Estradiol and progesterone influencel-5-hydroxytryptophan-induced myoclonus in male guinea pigs: Sex differences in serotonin-steroid interactions

The effects of castration in males and sex differences in the effects of estradiol and progesterone on L-5-hydroxytryptophan (L-5-HTP)-induced myoclonus in guinea pigs were examined. Castration had no effect on L-5-HTP-induced myoclonus in males. There were sex differences in sensitivity to L-5-HTP. In the absence of steroids, L-5-HTP-induced myoclonus was higher in gonadectomized males than females. A low dose of estradiol benzoate (EB; 3.5 micrograms) given 46 h before L-5-HTP (100 mg/kg) enhanced myoclonus in gonadectomized females but not males. However, at a higher dose of EB (10 micrograms) and a lower dose of L-5-HTP (80 mg/kg), myoclonic responding was enhanced in males. These findings indicate that estradiol has a similar effect on L-5-HTP-induced myoclonus in males and females, but do not rule out the possibility of sex differences in sensitivity to L-5-HTP when both sexes are given estradiol priming. When L-5-HTP was given 6 h after 0.5 mg progesterone in estradiol-primed males, myoclonus was enhanced. Progesterone treatment reverses the facilitative effect of EB on L-5-HTP-induced myoclonus in females. Therefore, progesterone has opposite effects on L-5-HTP-induced myoclonus in males and females. These findings were discussed with respect to the interaction of steroids and 5-HT transmission in the regulation of steroid-dependent reproductive behavior.     

Abbreviation of the period of sexual behavior in female guinea pigs by the progesterone antagonist RU 486

In previous studies we have tested the hypothesis that the termination of the period of sexual behavior in female guinea pigs results from the loss of progestin receptors from hypothalamic cell nuclei. We have shown that hormonal manipulations that delay heat termination also delay loss of hypothalamic nuclear progestin receptors. In order to determine if accelerated nuclear receptor loss results in abbreviation of the period of sexual behavior, we tested the effect of 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propyl)-estra-4,9-diene-3-one (RU 486), a progesterone antagonist, on heat termination. Ovariectomized guinea pigs were treated with estradiol benzoate. Forty hours later, they received progesterone followed 4 h later by injection of RU 486 or vehicle. RU 486 injected 4 h after progesterone caused heat abbreviation. We have found that RU 486 administration to estradiol-treated guinea pigs causes accumulation of progestin receptors in cell nuclear extract. Because this accumulation can be detected only when assay conditions are used that promote exchange of RU 486 progestin receptor complexes (15 degrees C incubation rather than 0 degree C); our routine assay conditions (at 0 degree C) can be used to measure primarily receptors that are occupied by progesterone. In order to confirm that RU 486 decreased progesterone-occupied nuclear progestin receptor levels when injected 4 h after progesterone, animals treated as in the behavioral experiment were killed 6 or 10 h after progesterone injection (2 or 6 h after RU 486), and nuclear progestin receptor levels were measured. RU 486 treatment resulted in lowered nuclear concentrations of hypothalamic progestin receptors at both times. These results support our hypothesis that the termination of the period of sexual receptivity in female guinea pigs is the result of loss of progestin receptors from hypothalamic cell nuclei.     

Hypersensitivity to central serotonin receptor activation in scrapie-infected hamsters and the effect of serotonergic drugs on scrapie symptoms

Low doses of the serotonin agonist, quizapine, and the serotonin precursor,l-5-hydroxytryptophan methyl ester, produce small but significant reductions in scrapie-induced ataxia and action jerks in hamsters.Higher doses of both drugs elicit a behavioral syndrome specific for central serotonin receptor activation. Scrapie-infected hamsters show a dramatic hypersensitivity to both drugs compared to control animals. This suggests that scrapie infection in hamsters causes a disturbance in the serotonergic pathway of the brain stem.     

Loss of hypothalamic nuclear-bound progestin receptors: Factors involved and the relationship to heat termination in female guinea pigs

The hypothesis that the termination of sexual receptivity (heat) in female guinea pigs results from loss of progestin receptors from hypothalamic cell nuclei was tested. First, we attempted to find an optimal dose of progesterone that would result in a prolonged period of sexual receptivity. Ovariectomized guinea pigs were implanted with 10% estradiol capsules. Forty hours later, each received one of several sized progesterone capsules before being tested hourly for lordosis. Surprisingly, none of the progesterone doses resulted in delayed heat termination. In order to determine whether elevated levels of estradiol and progesterone maintain elevated levels of nuclear progestin receptors despite the lack of effect on heat duration, animals were treated as described above except that only one size progesterone capsule (3.0 cm) or an empty capsule was implanted. Despite elevated serum progesterone concentrations, nuclear progestin receptor levels decreased gradually and approached control levels at about the same time as heat termination had occurred in similarly-treated animals. Cytosol progestin receptor levels decreased following progesterone treatment and remained lowered at all times measured. In order to further investigate the relationship between blood progesterone concentrations and retention of nuclear progestin receptors we decreased blood progesterone concentrations by removing progesterone capsules 2 h following insertion. Nuclear progestin receptor levels declined gradually concurrent with a decline in serum progesterone levels in animals exposed to progesterone capsules for only 2 h. In animals exposed to capsules continuously, nuclear progestin receptor levels again decreased but at a slightly slower rate. In order to test the effect of progesterone capsule removal on female sexual behavior, ovariectomized guinea pigs were treated as described and tested hourly for lordosis. Fewer animals in the group exposed to progesterone capsules for 2 h became sexually receptive as compared to animals continuously-exposed to progesterone capsules. Of those animals that did respond, heat termination had occurred by the same time that nuclear progestin receptor levels had returned to control levels in similarly-treated animals. These experiments support the hypothesis that heat termination results from the loss of progestin receptors from hypothalamic cell nuclei. In addition, they demonstrate that circulating progesterone levels play a role in regulating nuclear progestin receptor retention.     

Tryptophan metabolism and the occurrence of amino acids and serotonin in the leech (Hirudo medicinalis) nervous system.

The occurrence and distribution of serotonin (5-HT) and amino acids along the central nerve chain of the leech, Hirudo medicinalis, was analyzed using dansyl-chloride in order to obtain information on the functional roles of amines and amino acids. There was no statistical variation in the occurrence of most of the amino acids or serotonin in the different parts of the dorsal nerve chain of the leech. A variation in the serotonin content was found during the year with the highest level occurring in winter. Leech ganglia also accumulated 3H-tryptophan and metabolized part of it to form 5-HTP, 5-HT, and 5-HIAA. The results are discussed from the point of view of 5-HT being a transmitter substance.     

Resident-intruder trait aggression is associated with differences in lysine vasopressin and serotonin receptor 1A (5-HT1A) mRNA expression in the brain of pre-pubertal female domestic pigs (Sus scrofa)

Aggressive behaviour exhibited by domestic pigs following encounters with unfamiliar individuals is a serious welfare and economical problem. Aggression resulting in skin lesions is similarly prevalent in prepubertal pigs of either sex. Little is known about the neural circuits and neuropeptides that control aggression in the pig. Because there is evidence for the involvement of the vasopressin and serotonergic systems in the regulation of aggressive behaviour in male mammals, we sought differences using quantitative in situ hybridisation of vasopressin and serotonin 1A receptor (5-HT1A) mRNA expression within specific brain regions of aggressive and nonaggressive prepubertal female pigs. The number of cells expressing vasopressin mRNA was significantly higher in aggressive pigs in the medial amygdala, lateral septum (LS) and showed a similar trend in the bed nucleus of the stria terminalis (BnST) but not the paraventricular nucleus (PVN) or supraoptic nucleus. The 5-HT1A receptor was widely expressed through the porcine brain and a significantly lower intensity (silver grain density) of 5-HT1A mRNA expression was observed in the BnST. In the medial amygdala and LS fewer cells expressed 5-HT1A mRNA in aggressive pigs but no differences were found in the PVN. In the absence of inbred strains or selection lines, these findings have shown that prior identification of phenotypic behavioural extremes in a population in advance of neural studies is a useful technique. Moreover, these findings support a central role for vasopressin and serotonin in the mediation of high trait aggression in prepubertal female pigs.     

Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers

The precursor of serotonin, L-5-hydroxytryptophan (L-5-HTP), was radiolabelled with 11C in the beta-position, yielding [beta-11C]serotonin after decarboxylation, allowing positron emission tomography studies of L-5-HTP uptake across the blood-brain barrier. We studied 8 healthy volunteers and 6 patients with histories of DSM-III major depression, 2 with repeated examinations after clinically successful treatment. We report a significantly lower uptake of [11C]5-HTP across the blood-brain barrier in depressed patients, irrespective of phase of illness. The findings emphasize that serotonin is involved in depressive pathophysiology and support earlier suggestions that the transport of 5-HTP across the blood-brain barrier is compromised in major depression.     

Tryptophan hydroxylase and 5-HTP-decarboxylase activity in cockroach brain and the effects of p-chlorophenylalanine and 3-hydroxybenzylhydrazine (NSD-1015)

The activities of two enzymes of the serotonin biosynthetic pathway, namely tryptophan hydroxylase (TPH) and 5-hydroxytryptophan-decarboxylase (5-HTP-D), were determined in the cockroach, Periplaneta americana, brain using radiometric techniques, significant levels of both enzymes were found. p-Chlorophenylalanine (PCPA) inhibited brain TPH activity strongly both in vitro and in vivo. In vitro, 10 mM PCPA reduced the TPH activity by 76% and in vivo either 15 micrograms/g or 30 micrograms/g of PCPA inhibited brain TPH activity by 80-85%. The activity of 5-HTP-D enzyme was inhibited significantly in vivo by 3-hydroxybenzylhydrazine, commonly known as NSD-1015. A recovery in the activity of 5-HTP-D enzyme was observed 12 h after 50 micrograms/g of NSD-1015 but 100 micrograms/g caused an inhibition lasting for the 24 h period studied.     

Biochemical and radioautographic analysis of estrogen-inducible progestin receptors in female ferret brain and pituitary: Correlations with effects of progesterone on sexual behavior and gonadotropin-releasing hormone-stimulated secretion of luteinizing hormone

Cytosolic binding molecules for the synthetic progestin [3H]R5020, were isolated in vitro from several brain regions including preoptic area/anterior hypothalamus, mediobasal hypothalamus, medial amygdala and parietal cortex as well as the pituitary gland of ovohysterectomized female ferrets. Binding of [3H]R5020 to cortical cytosols was saturable, of high affinity (apparent dissociation constant of 2.0 nM), and was steroid specific. Pretreatment of ferrets with a Silastic capsule containing estradiol caused significant increments in the concentration of cytosolic R5020 binding sites in hypothalamus and pituitary gland, but not in the other brain regions studied. Brains of additional ovohysterectomized ferrets, which had been primed with estradiol prior to receiving an i.v. injection of [3H]R5020, were processed radioautographically. Intense labeling of cells was seen in the medial and lateral preoptic area, in the lateral hypothalamus, and in the ventromedial and arcuate nuclei of the hypothalamus. Radioautograms from the brains of additional ovohysterectomized ferrets given an i.v. injection of [3H]estradiol revealed labeled cells in all of the above regions, in addition to the basolateral portion of the septum, the bed nucleus of the stria terminalis, and in the anterior amygdaloid area as well as the medial and cortical nuclei of the amygdala. This distribution of neural progestin and estrogen binding sites resembles those previously reported for these steroids in the rat, guinea pig, hamster and macaque. Functional studies showed that acute s.c. implantation of a Silastic capsule containing progesterone to ovohysterectomized ferrets, which had been primed with a low dosage of estradiol, failed to augment their sexual receptivity in limited tests with stimulus males given 4 and 8 h after progesterone treatment. This result contrasts with the well-established facilitatory effect of progesterone on sexual receptivity in rat and guinea pig. Chronic exposure to a progesterone capsule caused significant reductions in sexual receptivity in ovohysterectomized ferrets which were implanted concurrently with a second Silastic capsule containing a high dosage of estradiol. Similar effects of progesterone have been reported in rat and guinea pig, but not in the rhesus monkey. Thus species differences in the ability of progesterone to facilitate or inhibit sexual receptivity are not readily explained by species differences in the neural distribution of estrogen-induced progestin receptors.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double-blind randomized crossover trial of pergolide versus L-Dopa

Summary A double-blind randomized crossover study of 0.125 mg Pergolide (Lilly®) at bedtime versus 250 mg L-Dopa + Carbidopa (Roche®) was conducted in 16-day phases in 11 patients with idiopathic restless legs syndrome. Two patients reported a partial and 9 patients a complete relieve of motor restlessness while receiving Pergolide. Only 1 patient experienced an improvement of restlessness after L-Dopa. The patients showed polysomnographically a mean decrease in NMS cluster disturbed time by 45% from control on L-Dopa (p < 0.025) and by 79% from control on Pergolide (p < 0.001). In addition, Pergolide increased the total sleep time compared to L-Dopa (p < 0.05). In conclusion, the dopamine agonist Pergolide is superior to L-Dopa in the treatment of RLS and NMS.     

Comparative analysis of serotonin receptor (HTR1A/HTR1B families) and transporter (slc6a4a/b) gene expression in the zebrafish brain

In this study we analyze 5-hydroxytryptamine [5-HT]; serotonin) signaling in zebrafish, an increasingly popular vertebrate disease model. We compare and contrast expression of the 5-HT transporter genes slc6a4a and slc6a4b, which identify 5-HT-producing neurons and three novel 5-HT receptors, htr1aa, htr1ab, and htr1bd. slc6a4a and slc6a4b are expressed in the raphe nuclei, retina, medulla oblongata, paraventricular organ, pretectal diencephalic complex, and caudal zone of the periventricular hypothalamus, in line with the expression profiles of homologues from other vertebrates. Our analysis of serotonin transporter (SERT)-encoding genes also identifies parallel genetic pathways used to build the 5-HT system in zebrafish. In cells in which 5-HT is synthesized by tph1, slc6a4b is used for re-uptake, whereas tph2-positive cells utilize slc6a4a. The receptors htr1aa, htr1ab, and htr1bd also show widespread expression in both the larval and adult brain. Receptor expression is seen in the superior raphe nucleus, retina, ventral telencephalon, optic tectum, thalamus, posterior tuberculum, cerebellum, hypothalamus, and reticular formation, thus implicating 5-HT signaling in several neural circuits. We also examine larval brains double-labeled with 5-HTergic and dopaminergic pathway-specific antibodies, to uncover the identity of some 5-HTergic target neurons. Furthermore, comparison of the expression of transporter and receptor genes also allows us to map sites of autoreceptor activity within the brain. We detect autoreceptor activity in the pretectal diencephalic cluster (htr1aa-, htr1ab-, htr1bd-, and slc6a4a-positive), superior raphe nucleus (htr1aa-, htr1ab-, and slc6a4a-positive), paraventricular organ (htr1aa-, htr1ab-, htr1bd-, and slc6a4b-positive), and the caudal zone of the periventricular hypothalamus (htr1ab- and slc6a4b-positive).     

Changes in endorphins and 5-hydroxyindoleacetic acid in cerebrospinal fluid as a result of treatment with a serotonin reuptake inhibitor (zimelidine) in chronic pain patients

Both the endorphin and the serotonin systems seem to be involved in pain perception, and a significant positive correlation between the levels of endorphins and 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) has been established. In the present study, 20 chronic pain patients were treated with zimelidine, a rather selective inhibitor of serotonin reuptake, or placebo. Zimelidine produced a significant pain relief and a significant reduction of the levels of endorphins and 5-HIAA in CSF, while no significant changes occurred during placebo treatment. The results indicate that both the endorphin and the serotonin systems are involved in pain perception and that the systems are functionally related.     

Intrahypothalamic 5,7-dihydroxytryptamine: Temporal analysis of effects on 5-hydroxytryptamine content in brain nuclei and on facilitated lordosis behavior

The long-term relationship between serotonin (5-HT) levels in discrete hypothalamic nuclei and female rat sexual behavior, the lordosis response, was examined following intrahypothalamic injection of 5,7-dihydroxytryptamine (5,7-DHT). One week following 5,7-DHT injection, 5-HT levels in the ventromedial hypothalamic nucleus, dorsomedial nucleus, anterior hypothalamic nucleus and the medial preoptic nucleus were approximately 90% depleted as compared to sham animals. Other hypothalamic and preoptic areas including the arcuate-median eminence, vertical nucleus of diagonal band and lateral septal nucleus showed smaller reductions in 5-HT, from 40 to 70% of sham values. At this time estrogen-dependent lordosis behavior in the lesioned group was facilitated. Behavioral facilitation was greatest at 4 weeks post lesion when depletion of 5-HT in the VMN was maximal. 5-HT levels increased at 57 days after 5,7-DHT treatment in most areas, and by 71 days post lesion, no significant differences in 5-HT levels were found between sham and 5,7-DHT-treated groups. Concomitant with the increases in 5-HT, facilitated lordosis behavior gradually decreased. Loss of behavioral facilitation appeared to be most closely related to increases in content of 5-HT in the ventromedial nucleus. These results further support the hypothesis that 5-HT endings in the hypothalamus exert tonic inhibitory regulation over hormone-dependent lordosis in the female rat. They also indicate that regenerating 5-HT fibers in the hypothalamus can reinstate a normal pattern of hormone-dependent behavioral function.     

Tryptophan hydroxylase and 5-HTP-decar☐ylase activity in cockroach brain and the effects of p-chlorophenylalanine and 3-hydroxybenzylhydrazine (NSD-1015)

The activities of two enzymes of the serotonin biosynthetic pathway, namely tryptophan hydroxylase (TPH) and 5-hydroxytryptophan-decar☐ylase (5-HTP-D), were determined in the cockroach, Periplaneta americana, brain using radiometric techniques, significant levels of both enzymes were found, p-Chlorophenylalanine (PCPA) inhibited brain TPH activity strongly both in vitro and in vivo. In vitro, 10 mM PCPA reduced the TPH activity by 76% and in vivo either 15 μg/g or 30 μ/g of PCPA inhibited brain TPH activity by 80–85%. The activity of 5-HTP-D enzyme was inhibited significantly in vivo by 3-hydroxybenzylhydrazine, commonly known as NSD-1015. A recovery in the activity of 5-HTP-D enzyme was observed 12 h after 50 μg/g of NSD-1015 but 100 μ/g caused an inhibition lasting for the 24 h period studied.     

Acute antipyschotic efficacy and side effects in schizophrenia: association with serotonin transporter promoter genotypes

BACKGROUND: The serotonin transporter (5-HTT) plays an important role in serotonergic neurotransmission. In the present study, we investigated the effects of the 44 bp insertion/deletion polymorphism in the promoter region of 5-HTT gene (5-HTTLPR) on symptomatology of psychosis and clinical response to antipsychotic drugs. METHODS: In total 56 patients acutely treated with haloperidol or risperidone either for the first episode of schizophrenia, schizophreniform or schizoaffective disorders, or for the relapse of these psychotic disorders after tapering their maintenance treatment, were genotyped for the 5-HTTLPR L and S alleles and for the new A/G functional variant within the L alelle (La/g). Psychopathological symptoms were assessed with the Brief Psychiatric Rating Scale (BPRS) and with Clinical Global Impression (CGI) twice: at 8-12 days after the first dose of antipsychotic and after 4 weeks. Extrapyramidal side effects were assessed with the Simpson-Angus Extrapyramidal Side Effects Scale (EPS), the Barnes Akathisia Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). RESULTS: Age, body mass index (BMI), illness duration, drug type and dosage were considered as covariates when analysing association with genetic variants as they were associated with baseline or final BPRS and CGI scores and/or extrapyramidal side effects. 5-HTTLPR was not associated with baseline and final BPRS and CGI scores or with the CGI% reduction. However, the 5-HTTLPR S allele was associated with a lower improvement in BPRS scores (P=0.022) and this effect was even stronger after pooling subjects with S or Lg containing alleles (P=0.006). We did not observe any effect of 5-HTTLPR on acute antipsychotics side effects. CONCLUSION: Present result supports a contribution of serotonin system to neuroleptics efficacy for the treatment of schizophrenia. The analysis of the La/g functional variant may significantly improve the predictive power of 5-HTTLPR genotyping and represent a step further towards the development of the personalized antipsychotic treatment.     

Facilitation or inhibition of the oestradiol-induced gonadotrophin surge in the immature female rat by progesterone: effects on pituitary responsiveness to gonadotrophin-releasing hormone (GnRH), GnRH self-priming and pituitary mRNAs for the progesterone receptor A and B isoforms

Progesterone can either facilitate or inhibit the oestradiol (E(2))-induced gonadotrophin surge. We have previously developed immature female rat models to characterise and investigate the mechanisms of progesterone inhibition or facilitation. The aim of the present study was to determine the role of pituitary responsiveness to gonadotrophin-releasing hormone (GnRH) and GnRH self-priming under conditions of progesterone-facilitation and progesterone-inhibition, and whether the underlying mechanisms reflect changes in mRNAs encoding the A and B isoforms of the progesterone receptor (PR) in the pituitary gland. Pituitary responsiveness to GnRH, determined by measuring the luteinising hormone (LH) response to one i.v. injection of GnRH, was decreased by 60-80% (P < 0.001) in the progesterone-inhibition model. GnRH self-priming, estimated as the increment in the LH response to the second of two injections of GnRH separated by 60 min, was also significantly reduced (P < 0.05) in this model. In the progesterone-facilitation model, the LH response to GnRH injection was increased 2.5-3-fold (P < 0.05), an effect suppressed by the progesterone receptor antagonist, mifepristone. Progesterone-facilitation of LH release and increased pituitary responsiveness to GnRH were blocked by sheep anti-GnRH serum injected i.v. immediately after insertion of progesterone implants. The PR-B mRNA isoform, measured by solution hybridisation/RNase protection assay, was the predominant form in the pituitary of the immature female rat. PR-B was increased by E(2) and decreased by progesterone in both models. Thus, in immature female rats, progesterone-inhibition of the E(2)-induced LH surge is due to significant reduction in pituitary responsiveness to GnRH as well as in the magnitude of GnRH self-priming. Progesterone-facilitation of the E(2)-induced LH surge is due to increased pituitary responsiveness to GnRH, which is mediated by PR, and depends on endogenous GnRH release. The differences between progesterone-facilitation and progesterone-inhibition are not due to differences in regulation of pituitary PR-B mRNA.     

Neuropeptide galanin and its effects on metabolic and reproductive disturbances in female rats with estradiol valerate (EV) - Induced polycystic ovary syndrome (PCOS)

A functional role of the neuropeptide galanin, executed through the three G-protein coupled receptor subtypes GAL₁₋₃, has been demonstrated in many biological systems and under pathological circumstances. Galanin is involved in many central and peripheral actions, in particular associated with endocrine mechanisms such as anterior pituitary hormone regulation, reproduction, glucose metabolism and also inflammation. The role of galanin in the pathology of the polycystic ovary syndrome (PCOS) and possible therapeutic effects are unknown. However, based on the well known neuroendocrine changes in PCOS patients, it may be assumed that galanin via effects on gonadotropin-releasing hormone (GnRH) secretory neurons could play a significant role in the development of PCOS. The aim of this study was to examine possible therapeutic effects of galanin on hormonal, metabolic and molecular parameters in PCOS. Accordingly, intraperitoneal injection of galanin in a dose- dependent manner in female PCOS rats induced a significant reduction in inflammatory markers (TNF-α, IL-6), an increase in FSH and a decrease in LH, insulin and testosterone (using ELISA kit) compared to the PCOS groups. Moreover, data from real-time quantitative PCR showed significantly ameliorated changes in the mRNA levels of the steroidogenic acute regulatory protein (StAR) and aromatase cytochrome P450 (CYP19). Taken together, galanin has neuroendocrine, anti- and pro-inflammatory and metabolic effects, and we therefore suggest that treatment with this peptide could represent new therapeutic approach for managing hormonal and metabolic disturbances in the PCOS disease.     

Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) effectively treat various anxiety disorders, although symptoms of anxiety are often exacerbated during early stages of treatment. We previously reported that acute treatment with the SSRI citalopram enhances the acquisition of auditory fear conditioning, which is consistent with the initial anxiogenic effects reported clinically. Here, we extend our findings by assessing the effects of acute SSRI treatment on the expression of previously acquired conditioned fear. METHODS: Rats underwent fear conditioning drug-free. Tone-evoked fear responses were tested after drug treatment the following day. This protocol more closely resembles the clinical setting than pre-conditioning treatment, because it evaluates effects of treatment on a pre-existing fear rather than on the formation of a new fear memory. RESULTS: A single pre-testing injection of the SSRIs citalopram or fluoxetine significantly increased fear expression. There was no effect of the antidepressant tianeptine or the norepinephrine reuptake inhibitor tomoxetine, indicating that this effect is specific to SSRIs. The SSRI-induced enhancement in fear expression was not blocked by tropisetron, a 5-HT(3) receptor antagonist, but was blocked by SB 242084, a specific 5-HT(2C) receptor antagonist. CONCLUSIONS: Enhanced activation of 5-HT(2C) receptors might be a mechanism for the anxiogenic effects of SSRIs observed initially during treatment.     

Synergistic antiplatelet and antithrombotic effects of a prostacyclin analogue (iloprost) combined with a thromboxane antagonist (sulotroban) in guinea pigs and rats

The stable PGI₂-analogue iloprost and the TXA₂-receptor antagonist sulotroban were investigated for possible cooperative effects on platelet function and experimental thrombus formation in guinea pigs and rats.

Iloprost and sulotroban inhibit intravascular platelet aggregation in guinea pigs and rats induced by the stable endoperoxide U 46.619 and collagen, with iloprost beeing the more potent and (for collagen) more efficacious drug. Combinations of both compounds show synergistic or additive effects on in vivo platelet function. Thrombus formation in rats induced by vascular damage is strongly reduced by combining doses of iloprost and sulotroban (BM 13.177) which given alone are ineffective.

These results suggest a cooperative enhancement of antiplatelet and antithrombotic effects for combinations of iloprost and sulotroban. In view of disadvantages of currently used platelet inhibitors this cooperativity may offer a new approach in anti-platelet therapy.