Anxiogenic effects of neurosteroid exposure: sex differences and altered GABAA receptor pharmacology in adult rats

Acute exposure to progesterone or its neurosteroid derivative allopregnanolone (3alpha,5alpha-THP) is anxiolytic, consistent with the GABA modulatory effects of 3alpha,5alpha-THP at the GABA(A) receptor. However, continuous exposure to progesterone increases anxiety in association with increased expression of the benzodiazepine-insensitive GABA(A) receptor alpha4 subunit. Furthermore, negative mood symptoms and altered GABA(A) receptor pharmacology in patients with premenstrual dysphoric disorder occur in the early luteal phase in association with peak circulating levels of progesterone and 3alpha,5alpha-THP. Because sex differences have been reported in steroid-regulated anxiety responses, the present study investigated the role of sex and development in the regulation of anxiety after short-term exposure to 3alpha,5alpha-THP. To this end, we compared the effects of hormone administration in adult male, adult female, and juvenile female rats. Increased anxiety in the elevated plus maze was evident in all groups after 48-h exposure to either 3alpha,5alpha-THP or progesterone. At this time point, alterations in the anxiolytic profile of benzodiazepine agonists and antagonists were also observed in both adult males and females in the elevated plus maze. However, sex differences in the acoustic startle response were observed after short-term hormone treatment such that only female rats displayed an increased response indicative of higher anxiety levels. These results suggest that although neurosteroid exposure may influence both the pharmacological properties of the GABA(A) receptor and the manifestation of anxiety in both sexes, the effects of neurosteroids may be modulated in a sex- and task-specific manner.     

Decreased anxiety-like behavior,reduced stress hormones,and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon

Mice lacking protein kinase Cepsilon (PKCepsilon) are supersensitive to positive allosteric modulators of gamma aminobutyrate type A (GABA(A)) receptors. Since many of these compounds are anxiolytic, we examined whether anxiety-like behavior is altered in these mice. PKCepsilon-null mice showed reduced anxiety-like behavior and reduced levels of the stress hormones corticosterone and adrenocorticotrophic hormone (ACTH). This was associated with increased sensitivity to neurosteroid modulators of GABA(A) receptors. Treatment of PKCepsilon-null mice with the GABA(A) receptor antagonist bicuculline restored corticosterone levels and anxiety-like behavior to wild-type levels. These results suggest that increased GABA(A) receptor sensitivity to neurosteroids contributes to reduced anxiety-like behavior and stress hormone responses in PKCepsilon-null mice. The findings also suggest PKCepsilon as a possible therapeutic target for development of anxiolytics.     

Neurosteroid regulation of GABA(A) receptors: Focus on the alpha4 and delta subunits

Neurosteroids, such as the progesterone metabolite 3alpha-OH-5alpha[beta]-pregnan-20-one (THP or [allo]pregnanolone), function as potent positive modulators of the GABA(A) receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the alpha4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in alpha4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in delta-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Cl(-) current generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.     

Premenstrual syndrome

Premenstrual syndrome, a common cyclic disorder of young and middle-aged women, is characterized by emotional and physical symptoms that consistently occur during the luteal phase of the menstrual cycle. Women with more severe affective symptoms are classified as having premenstrual dysphoric disorder. Although the etiology of these disorders remains uncertain, research suggests that altered regulation of neurohormones and neurotransmitters is involved. Premenstrual syndrome and premenstrual dysphoric disorder are diagnoses of exclusion; therefore, alternative explanations for symptoms must be considered before either diagnosis is made. The disorders can manifest with a wide variety of symptoms, including depression, mood lability, abdominal pain, breast tenderness, headache, and fatigue. Women with mild symptoms should be instructed about lifestyle changes, including healthy diet, sodium and caffeine restriction, exercise, and stress reduction. Supportive strategies, such as use of a symptom diary, may be helpful in diagnosing and managing the disorders. In women with moderate symptoms, treatment includes both medication and lifestyle modifications. Dietary supplements, such as calcium and evening primrose oil, may offer modest benefit. Selective serotonin reuptake inhibitors such as fluoxetine and sertraline are the most effective pharmacologic agents. Prostaglandin inhibitors and diuretics may provide some relief of symptoms. Only weak evidence supports the effectiveness of gonadotropin-releasing hormone agonists, androgenic agents, estrogen, progesterone, or other psychotropics, and side effects limit their use.     

Premenstrual syndrome and premenstrual dysphoric disorder

Premenstrual syndrome is defined as recurrent moderate psychological and physical symptoms that occur during the luteal phase of menses and resolve with menstruation. It affects 20 to 32 percent of premenopausal women. Women with premenstrual dysphoric disorder experience affective or somatic symptoms that cause severe dysfunction in social or occupational realms. The disorder affects 3 to 8 percent of premenopausal women. Proposed etiologies include increased sensitivity to normal cycling levels of estrogen and progesterone, increased aldosterone and plasma renin activity, and neurotransmitter abnormalities, particularly serotonin. The Daily Record of Severity of Problems is one tool with which women may self-report the presence and severity of premenstrual symptoms that correlate with the criteria for premenstrual dysphoric disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision. Symptom relief is the goal for treatment of premenstrual syndrome and premenstrual dysphoric disorder. There is limited evidence to support the use of calcium, vitamin D, and vitamin B6 supplementation, and insufficient evidence to support cognitive behavior therapy. Serotonergic antidepressants (citalopram, escitalopram, fluoxetine, sertraline, venlafaxine) are first-line pharmacologic therapy.     

Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test

The present study investigated the effect of acute systemic administration of six progesterone metabolites on formalin-induced pain in the rat. The 3α-hydroxylated metabolites allopregnanolone and pregnanolone are highly potent positive modulators at the GABA_A receptor and produced a biphasic effect on pain in the formalin test. Dose-dependent antinociception was observed at lower doses (maximal antinociception at 0.16 mg/kg) and was reversed at higher doses. Bicuculline abolished the antinociceptive effect. The 3β-hydroxylated epipregnanolone and isopregnanolone are inactive or only weekly active at the GABA_A receptor, and did not affect formalin-induced pain. 5α- and 5β-dihydroprogesterone have also been shown to have low affinity for the GABA_A receptor, but can be rapidly metabolized to their 3α-hydroxylated counterparts. In the formalin test, they produced a biphasic effect on pain similar to that of pregnanolone and allopregnanolone, but with lower potency. The effect was reversible by bicuculline, showing involvement of the GABA_A receptor, and was blocked by indomethacin, implying that the antinociceptive effect is dependent on their conversion to allopregnanolone or pregnanolone. The results indicate that GABA-ergic progesterone metabolites modulate nociception. A change in levels of GABA-ergic progesterone metabolites, such as is observed in depression, chronic fatigue and premenstrual dysphoric disorder could, therefore, contribute to the pain complaints associated with these disorders.     

Neurosteroids in the context of stress: implications for depressive disorders

Animal models indicate that the neuroactive steroids 3alpha,5alpha-THP (allopregnanolone) and 3alpha,5alpha-THDOC (allotetrahydroDOC) are stress responsive, serving as homeostatic mechanisms in restoring normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following stress. While neurosteroid increases to stress are adaptive in the short term, animal models of chronic stress and depression find lower brain and plasma neurosteroid concentrations and alterations in neurosteroid responses to acute stressors. It has been suggested that disruption in this homeostatic mechanism may play a pathogenic role in some psychiatric disorders related to stress. In humans, neurosteroid depletion is consistently documented in patients with current depression and may reflect their greater chronic stress. Women with the depressive disorder, premenstrual dysphoric disorder (PMDD), have greater daily stress and a greater rate of traumatic stress. While results on baseline concentrations of neuroactive steroids in PMDD are mixed, PMDD women have diminished functional sensitivity of GABA(A) receptors and our laboratory has found blunted allopregnanolone responses to mental stress relative to non-PMDD controls. Similarly, euthymic women with histories of clinical depression, which may represent a large proportion of PMDD women, show more severe dysphoric mood symptoms and blunted allopregnanolone responses to stress versus never-depressed women. It is suggested that failure to mount an appropriate allopregnanolone response to stress may reflect the price of repeated biological adaptations to the increased life stress that is well documented in depressive disorders and altered allopregnanolone stress responsivity may also contribute to the dysregulation seen in HPA axis function in depression.     

Influence of the ovarian cycle on the central nervous system

Estradiol, progesterone and some of their metabolites modulate the activity of neurotransmitters and neuropeptides in the CNS. The distribution and concentrations of sex steroids in the various CNS regions is partly dependent on the serum levels, but also on the local synthesis of the steroids. In general, estradiol and testosterone exert a stimulatory, progesterone an inhibitory effect on neuronal activities which are mediated by excitatory (e.g. glutamate, aspartate), and inhibitory amino acids (e.g. GABA) and neuropeptides (e.g. beta-endorphin), respectively. Gonadotropin release is primarily governed by the rhythm of pulsatile secretion of GnRH in the hypothalamus which is controlled by estradiol and progesterone by means of inhibitory or stimulatory modulation of the amplitude and frequency of GnRH pulses. The discharges of GnRH neurons triggered by excitatory amino acids are modulated by estradiol, while the inhibitory effect of progesterone is mediated by GABA and beta-endorphin which cause hyperpolarization of the GnRH neurons and consequently a reduced pulse frequency. The pulse amplitudes are primarily influenced by estradiol, but neuropeptide Y, neurotensin and noradrenaline contribute to their preovulatory enhancement. The postovulatory rise in core temperature is caused by the increasing level of progesterone and its metabolite 3 alpha-pregnanolone, respectively. Despite of this, up to 20% of ovulatory cycles do not show any rise in body temperature. Although 3 alpha-pregnanolone has sedative activities, there is no change in sleep quality during the luteal phase due to their low serum levels. It could be demonstrated that performance on tests of articulatory and fine motor skills are enhanced in the late follicular phase as compared to the menstruation phase, while spatial ability was better during menses. Estrogens may influence mood and well-being in a favorable manner, while in predisposed women progesterone may cause symptoms of premenstrual syndrome. In most women there are, however, no cycle-dependent mood changes. An increase in appetite can be observed during the periovulatory phase and before menses, while sexual interest increases in the follicular phase. Somatic complaints (back pain, abdominal pain, breast tenderness) which are highest before and during menstruation, are probably associated with a lowered pain threshold due to a fall in the beta-endorphin levels in the CNS.     

Self-Focused Attention and Symptoms Across Menstrual Cycle Phases in Women With and Without Premenstrual Disorders

Premenstrual disorders, which include premenstrual dysphoric disorder and premenstrual syndrome involve cyclically occurring affective, behavioral, and physical symptoms. Despite high comorbidity rates and symptom overlap with mood and anxiety disorders, there has been a lack of research investigating psychological constructs that contribute to etiology and/or maintenance of premenstrual disorders. The current study hypothesized that self-focused attention (SFA) on emotional and somatic symptoms may contribute to premenstrual distress. Participants were 61 women, including 29 women with a premenstrual disorder (PMD subgroup) and 32 controls. Participants rated symptoms and SFA responses each day for 30 days. Findings indicated that women in the PMD group reported greater use of SFA responses to symptoms compared to the control group, and during the premenstrual compared to intermenstrual phases. SFA partially mediated the relationship between menstrual cycle phase and symptoms. The interaction between physiological menstrual cycle changes and psychological contributions provides a more comprehensive explanation for premenstrual disorders, and future research is warranted to clarify this relationship.     

Neurosteroid binding sites on GABA(A) receptors

Controlling neuronal excitability is vitally important for maintaining a healthy central nervous system (CNS) and this relies on the activity of type A gamma-aminobutyric acid (GABA(A)) neurotransmitter receptors. Given this role, it is therefore important to understand how these receptors are regulated by endogenous modulators in the brain and determine where they bind to the receptor. One of the most potent groups of modulators is the neurosteroids which regulate the activity of synaptic and extrasynaptic GABA(A) receptors. This level of regulation is thought to be physiologically important and its dysfunction may be relevant to numerous neurological conditions. The aim of this review is to summarise those studies that over the last 20 years have focussed upon finding the binding sites for neurosteroids on GABA(A) receptors. We consider the nature of steroid binding sites in other proteins where this has been determined at atomic resolution and how their generic features were mapped onto GABA(A) receptors to help locate 2 putative steroid binding sites. Altogether, the findings strongly suggest that neurosteroids do bind to discrete sites on the GABA(A) receptor and that these are located within the transmembrane domains of alpha and beta receptor subunits. The implications for neurosteroid binding to other inhibitory receptors such as glycine and GABA(C) receptors are also considered. Identifying neurosteroid binding sites may enable the precise pathophysiological role(s) of neurosteroids in the CNS to be established for the first time, as well as providing opportunities for the design of novel drug entities.     

Radioimmunoassay of Prostaglandins Fα, E1 and E2 in Human Plasma

Abstract. Antibodies against prostaglandins (PG)F₂α, E₁ and E₂ were obtained in rabbits immunized with respectively PG F₂α, PG E₁ and PG E₂ conjugated to bovine serum albumin by carbodiimide. A radioimmunoassay capable of measuring 7 pg of PG Fα, 2 pg of PG E₂ and 14 pg of PG Ej in human peripheral plasma is described. Plasma samples (pH 3, citric acid) are extracted with cyclohexane: ethyl acetate, 1:1 and then chromatographed on silicic acid columns to separate the prostaglandins into three fractions: fraction I, PG A, PG B and some unknown immunoraactive compounds; fraction II, PG E and fraction III PG Fα. The recovery is 80 %± 6. 2. Mean plasma levels iu adults of PG Fa and PG E, expressed in pg/ml: -PG Fα 12 ± 2. 8 (n = 25 men), 8 ± 2. 3 (n = 18 women, follicular phase), 7 ± 1. 4 (n = 18 women, luteal phase). -PG E₁ 40. 5 + 7. 6 (n = 13 men), 38 + 17. 1 (n = 10 women). -PG E₂ 4. 5 ± 1 (n = 12 adult subjects).
The major characteristics of the method described herein are the following: - a large volume of plasma has to be processed (10 ml or more for PG Fa and PG E₁, 5 ml or more for PG E₂). - a chromatographic step is necessary to separate the different prostaglandins which makes it possible to circumvent problems of immunological cross reactivity and interference with unknown immunoreactive compounds. - great care has been taken in collection of blood samples, especially to insure complete removal of blood cells namely platelets.     

Fast non-genomic effects of progesterone-derived neurosteroids on nociceptive thresholds and pain symptoms

Fast Inhibitory controls mediated by glycine (GlyRs) and GABAA receptors (GABAARs) play an important role to prevent the apparition of pathological pain symptoms of allodynia and hyperalgesia. The use of positive allosteric modulators of these receptors, specifically expressed in the spinal cord, may represent an interesting strategy to limit or block pain expression. In this study, we have used stereoisomers of progesterone metabolites, acting only via non-genomic effects, in order to evaluate the contribution of GlyRs and GABAARs for the reduction of mechanical and thermal heat hypernociception. We show that 3alpha neurosteroids were particularly efficient to elevate nociceptive thresholds in naive animal. It also reduced mechanical allodynia and thermal heat hyperalgesia in the carrageenan model of inflammatory pain. This effect is likely to be mediated by GABAA receptors since 3beta isomer was inefficient. More interestingly, 3alpha5beta neurosteroid was only efficient on mechanical allodynia while having no effect on thermal heat hyperalgesia. We characterized these paradoxical effects of 3alpha5beta neurosteroid using the strychnine and bicuculline models of allodynia. We clearly show that 3alpha5beta neurosteroid exerts an antinociceptive effect via a positive allosteric modulation of GABAARs but, at the same time, is pronociceptive by reducing GlyR function. This illustrates the importance of the inhibitory amino acid receptor channels and their allosteric modulators in spinal pain processing. Moreover, our results indicate that neurosteroids, which are synthesized in the dorsal horn of the spinal cord and have limited side effects, may be of significant interest in order to treat pathological pain symptoms.     

Neurosteroid modulation of synaptic and extrasynaptic GABA(A) receptors

Certain naturally occurring pregnane steroids act in a nongenomic manner to potently and selectively enhance the interaction of the inhibitory neurotransmitter GABA with the GABA(A) receptor. Consequently such steroids exhibit anxiolytic, anticonvulsant, analgesic, sedative, hypnotic, and anesthetic properties. In both physiological and pathophysiological scenarios, the pregnane steroids may function as endocrine messengers (e.g., produced in the periphery and cross the blood-brain barrier) to influence behaviour. However, additionally "neurosteroids" can be synthesised in the brain and spinal cord to act in a paracrine or autocrine manner and thereby locally influence neuronal activity. Given the ubiquitous expression of the GABA(A) receptor throughout the mammalian central nervous system (CNS), physiological, pathophysiological, or drug-induced pertubations of neurosteroid levels may be expected to produce widespread changes in brain excitability. However, the neurosteroid/GABA(A) receptor interaction is brain region and indeed neuron specific. The molecular basis of this specificity will be reviewed here, including (1) the importance of the subunit composition of the GABA(A) receptor; (2) how protein phosphorylation may dynamically influence the sensitivity of GABA(A) receptors to neurosteroids; (3) the impact of local steroid metabolism; and (4) the emergence of extrasynaptic GABA(A) receptors as a neurosteroid target.     

Characterization of the discriminative stimulus effects of the neuroactive steroid pregnanolone in DBA/2J and C57BL/6J inbred mice

Neurosteroids represent a class of endogenous compounds that exert rapid, nongenomic effects through neurotransmitter receptor systems such as GABA(A). Two neurosteroids, allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) and pregnanolone (3alpha-hydroxy-5beta-pregnan-20-one), possess anxiolytic and sedative properties and show substitution for ethanol, benzodiazepines, and barbiturates in drug discrimination assays. This study aimed to examine the effects of strain and sex on the discriminative stimulus effects of pregnanolone. Twelve male and female DBA/2J mice and 12 male and female C57BL/6J mice were trained to discriminate 10 mg/kg pregnanolone from saline. The male C57BL/6J mice had to be removed from the study due to increased seizures apparently associated with the chronic intermittent pregnanolone administration used in drug discrimination. GABA(A)-positive modulators, neuroactive steroids, N-methyl-d-aspartate (NMDA) antagonists, and 5-hydroxytryptamine (5-HT)(3) agonists were tested for pregnanolone substitution. In DBA/2J and C57BL/6J mice, a benzodiazepine, barbiturate, and GABAergic neuroactive steroids all substituted for the stimulus effects of pregnanolone. NMDA antagonists, 5-HT(3) agonists, and zolpidem failed to substitute for pregnanolone's discriminative stimulus in either sex or strain. Pentobarbital and midazolam were more potent in producing pregnanolone-like discriminative stimulus effects in DBA/2J mice. Differences in sensitivities to neurosteroids between the two strains were not evident. These results provide a comprehensive look at pregnanolone's discriminative stimulus effects in two commonly used strains of mice. The present data suggest that many of the previously documented neurosteroid-induced behavioral differences between the DBA/2J and C57BL/6J are acute effects and are not apparent in a drug discrimination procedure.     

Prevalence of premenstrual syndrome in autism: a prospective observer-rated study

A systematic, prospective observer-rated study was carried out to determine the prevalence of late luteal phase dysphoric disorder (premenstrual syndrome) in women with autism. A group of women with autism and learning disability (n = 26) was compared with a group of women with a non-autism learning disability (n = 36) matched for age, in-patient status, intelligence, marital status, parity, behavioural problems and ethnicity. Observers rated DSM-IV symptoms of late luteal phase dysphoric disorder every day from each subject over three consecutive menstrual cycles. Using a premenstrual increase in DSM-IV symptoms of >or= 30% as evidence of fulfilment of diagnostic criteria, the prevalence of late luteal phase dysphoric disorder was 92% in the autism group compared with 11% in the control group. This difference was highly statistically significant. The principal conclusion from this study is that there is a marked increase in premenstrual syndrome in women with autism compared with matched controls.     

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5]imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide (RWJ-51204), a new nonbenzodiazepine anxiolytic

5-ethoxymethyl-7-fluoro-3-oxo-1,2,3,5-tetrahydrobenzo[4,5] imidazo[1,2a]pyridine-4-N-(2-fluorophenyl)carboxamide) (RWJ-51204) binds selectively and with high affinity (K(i) = 0.2-2 nM) to the benzodiazepine site on GABA(A) receptors. Considering the GABA shift, the intrinsic modulatory activity of RWJ-51204 is lower than that of full agonist anxiolytics (lorazepam, diazepam, alprazolam, and clonazepam) but similar to partial agonists (bretazenil, abecarnil, panadiplon, and imidazenil). RWJ-51204 was orally active in anxiolytic efficacy tests; pentylenetetrazole induced seizure inhibition in mice (ED(50) = 0.04 mg/kg), Vogel conflict in rats (ED(50) = 0.36 mg/kg), elevated plus-maze in rats (minimal effective dose = 0.1 mg/kg), and conflict in squirrel monkeys (ED(50) = 0.49 mg/kg). RWJ-51204 attenuated chlordiazepoxide-induced motor impairment in mice. Usually, RWJ-51204 was more potent than reference anxiolytics in rodent efficacy tests but less potent in monkey conflict. Usually, the slope of the dose-response lines for RWJ-51204 was more shallow than the full agonist anxiolytics but steeper than partial agonists in efficacy tests but typically shallow in tests for central nervous system side effects. In monkeys only mild or moderate sedation was observed at doses equivalent to 20 or 40 times the anxiolytic ED(50). RWJ-51204 fits into the partial agonist class of GABA(A) receptor modulators. In conclusion, RWJ-51204 exhibits a profile in in vitro experiments and in animal models, in mice and monkeys (but not in rats), suggesting that it has a profile of anxiolytic activity associated with less sedation, motor impairment, or muscle relaxation than currently available GABA(A) receptor modulators, i.e., the benzodiazepines.     

Stimulation by intragastrically administered E2 prostaglandins of human gastric mucus output

Abstract. Prostaglandin E₂ and 15(R)15 methyl prostaglandin E₂ were instilled intragastrically to study gastric mucus output in healthy male subjects during an infusion of pentagastrin. Mucus was measured by determining total, free, and bound N-acetyl neuraminic acid (NANA) in gastric recoveries. NANA is a sialic acid located at the end terminals on the carbohydrate chains of mucus glycoprotein. It contributes to viscosity and prevents enzymatic degradation of mucus.
The methyl analogue of prostaglandin E₂ increased the gastric output of NANA and inhibited gastric acid secretion in a dose-dependent fashion. NANA produced in response to the analogue was bound to mucus glycoprotein. Prostaglandin E₂ increased the output of NANA without affecting the gastric acid secretion. Both prostaglandin E₂ and its methyl analogue increased volumes, pH, and NANA content of gastric aspirates withdrawn prior to start of the pentagastrin infusion, indicating a stimulation of the alkaline gastric secretion.
The results show that oral E₂ prostaglandins have dual effects on gastric secretion, and that their ability to stimulate mucus production is not secondary to gastric acid inhibition. Further studies are needed to examine whether their effect is mainly to increase the incorporation of NANA into mucus glycoproteins, or to stimulate the release and/or production of gastric mucus, and also to quantitate the gastric nonparietal secretion.
The stimulatory properties of E₂ prostaglandins on gastric mucus and alkaline secretion may be one mechanism by which they protect the gastric mucosa against experimentally induced damage.     

Mindfulness and Coping with Dysphoric Mood: Contrasts with Rumination and Distraction

Past research has shown that rumination exacerbates dysphoric mood whereas distraction attenuates it. This research examined whether the practice of mindfulness meditation could reduce dysphoric mood even more effectively than distraction. A dysphoric mood was induced in 139 female and 38 male participants who were then randomly assigned to a rumination, distraction, or meditation condition. As predicted, participants instructed to meditate reported significantly lower levels of negative mood than those in either of the two other conditions. Distraction was associated with a lessening of dysphoric mood when compared to rumination but was not as effective as mindfulness meditation. The implications of these findings are discussed.     

PLASMA FREE FATTY ACIDS AND PROSTAGLANDIN E1 IN MIGRAINE AND STRESS

SYNOPSIS
The relationship of plasma FFA, plasma PGE₁ and platelet serotonin changes were investigated in migrainous patients and in patients subjected to stressful procedures.
Plasma FFA levels rose and platelet serotonin content fell during the migrainous episode in the majority of patients. These changes were statistically significant. Plasma FFA levels and platelet serotonin changed reciprocally in 60% of cases. No statistically significant change in plasma FFA levels were observed in patients subjected to stressful procedures or during cluster headache.
Plasma levels of PGE₁ showed no significant change during migraine. No difference in PGE₁ between venous and arterial plasma was found in normal subjects and in patients with various neurologic diseases. Plasma levels of natural PGE₁ do not accurately reflect the rate of PGE₁ synthesis in the body and this may account for these negative results.
The migraine attack is accompanied by a rise in plasma FFA. However, this rise is not necessarily the cause for serotonin release which occurs during migraine. Both the amine and PGE₁ could release FFA from body stores. Identification of the individual FFA released would be necessary to resolve the problem. The role of PGE₁ in migraine, might be assessed by estimation of its more stable 15-keto-dihydro metabolite which reflects more accurately its rate of synthesis. This could demonstrate whether PGE 1 plays a part in the biochemical process of headache.     

Prostaglandin - E 2 Levels in the Saliva of Common Migrainous Women

SYNOPSIS
Prostaglandin E₂ (PG-E₂) levels were measured in the saliva of 6 women suffering from common migraine, during an attack, and in the interval between attacks; the results obtained were compared to the levels found in a matched control group of healthy women. There was a significant increase in the levels of PG-E₂ during migraine attack P<0.05. These results may suggest that PG-E₂ takes an important role in the mechanism of migraine.