have been identified, they note.

"This neuroactive-steroid connection may prove to be involved in sedative-hypnotic actions, aging, stress, and alcohol abuse," they continue. The steroids derived from progesterone may help explain the symptoms of pregnancy and menstruation, and perhaps one of psychiatry's oldest conundrums: why men and women have such a striking difference in the incidence of anxiety and mood disorders, they add.

In their study, Smith and colleagues experimentally induced progesterone withdrawal, which, as expected, triggered a sharp drop in allopregnanolone. Normally, allopregnanolone acts as an endogenous sedative by enhancing the effects of GABA. The authors found that when levels of progesterone and its metabolite allopregnanolone fell, there was a corresponding increase in the production of the alpha-4 molecule. This radically weakened GABA's anxiolytic effects.

Following this sequence of events to its implicit conclusion, the scientists then blocked production of the alpha-4 molecule and found that, as would be expected, the progesterone withdrawal syndrome was also blocked.

Since benzodiazepines potentiate GABA, the authors decided to test the hypothesis that there is cross-tolerance to progesterone, allopregnanolone, and benzodiazepines. They found that 24 hours after progesterone withdrawal, the GABA-potentiating effect of lorazepam fell drastically, in some cases disappearing completely. They confirmed that this was a result of the withdrawal of the progesterone metabolite allopregnanolone by using another drug to block the initial formation of allopreg-nanolone during progesterone exposure. When they did this, the insensitivity to lorazepam following progesterone withdrawal did not occur. Further tests found that the decreased sensitivity to lorazepam correlated with increased seizure activity.

In humans, it has been reported that women who suffer from PMS are insensitive to benzodiazepines. In addition, some women suffer from catamenial epilepsy, a form of seizure activity altered by the menstrual cycle that occurs toward the end of menses when progesterone drops. Withdrawal from ethanol, another GABA-modulating drug, is also characterized by seizure susceptibility, the authors note. All of these observations point to the potential clinical relevance of the research.

"Our results indicate that fluctuations in endogenous progesterone levels may result in plasticity of the GABA-alpha receptor through the GABA-modulating allopregnan-olone," the authors conclude. "Fluctuations in levels of these neuroactive steroids are associated with the menstrual and pregnancy cycles, and are induced by stress in males. Manipulation of the GABA-alpha receptor alpha-4 subunit levels may prevent cross-tolerance with sedative drugs and reduce generalized excitability and increased seizure susceptibility associated with periods of endogenous progesterone withdrawal."


GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid.

Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JM, Li X.

Department of Neurobiology and Anatomy, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19129, USA. smiths@auhs.edu

The hormone progesterone is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) in the brains of males and females. In the brain, 3alpha,5alpha-THP acts like a sedative, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid), the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety and seizure susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3alpha,5alpha-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines and ethanol can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3alpha,5alpha-THP which enhance transcription of the gene encoding the alpha4 subunit of the GABA(A) receptor. We also find that increased susceptibility to seizure after progesferone withdrawal is due to a six fold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the alpha4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal.


Menstrual cycle effects on cortical excitability.

Click here to read 

Smith MJ, Keel JC, Greenberg BD, Adams LF, Schmidt PJ, Rubinow DA, Wassermann EM.

National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.

OBJECTIVE: To determine whether there are menstrual cycle-related effects on cortical excitability in normal women. BACKGROUND: Ovarian steroid hormones affect neurotransmission in the brain. Data from animal experiments have shown that progesterone metabolites enhance the action of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the cortex, producing benzodiazepine-like (e.g., diazepam and lorazepam) physiologic and behavioral effects. Estradiol has excitatory effects on measures of neuronal excitability, possibly acting through the glutamate system. These effects have been difficult to detect in women using conventional techniques. However, recently, paired transcranial magnetic stimulation (TMS) has been used to detect the effects of GABAergic and glutamatergic drugs in humans. We used this method to measure the effects of the menstrual cycle in normal women. METHODS: We tested 13 healthy women during the follicular (low-progesterone) and luteal (high-progesterone) phases of the menstrual cycle using paired TMS. The effect of a subthreshold conditioning pulse on the cortex was tested by measuring the response to a second suprathreshold test pulse and comparing it with the response elicited by the test pulse administered alone. RESULTS: Conditioning TMS produced more inhibition in the luteal phase than in the follicular phase (p = 0.01), of similar magnitude to the reported effect of benzodiazepine drugs. CONCLUSIONS: This study provides the first direct evidence of changes in the excitability of a cortical network with the menstrual cycle. The results also show a potential confound for studies using transcranial magnetic stimulation in populations that include menstruating women.


Withdrawal properties of a neuroactive steroid: implications for GABA(A) receptor gene regulation in the brain and anxiety behavior.

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Smith SS.

Deppartment of Physiology and Pharmacology, SUNY Health Science Center at Brooklyn, 450 Clarkson Ave., Brooklyn, NY 11203, USA. sheryl_smith@netmail.hscbklyn.edu

Early work in the field established that the 5 alpha-reduced metabolite of progesterone 3 alpha-OH-5 alpha-pregnan-20-one (allopregnanolone or 3 alpha,5 alpha-THP) is a potent positive modulator of the GABA(A) receptor (GABAR), the receptor mediating the effects of the primary inhibitory transmitter in the brain. This steroid acts in a manner similar to sedative drugs, such as the barbiturates, both in terms of potentiating GABA-induced inhibition in vitro and in behavioral assays, by reducing anxiety and seizure susceptibility. Because sedative compounds exhibit withdrawal properties that result in behavioral hyperexcitability, our laboratory has more recently investigated the effect of prolonged application and rapid removal (i.e. 'withdrawal') of this steroid, administered in vivo to female rats. Withdrawal from 3 alpha,5 alpha-THP produces a state of increased anxiety and lowered seizure threshold, similar to withdrawal from other GABA-modulatory drugs such as the benzodiazepines and alcohol. Hormone withdrawal also produced increases in the alpha 4-containing GABAR, an effect correlated with insensitivity of the GABAR to modulation by the benzodiazepine class of tranquilizers, as would normally occur under control conditions. In addition, changes in intrinsic channel properties, including a marked acceleration in the decay rate was also observed as a result of declining levels of 3 alpha,5 alpha-THP. Such a change would result in less inhibitory total current, and the resulting increase in neuronal excitability could then underlie the observed behavioral excitability following hormone withdrawal. These results suggest that actions of this steroid on a traditional transmitter receptor in the brain lead to alterations in GABAR subunit composition that result in changes in the intrinsic channel properties of the receptor and behavioral excitability. These results may have implications for endogenous fluctuations in this hormone which may accompany premenstrual dysphoric disorder.

 

 

 

 

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Last updated 22 July 2015