alteration of 5-ht uptake by plasma fractions in the premenstrual syndrome

$: Alteration of 5-HT uptake by plasma fractions in the premenstrual syndrome$
J Neural Transm [GenSect] (1990) 79:41-50 __ Journal of

Neural Transmission

�9 by Springer-Verlag 1990

Alteration of 5-HT uptake by plasma fractions in the premenstrual syndrome

C. R. Ashby, Jr. *, L. A. Carr 1, C. L. Cook 2, M. M. Steptoe 2, and D. D. Franks 3

i Department of Pharmacology and Toxicology, 2 Department of Obstetrics and Gynecology, and 3 Department of Psychiatry and Behavioral Sciences,

University of Louisville, Louisville, Kentucky, U.S.A.

Accepted January 30, 1989

Summary. The effects of plasma and an aqueous plasma fraction from patients with premenstrual syndrome (PMS) and control subjects on the uptake of 5- hydroxytryptamine (5-HT) in washed human platelets and rat forebrain synaptosomes were studied. Pre- and postmenstrual samples of unextracted plasma from the control group significantly enhanced platelet uptake of 5-HT. In contrast, an aqueous fraction following extraction of the plasma with organic solvents caused a dose-dependent decrease of 5-HT uptake. Plasma obtained from patients with PMS caused less stimulation of 5-HT uptake compared to plasma from the control group. The aqueous fraction of premenstrual plasma from patients tended to inhibit 5-HT uptake to a greater extent than a similar plasma fraction from controls. The inhibition of 5-HT uptake was associated with an increase in Km- Aqueous plasma fractions from both groups also inhibited 5-HT uptake in brain synaptosomes. However, there were no significant differences between groups. The results of the platelet study suggest that there may be quantitative differences in the plasma concentration of endogenous factors that affect 5-HT uptake between patients with PMS and control subjects and that such differences may exp!ain the previously reported alteration of platelet 5-HT uptake and content associated with PMS symptoms.

Keywords: Plasma, premenstrual syndrome, platelets, synaptosomes, 5-HT uptake.

Introduction

The premenstrual syndrome (PMS) is comprised of a variety of psychological and somatic symptoms that occur in the luteal phase of the menstrual cycle (Dalton, 1984; Dunlay, 1983). These symptoms include depression, fatigue,

* Present address: Department of Psychiatry, State University of New York, Stony Brook, New York, U.S.A.

42 c .R . Ashby et al.

irritability, insomnia, headaches, water retention, aggressive and suicidal ten- dencies, increased pain sensitivity and cravings for certain foods (O'Brien, 1985). Since there is considerable evidence which implicates serotonin (5-HT) in the physiological regulation of sleep (Jouvet, 1969), pain perception (Messing et al., 1976), affective behavior (van Praag, 1986), aggression (Brown et al., 1982) and appetite (Blundell, 1979), a decrease in brain serotonergic activity possibly may be involved in the pathophysiology of PMS.

Several recent studies have suggested that platelet serotonergic mechanisms may be altered in PMS. Specifically, platelet uptake and content of 5-HT were decreased significantly in premenstrual samples from patients with PMS (Taylor et al., 1984; Ashby et al., 1988). It has also been shown that there is a significant premenstrual decrease in whole blood 5-HT levels in patients with PMS compared to controls (Rapkin et al., 1987).

Recent evidence has indicated that brain and plasma contain factors that affect 5-HT uptake in platelets (Brusov et al., 1985) and brain synaptosomes (Rehavi et al., 1985). Alteration of the plasma concentration or activity of one or more of these endogenous factors may be responsible for the changes in platelet 5-HT mechanisms observed in patients with PMS. In this study, the effects of plasma and an aqueous plasma fraction from PMS and control subjects on 5-HT uptake in human platelets were studied to ascertain whether endogenous factors were responsible for the transient inhibition of platelet 5-HT uptake associated with PMS symptoms. In addition, the effects of the aqueous fraction on 5-HT uptake in rat brain synaptosomes were studied to determine whether any effects in platelets could be extrapolated to brain serotonergic neurons.

Material and methods

Selection of study subjects

The 11 female volunteers who participated in this study were recruited through the De- partment of Obstetrics and Gynecology at the University of Louisville. All individuals were required to fulfill criteria previously described (Ashby et al., 1988) to insure that patients with PMS and control subjects constituted distinct and homogeneous groups. Each subject made daily (morning and afternoon) entries on a visual analogue scale to measure anxiety (Bond and Lader, 1974) and recorded daily various psychological and somatic symptoms in a menstrual symptom diary (Abraham, 1983) for two menstrual cycles. All subjects were required also to complete the Minnesota Multiphasic Personality Inventory (MMPI) during the postmenstrual week of cycle one to assess the overall psychological profile of the individual and to eliminate subjects from the study who had evidence of other psychiatric disorders. The MMPI was administered again during the premenstrual phase of cycles three or four to confirm the results from cycle one. Both control and PMS groups were studied concurrently and there were no differences in age, parity, marital status or length of the menstrual cycle between the two groups.

Preparation of plasma and plasma extracts

Each study subject determined the midcycle LH surge and the time of ovulation by means of a self-administered ovulation test (Quidel) which qualitatively measures urine LH levels.

Effect of plasma on 5-HT uptake in PMS 43

Between 8 and 10 days following the LH surge (premenstrual sample) and between 5 and 7 days after the onset of menstruation (postmenstrual sample), blood (28 ml) was drawn after an overnight fast by antecubital venopuncture between 8:00 and 9:00 a.m. The blood was collected in 16 • 75 mm vials (Monoject, St. Louis, Mo.) containing tripotassium EDTA and immediately centrifuged at 20,000 x g for 30 minutes at 4 ~ The resultant supernatant was collected and stored at - 20 ~ until assayed.

An aqueous fraction of plasma was prepared using a modification of a previously reported method (Angel et al., 1985). Two ml of plasma were added to 15 ml glass centrifuge tubes, diluted 1 : 4 with 0.9% NaC1 and heated for 10 minutes at 90 ~ The samples were centrifuged at 20,000 x g for 20 minutes at 4 ~ The supernatant was collected, extracted with hexane (3 : 2) and then centrifuged at 4,000 x g for 5 minutes. The aqueous phase was extracted with chloroform (3:2) and then centrifuged at 4,000 x g for 20 minutes. The aqueous phase layer was collected and evaporated at 60 ~ (N-EVAP, Organomation) under a nitrogen stream. The resulting residue was reconstituted by adding 200 ~tl of 0.9% NaC1 per ml of extracted plasma. The resulting suspension was centrifuged at 20,000 x g for 30 minutes at 4 ~ and the supernatant was collected.

Uptake of 5-HT in washed platelets

Platelets from outdated (no more than two days beyond the expiration date) platelet-rich plasma samples obtained from the Louisville Regional Blood Center were prepared by a method described in a previous report (Majerus and Baenzinger, 1974).

Platelet 5-HT uptake was determined as described previously (Ashby et al., 1988), except that the platelets were incubated with only one concentration of 5-HT (0.2 or 0.5 ~tM) and varying volumes of plasma or aqueous plasma fraction. The samples were assayed in triplicate and the results expressed as percent of samples with no added plasma.

The effects of the aqueous plasma fraction on the kinetics of platelet 5-HT uptake were determined as previously described (Ashby et al., 1988) except that five concentrations of 5-HT were used: 0.2, 0.4, 0.8, 1.2 and 2.0 ~tM (final concentration). All samples were assayed in triplicate. The Km and Vmax were determined using the Lineweaver-Burke plot.

Uptake of 5-HT in rat brain synaptosomes

Adult male Sprague-Dawley rats (200-275 g, Charles River Laboratories Inc., Portage MI) were killed by decapitation. Forebrain tissue (area anterior to the rostral hypothalamus) was dissected immediately, weighed and homogenized in 20 vols 0.32 M ice-cold sucrose. A crude synaptosomal preparation was prepared according to a method previously described (Angel and Paul, 1984).

The uptake of serotonin into synaptosomes was determined by slight modification of a previous method (Angel and Paul, 1984). The synaptosomes were incubated with one concentration of 5-HT (150nM) and the blanks were determined using 1 ~tM fluoxetine (Lilly Research Laboratories). All samples were assayed in triplicate. The results were expressed as percent of samples without plasma extract.

Statistical analysis

The data concerning the effects of plasma on platelet 5-HT uptake and aqueous plasma fraction on platelet and synaptosomal 5-HT uptake were subjected to repeated analysis of variance (2-way, mixed model; Bliss, 1967). Post hoc analyses were done using the Student- Newman-Keuls test. Comparison of the kinetic values for platelet uptake were analyzed using Student's unpaired t-test.

44 C.R. Ashby et al.

Results

The addi t ion of 30 gl plasma from both control subjects and patients caused an increase in the uptake of 5-HT in washed platelets (Table 1). However, plasma f rom controls caused a significantly greater increase in 5-HT uptake compared to plasma f rom patients during both sampling intervals. In contrast to the effects of plasma, the aqueous fraction remaining after organic extraction of plasma f rom patients and control subjects produced a significant, dose- dependent inhibition of 5-HT uptake in platelets (Table 2). The higher concentrations of the aqueous fraction from plasma obtained during the premenstrual interval f rom patients tended to cause a greater degree of inhibition than samples obtained from controls or f rom patients at other time intervals. How- ever, the difference was significant only with 60 ~1. Analysis of the uptake kinetics

Table 1. Effect of plasma from control subjects and PMS patients on [3H]5-HT uptake in washed platelets

Premenstrual Postmenstrual

Control PMS Control PMS

186 4- 28 (5) 128 • 10 (5)* 190 4- 25 (5) 112 4- 2 (6)*

Thirty gl of plasma were preincubated with 80 gl of washed platelet suspension for 10 rain at 37~ 0.1 gCi [3H]5-HT (final concentration 0.2txM) were added and the incubation was continued for 1 min. Each value represents the mean 4- S.E.M. (% uptake compared to control with no plasma). Values in parentheses represent the number of subjects. The mean control value for uptake was 4.29 4-0.26pmoles/108 platelets/min. * Significantly different from control (p < 0.05)

Table 2. Effect of aqueous plasma fraction from control subjects and PMS patients on [3H]5-HT uptake in washed platelets

gl plasma fraction Premenstrual Postmenstrual


20 74• 754-3(6) 87• 764-6(6) 40 644-7(5) 53• 654-4(5) 614-6(6) 60 314-6(5) 14+1(5)* 35+7(5) 374-9(6)

Varying volumes of aqueous plasma fraction or buffer were preincubated with 120 gl of washed platelet suspension for 10min at 37~ 0.1 ~tCi I-3H]5-HT (final concentration 0.5 gM) were added and the incubation was continued for 1 min. Each value represents the mean + S.E.M. (% of uptake with no extract). Values in parentheses represent the number of subjects. * Significantly different from premenstrual control (p < 0.05)


Table 3. Effect of aqueous plasma fraction on kinetics of [3H] 5-HT uptake in washed platelets

N K m Vmax (gM) (pmols 5 HT/108

platelets/min)

No added aqueous fraction 4 0.28 4- 0.03 11.3 4- 2.1

Aqueous fraction 4 0.90 4- 0.22* 8.5 + 1.2

Forty gl of aqueous plasma fraction obtained from control subjects during the premenstrual interval were preincubated with 120 gl of washed platelets sand 20 ~tl 0.9% NaC1 for 10 min at 37 ~ 0.1 gCi [3HI 5-HT and various concentrations of unlabeled 5-HT were added and the incubation was continued for 1 min. Each value represents the mean 4- S.E.M. * Significantly different from control (p < 0.05)

Table 4. Effect of aqueous plasma fraction from control subjects and PMS patients on [3H]5-HT uptake in rat forebrain synaptosomes

gl plasma fraction Premenstrual Postmenstrual


20 73 + 11 (5) 82 4- 3 (5) 73 + 7 (5) 80 4- 5 (6) 40 73 4- 4 (5) 53 4- 2 (5) 53 + 6 (5) 63 4- 8 (6) 60 604-7(5) 504-5(6) 364-3(4)* 494-7(6)

Two hundred ~tl of crude synaptosome preparation were preincubated for 10min with varying volumes of aqueous plasma fraction and buffer in a final volume of 900 gl. One hundred gl of [3H]5-HT (1.5 gM) were added and the incubation was continued for 2 min. Each value represents the mean+ S.E.M. (% of uptake with no plasma). Values in parentheses represents the number of subjects. * Significantly different from premenstrual control (p < 0.05)

indicated that 40 gl of aqueous fract ion f rom premens t rua l samples of the controls significantly increased the K m for platelet 5-HT uptake (Table 3).

To determine whether the effects of the aqueous fract ion on platelet serotonergic mechanisms could be ext rapola ted to the central nervous system, 5- H T up take in rat brain synaptosomes in the presence of this fract ion was also investigated. Aqueous p lasma fractions f rom both subject groups significantly decreased 5-HT uptake in synaptosomes in a dose-dependent fashion (Table 4; p < 0.05). A l though higher concent ra t ions o f p lasma fractions obta ined pre- menst rual ly f rom patients with PMS seemed to have a greater inhibi tory effect on 5-HT uptake than control subjects, the differences were not statistically significant. Sixtly gl o f aqueous fract ion o f the plasma obta ined f rom controls


during the postmenstrual interval caused a significantly greater inhibition of uptake compared to that obtained in the premenstrual interval.

To determine if the effects of plasma fractions on 5-HT uptake could have been due to organic solvent residue from the extraction procedure or to an increase in salt concentration, 8 ml of 0.9% NaC1 solution were extracted with organic solvents as described above. Incubation of 40 gl of the aqueous fraction with platelets or synaptosomes had no effect on 5-HT uptake. In addition, extracts of solutions of 5-HT (20 nM), tryptophan (10 gM) or albumin (6% w/v in 0.9% saline) had no inhibitory effect on platelet 5-HT uptake.

Discussion

The results of this study suggest the existence of at least two different endogenous factors in the plasma of both patients with PMS and control subjects which can alter uptake of 5-HT in washed human platelets. Stimulation of 5-HT uptake by platelets, which was most apparent with plasma from control subjects, occurred only with unextracted plasma, suggesting that it was caused by a lipid soluble or heat labile stubstance. A previous study likewise has shown that 30 gl of plasma from normal volunteers increased platelet 5-HT uptake by approximately 30% (Abraham et al., 1987). Although the identity of this factor has not been elucidated, a possible candidate is serotonectin, a glycoprotein found in plasma and platelet membranes (Tamir et al., 1985). Several reports have indicated that serotonectin binds 5-HT with high affinity and increases the uptake of 5-HT in platelets washed with isotonic saline (Tamir et al., 1983; Gershon and Tamir, 1984). A similar substance, plasma a~ acid glycoprotein also has been shown to increase platelet 5-HT uptake (Abraham et al., 1987). The observed difference in uptake of 5-HT between PMS patients and control subjects after the addition of 30 gl of plasma may be due to control plasma having a higher concentration of free serotonectin or am acid glycoprotein or the serotenectin that is present may bind with higher affinity to platelets. Al- ternatively, an enhanced concentration of an inhibitory factor in PMS patients, as described below, may have masked the effects of the stimulating factor.

In contrast to the effects observed with plasma, aqueous fractions of plasma from both patients and control subjects inhibited 5-HT uptake in platelets. One previous study also has shown a dose-dependent inhibition of platelet 5-HT uptake following the addition of human plasma extracts (Brusov et al., 1985). However, that study used plasma only from normal subjects. In the present study, the difference in the degree of inhibition between the pre- and postmenstrual samples became more pronounced as the concentration of aqueous fraction from PMS patients was increased. This was in contrast to the control subjects in which little or no variation was observed between sampling intervals. These results support the hypothesis that the observed premenstrual decrease in Vma x for platelet 5-HT uptake in PMS patients (Ashby et al., 1988; Taylor et al., 1984) could be attributed, at least in part, to a greater plasma concentration of an endogenous factor that inhibits platelet 5-HT uptake premenstrually.


The results of the kinetic study in control subjects indicated an increase in the Km, suggesting that the inhibition of uptake by plasma fractions is com- petitive. Unfortunately, the lack of sufficient sample volumes precluded carrying out such studies in PMS patients, and thus it could not be determined whether the K m for uptake in the presence of plasma fractions from such individuals differs from normal subjects.

Although statistical analysis did not indicate a significant difference between groups with regard to the effects of plasma fractions on synaptosomal uptake of 5-HT, premenstrual samples from patients with PMS tended to inhibit synaptosomal uptake to a greater degree than samples from control subjects. The major contrast between the subject groups was a cycle-related alteration in 5- HT uptake in control subjects which was not apparent in the PMS group. Factors which may have precluded a more direct correlation of the effects of plasma fractions on platelets and synaptosomes include species differences and the possibility that serotonergic nerve terminals do not respond in precisely the same manner to endogenous factors as do blood platelets. This is further sup- ported by the observations that plasma inhibits 5-HT uptake in synaptosomes, in contrast to the stimulating effect on uptake in platelets (unpublished results from this laboratory).

The endogenous factor that inhibits 5-HT uptake in platelets and synaptosomes may be a beta-carboline (Faull et al., 1982). These compounds, par- ticularly the tetrahydro-j3-carbolines, are found in high concentrations in brain tissue, urine and blood platelets in rats and humans and have been shown to decrease 5-HT uptake in various tissues with some degree of specificity (Kellar et al., 1976; Rommelspacher et al., 1978; Kari et al., 1979). They have also been implicated in the etiology of anxiety, insomnia and depression (Skolnick et al., 1984; Huttunen et al., 1985; Langer et al., 1984). Based on these findings, it is possible that beta-carbolines may give rise to the symptoms of PMS by altering 5-HT neuronal function.

It is unlikely that the endogenous inhibitory factor is 5-HT itself, as several investigators have shown that this substance does not co-elute with 5-HT during column chromatography of rat brain extracts (Barbaccia et al., 1985). In addition, while plasma contains 4-15nM 5-HT (Anderson et al., 1987), the Km of platelets for 5-HT uptake is approximately 500nM (Meltzer et al., 1981; Lingjaerde, 1977). One study has suggested that the factor is an endogenous inhibitor of Na +/K § ATPase (Kamal et al., 1983). However, approximately 200 times more plasma is necessary to inhibit the ATPase enzyme by 50% compared to the amount required to inhibit 5-HT uptake in platelets and synaptosomes (Angel and Paul, 1984).

In conclusion, the results of this study indicate that both PMS and control subjects possess endogenous plasma factors that alter platelet and synaptosomal 5-HT uptake in a dose-dependent manner. Patients with PMS appeared to differ from control subjects in at least two respects. The former either have a tonic deficiency of a lipid soluble and/or heat labile endogenous uptake stimulating


factor or possess a factor which is much less active. Secondly, there appear to be phasic differences in the concentrat ion or activity of an endogenous factor which inhibits 5-HT uptake in platelets. The pat tern of uptake inhibition co- incided with previously described premenstrual alterations in platelet 5-HT uptake and content. It is unclear how inhibition of 5-HT uptake by endogenous factors may be related to serotonergic neuron activity or to PMS symptoms. It is possible that inhibition of uptake could result in decreased serotonergic neuronal activity (Blier and De Montigny, 1983) and a subsequent decrease in 5-HT release by a feedback mechanism.

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Authors' address: Dr. L. A. Carr, Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40292, U.S.A.

Received September 27, 1988

alteration of 5-ht uptake by plasma fractions in the premenstrual syndrome

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