Forced exercise-induced flushing of tail skin in ovariectomized mice, as a new experimental model of menopausal hot flushes

Hot flushes are the most common complaint of menopausal women. In the present study, a new animal model of hot flushes was established. Tail skin temperature was measured with a thermo tracer after mice were subjected to a forced exercise task using a motor driven treadmill. In ovariectomized mice, forced exercise for 10 min was most effective in increasing tail skin temperature over that of sham-operated mice. This elevation was blocked by estradiol replacement (1 mg/kg per week for 3 weeks), suggesting that our model simulates menopausal hot flushes.     

The statins fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals

Statins have pleiotropic vascular protective effects that are independent of their cholesterol-lowering effects. The aim of the present study was to determine if statins have anti-flushing actions in an animal model of forced exercise-induced temperature dysregulation in menopausal hot flushes, and to clarify the critical role of statins in regulating vascular reactivity in the tail arteries of ovariectomized rats. Administration of fluvastatin or pravastatin (3mg/kg/day for 7days, p.o.) significantly ameliorated the flushing of tail skin in ovariectomized mice, and the effect of each statin was comparable with that of estrogen replacement (1mg/kg/week for 3weeks, i.m.). In phenylephrine-pre-contracted rat-tail arteries, ovariectomy inhibited acetylcholine-induced relaxation, but augmented sodium nitroprusside-induced relaxation. These ovariectomy-altered vasodilator responses were restored by fluvastatin treatment as well as by estrogen replacement. Nitrite/nitrate levels in the plasma of ovariectomized animals showed significantly lower values than those in sham-operated animals; this ovariectomy-reduced production of nitric oxide was improved by fluvastatin treatment. These data provide the first experimental evidence that statins such as fluvastatin and pravastatin exert anti-flushing effects by improving vasomotor dysfunction through nitric oxide-mediated mechanisms in ovariectomized animals. Thus, therapeutic methods that target improvement of vasomotor dysfunction could be novel strategies for reducing menopausal hot flushes.     

Soybean isoflavones eliminate nifedipine-induced flushing of tail skin in ovariectomized mice

Hot flushes are one of the most frequent symptoms in menopausal women. We investigated effect of soybean isoflavones (Soyaflavone HG) on nifedipine-induced flushing in ovariectomized mice. Ovariectomy markedly aggravated nifedipine-induced increase in tail skin temperature. Soyaflavone HG (10 mg/kg, p.o., once a day for 5 days) inhibited nifedipine-induced flushing in ovariectomized mice. The inhibitory effect of Soyaflavone HG was significantly reversed by an estrogen-receptor antagonist, ICI 182,780, suggesting that Soyaflavone HG prevents nifedipine-induced flushing partially through estrogen receptors. We presented the experimental evidence suggesting that soybean isoflavones including Soyaflavone HG have the benefits for menopausal hot flushes.     

Effects of selective serotonin reuptake inhibitors on immobility time in the tail suspension test in streptozotocin-induced diabetic mice

We examined the effects of fluoxetine and fluvoxamine, selective serotonin reuptake inhibitors (SSRIs), and desipramine, a selective noradrenaline (NA) reuptake inhibitor, given alone or in combination with diazepam on immobility time in the tail suspension test in diabetic mice. Immobility time was significantly longer in diabetic than in nondiabetic mice. Diazepam (0.1 and 0.3 mg/kg s.c.) dose-dependently decreased immobility time in diabetic mice to the level observed in saline-treated nondiabetic mice. However, diazepam had no significant effect on immobility time in nondiabetic mice. Fluoxetine (3-56 mg/kg i.p.) and desipramine (1-30 mg/kg i.p.) produced marked, dose-dependent suppression of immobility time in both nondiabetic and diabetic mice. However, anti-immobility effects of fluoxetine and desipramine in diabetic mice were less than those in nondiabetic mice. Fluvoxamine (3-30 mg/kg i.p.) produced a dose-dependent suppression of immobility time in nondiabetic mice but not in diabetic mice. The anti-immobility effects of fluoxetine, fluvoxamine and desipramine in nondiabetic mice were antagonized by pretreatment with diazepam (0.3 mg/kg s.c.). Furthermore, fluoxetine, fluvoxamine and desipramine had no effect on the immobility time in diazepam (0.3 mg/kg s.c.)-treated diabetic mice. These results indicate that the anti-immobility effects of SSRIs and desipramine are less in diabetic mice than in nondiabetic mice in the tail suspension test. Furthermore, in diabetic mice, SSRIs and selective NA reuptake inhibitors did not affect immobility time even though the prolonged duration of immobility was suppressed by pretreatment with diazepam.     

Effects of chronic selective serotonin reuptake inhibitors on 8-OH-DPAT-induced facilitation of ejaculation in rats: comparison of fluvoxamine and paroxetine

Rationale Chronic treatment with selective serotonin reuptake inhibitors (SSRIs) can delay ejaculation in humans, but the extent of this effect differs between SSRIs. The involvement of 5-HT_1A receptors is likely, since 5-HT_1A receptor agonists accelerate ejaculation and chronic SSRI treatment is thought to desensitize 5-HT_1A receptors.Objectives This study was conducted to examine the effects of chronic pretreatment with the SSRIs fluvoxamine and paroxetine on the facilitation of ejaculation induced by the 5-HT_1A receptor agonist 8-OH-DPAT.Methods Sexually experienced Wistar rats with normal ejaculatory behavior were treated for 22 days with vehicle, fluvoxamine (30 mg/kg/day), or paroxetine (10 or 20 mg/kg/day, p.o.). On day 22, rats received a challenge with saline or 8-OH-DPAT (0.4 mg/kg, s.c.). Sexual behavior was tested on days 1, 8, 15, and 22 of the SSRI-treatment.Results Treatment with both doses of paroxetine, but not fluvoxamine, delayed ejaculation. 8-OH-DPAT strongly accelerated ejaculation under vehicle conditions. Pretreatment with paroxetine reduced the effects of 8-OH-DPAT on ejaculation in a dose-dependent manner and more strongly than fluvoxamine.Conclusions SSRIs affect 5-HT_1A receptors involved in ejaculation. The degree to which this occurs, with paroxetine exerting a stronger effect than fluvoxamine, might determine the extent of SSRI-induced delayed ejaculation.     

Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.     

Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats.

The purpose of this study was to investigate the effects of co-administration of tandospirone (a 5-HT(1A) receptor agonist) and individual selective serotonin reuptake inhibitors (SSRIs) on the contextual conditioned fear stress, using an anxiety model in rats. One day after fear conditioning, tandospirone (0.3-3 mg/kg, s.c.), paroxetine (5-20 mg/kg, i.p.), fluvoxamine (30-60 mg/kg, i.p.) and citalopram (3-30 mg/kg, i.p.) significantly inhibited the conditioned freezing in a dose-dependent manner, whereas, 14 days after fear conditioning, the anxiolytic effects of these drugs were weakened. Fourteen days after fear conditioning, co-administration of tandospirone (0.3 mg/kg, s.c.) with each SSRI [paroxetine (5 mg/kg, i.p.), fluvoxamine (30 mg/kg, i.p.) and citalopram (10 mg/kg, i.p.)], given at subeffective doses, markedly inhibited the conditioned freezing without affecting the locomotor activities and CYP3A4-related pharmacokinetic drug-drug interaction. These results elucidate the pharmacodynamic synergistic effects of tandospirone and SSRIs. Therefore, this augmentation therapy (SSRI+5-HT(1A) receptor agonist) may prove useful for some anxiety disorders.     

The Selective Serotonin Reuptake Inhibitor Paroxetine, but not Fluvoxamine, Decreases Methamphetamine Conditioned Place Preference in Mice

Monoamine transporters are the main targets of methamphetamine (METH). Recently, we showed that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), decreased METH conditioned place preference (CPP), suggesting that serotonin transporter (SERT) inhibition reduces the rewarding effects of METH. To further test this hypothesis, in the present study we investigated the effects of additional SSRIs, paroxetine and fluvoxamine, on METH CPP in C57BL/6J mice. In the CPP test, pretreatment with 20 mg/kg paroxetine abolished the CPP for METH, whereas pretreatment with 100 mg/kg fluvoxamine prior to administration of METH failed to inhibit METH CPP. These results suggest that paroxetine, a medication widely used to treat depression, may be a useful tool for treating METH dependence. Further, these data suggest that molecules other than the SERT [such as G protein-activated inwardly rectifying K+ (GIRK) channels] whose activities are modulated by paroxetine and fluoxetine, but not by fluvoxamine, are involved in reducing METH CPP by paroxetine and fluoxetine.     

The selective serotonin re-uptake inhibitors fluvoxamine and paroxetine differ in sexual inhibitory effects after chronic treatment

RATIONALE: The selective serotonin re-uptake inhibitors (SSRIs) delay orgasm and ejaculation in men. In men with rapid ejaculation it was shown that, of the SSRIs, paroxetine exerted the strongest delay in ejaculation and fluvoxamine the weakest. OBJECTIVES: In the present study, we compared the acute and chronic effects of fluvoxamine and paroxetine on sexual behavior in the male rat in order to compare their differential inhibitory effects on sexual behavior. METHODS: During a 4-week period, 48 male Wistar rats, selected on the basis of their sexual performance, were repeatedly tested for sexual behavior. All male rats received vehicle (saline, n=12), fluvoxamine (30 mg/kg, n=12), or paroxetine (10 mg/kg, n=12) daily for 2 weeks. Sexual behavioral tests were performed on days 1 (acute), 7, and 14. RESULTS: After acute oral administration, fluvoxamine and paroxetine did not inhibit sexual behavior. After 7 days and 14 days treatment, fluvoxamine mildly inhibited certain parameters of sexual behavior but ejaculation was never delayed. In contrast, paroxetine, after 7 days and particularly after 14 days treatment, strongly inhibited sexual behavior, including ejaculation. CONCLUSIONS: These results strongly concur with clinical data, suggesting that paroxetine, but not fluvoxamine, delays ejaculation. Because fluvoxamine does not delay ejaculation it may serve as an optimal treatment for depressive illness when sexual side effects, such as a delayed ejaculation, are undesired. The mechanisms whereby paroxetine and fluvoxamine, both being selective serotonin uptake inhibitors, differentially inhibit sexual behavior are unclear.     

A comparison of the effects of different serotonin reuptake blockers on sexual behaviour of the male rat.

In human males, SSRIs differentially affect (premature) ejaculation; paroxetine and fluoxetine markedly and sertraline, moderately inhibited ejaculation latency, whereas fluvoxamine did not inhibit this parameter (Waldinger, M.D., Hengeveld, M.W., Zwinderman, A.H., Olivier, B., The effect of SSRI antidepressants on ejaculation: a double-blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. J. Clin. Psychopharmacol. (in press)). The present studies tried to investigate, using sexual behaviour in male rats, whether such differences could also be found in animal paradigms of sexual behaviour. In a series of three experiments we compared various specific serotonin reuptake inhibitors (SSRIs) for their ability to suppress sexual behaviour in male rats. In the first experiment sexually experienced rats were tested 60 min after oral administration of clomipramine, fluvoxamine, fluoxetine (all in a range of 0, 3, 10 and 30 mg/kg p.o.), sertraline or paroxetine (both in a range of 0, 1, 3 and 10 mg/kg p.o.). Clomipramine, paroxetine and fluvoxamine did not significantly inhibit male sexual behaviour, although some trends were observed. Sertraline inhibited sexual behaviour at 3 and 10 mg/kg p.o., the effects being stronger at 3 mg/kg p.o. Fluoxetine (3 mg/kg p.o.) facilitated sexual behaviour, while at 30 mg/kg p.o. a modest increase in the postejaculatory interval was noted. In the second experiment, sexual behaviour of sexually naive male rats was slightly inhibited by paroxetine 10 mg/kg p.o., but sertraline (range 1-10 mg/kg p.o.), fluvoxamine and fluoxetine (both in a range of 3-30 mg/kg p.o.) were ineffective. In the last experiment the effects of paroxetine (0-10 mg/kg p.o.), fluvoxamine and fluoxetine (both 0-30 mg/kg p.o.) were studied during an exhaustion design in sexually experienced male rats. As rats get more 'sluggish' when they have had multiple ejaculations, we hoped to see stronger inhibitory effects in the last cycle prior to exhaustion. None of the drugs dose-dependently inhibited the pattern of sexual behaviour during the first sexual cycle. In the last cycle the patterning of sexual behaviour differed, but only paroxetine (10 mg/kg p.o.) inhibited sexual behaviour significantly. The total number' of ejaculations during the test was not reduced by any of the SSRIs tested. Contrary to human findings, we did not find major inhibitory effects of SSRIs on male rat sexual behaviour at non-sedative doses. The only differentiation that could be made is that paroxetine and sertraline had slightly stronger effects than the other 5-HT reuptake inhibitors. Masculine sexual behaviour in rats does not constitute a suitable model to investigate the differential mechanism of sexual inhibition of SSRIs that have been described in human males.     

Protective effect of geranylgeranylacetone against loxoprofen sodium-induced small intestinal lesions in rats

We studied the effect of the selective serotonin reuptake inhibitor (SSRI) paroxetine on the immobility time in the forced swimming test using different strains of mice (ICR, ddY, C57BL/6, BALB/c and DBA/2). There was a difference between strains in the response to paroxetine (although it induced anti-immobility effects in all strains of mice used). The mouse strain most sensitive to paroxetine was DBA/2; the ICR strain showed the lowest sensitivity. We previously demonstrated variations in the responses to another SSRI, fluvoxamine, in different strains of mice, which was in agreement with the present findings. In DBA/2 and ICR mice, the anti-immobility effects of paroxetine were significantly antagonized by the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY 100635). The noradrenergic α(1)-adrenoceptor antagonist prazosin significantly reduced the anti-immobility effects elicited by a high dose (5mg/kg) of paroxetine in DBA/2 and ICR mice. However, prazosin did not affect the anti-immobility effects of a lower dose of paroxetine (1mg/kg) in DBA/2 mice. This suggests that the anti-immobility effects of a higher dose of paroxetine in mice are associated with serotonergic and noradrenergic neurons. Prazosin did not the affect anti-immobility effects of fluvoxamine. These results suggest that there are differences between mice strains in the antidepressant-like effects of paroxetine (which are similar to those elicited by fluvoxamine). Moreover, involvement of the noradrenergic system was partly related to the anti-immobility effects of paroxetine (which are different to those elicited by fluvoxamine).     

Stimulus properties of the selective 5-HT reuptake inhibitor fluvoxamine in conditioned taste aversion procedures.

Previous attempts to train pigeons and rats to discriminate between the antidepressant fluvoxamine and its vehicle as assessed in a drug discrimination paradigm have been without success. The present experiments were, therefore, designed to assess in a conditioned taste aversion procedure (CTA) whether or not fluvoxamine possesses stimulus properties. Rats were exposed to a conditioned taste aversion (CTA) procedure. In Experiment I, subjects were given 15 mg/kg fluvoxamine p.o. or vehicle after drinking a novel tasting saccharin solution. In Experiment II, a comparison was made between the effects of 15 mg/kg fluvoxamine i.p., 30 mg/kg fluvoxamine i.p., NaCl, and lithium chloride (LiCl). In Experiment III, subjects were treated with either 10 mg/kg fluoxetine i.p., 30 mg/kg fluvoxamine i.p., or LiCl. CTA was observed after treatment with LiCl, but never after treatment with fluvoxamine or fluoxetine, suggesting that fluvoxamine does not have clear stimulus properties, which can serve as a discriminative stimulus in operant procedures. In a crossfamiliarization CTA procedure in mice, however, fluvoxamine elicited a reliable CTA, suggesting that under certain conditions (species, dose?) selective serotonin reuptake inhibitors (SSRIs) may lead to certain discriminable effects. It is as yet unclear why SSRIs apparently produce such weak and species or situation-dependent discriminable effects.     

Effects of oral administration of extracts of Hypericum perforatum (St John's wort) on brain serotonin transporter, serotonin uptake and behaviour in mice

The pharmacological effects of extracts of Hypericum perforatum (St John's wort) were characterized in-vitro and ex-vivo, in relation to its behavioural effects. In in-vitro experiments, St John's wort inhibited brain synaptosomal [(3)H]serotonin uptake in mice with little effect on specific [(3)H]paroxetine binding. For selective serotonin-reuptake inhibitors (SSRIs), the IC50 value for [(3)H]serotonin uptake (molar concentration of unlabelled drug necessary to displace 50% of specific uptake) correlated well with the inhibition constant K(i) value for [(3)H]paroxetine binding in mouse brain. Oral administration of St John's wort (900 mg kg(-1)), paroxetine (1 mg kg(-1)) and sertraline (10 mg kg(-1)) brought about significant increases in the K(m) value for [(3)H]serotonin uptake into brain synaptosomes 4 h later, and only SSRIs suppressed specific [(3)H]paroxetine binding in mouse brain. St John's wort and SSRIs significantly inhibited marble-burying behaviour in mice and the time-course of attenuation of this behaviour by St John's wort was similar to that of [(3)H]serotonin uptake inhibition. In the forced swimming test, St John's wort, but not SSRIs, suppressed the immobility time of mice after oral administration. These results provide the first in-vivo evidence to suggest that the mode of antidepressant action of St John's wort differs from that of SSRIs. Thus, this study may have a significant impact on phytotherapy with St John's wort.     

Involvement of 5-HT(2C) receptors in the anti-immobility effects of antidepressants in the forced swimming test in mice.

Several recent studies have demonstrated that 5-HT(1A), 5-HT(1B) and 5-HT(3) receptors were implicated in the mechanism of action of antidepressants in the mouse forced swimming test. Despite extensive evidence for a role of 5-HT(2C) receptors in depression, the precise role of these receptors in the effects of clinically established antidepressants was not directly investigated in the mouse forced swimming test. This work was aimed at exploring interactions between several doses of Ro 60-0175, a recently available, full and selective 5-HT(2C) agonist, and antidepressant drugs in the mouse forced swimming test. Spontaneous locomotor activity was measured as an index of intact sensorimotor functions and the dose-effect of Ro 60-0175 alone, as well as interactions with several antidepressants, such as tricyclic antidepressants (imipramine, desipramine and maprotiline) and selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, fluvoxamine and sertraline), were studied in the mouse forced swimming test. There was no intrinsic antidepressant-like effect of Ro 60-0175, but an impairment in locomotor function was detected when using doses higher than 4 mg/kg in the mouse. There was a synergistic effect of low doses of Ro 60-0175 with sub-active doses of imipramine, paroxetine, citalopram and fluvoxamine; an antagonism between the highest dose of Ro 60-0175 and the active doses of paroxetine and fluoxetine was also detected. There is evidence that 5-HT(2C) receptors may be involved in the action of antidepressants which are able to boost the concentration of serotonin in the synapse, i.e. SSRIs and imipramine     

Cardioprotective effect of fluvoxamine, sigma-1 receptor high affinity agonist

Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction (MI)-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. Here, we investigated the role of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy and cardioprotection. Male ICR mice were subjected to transverse aortic constriction (TAC) in the cardiac aortic arch. To confirm the cardioprotective role of Sig-1R stimulation by fluvoxamine, we treated mice with fluvoxamine (0.5 or 1 mg/kg) orally once a day for 4 weeks after onset of aortic banding. Interestingly, in untreated mice, Sig-1R expression in the left ventricle (LV) markedly decreased over 4 weeks with increased hypertrophy. By contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of Sig-1R expression in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a Sig-1R antagonist, NE-100 (1 mg/kg). Importantly, another SSRI with very low affinity for Sig-1R, paroxetine, did not exhibit antihypertrophic effects in TAC mice and in cultured cardiomyocyte treated with angiotensin II. Fluvoxamine treatment significantly restored TAC-induced impaired Akt and eNOS phosphorylation in LV. Our findings suggest that fluvoxamine protects heart against TAC-induced cardiac dysfunction via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role of Sig-1R stimulation by fluvoxamine in preventing cardiac hypertrophy and myocardial injury in TAC mice.     

Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.     

Effects of chronic treatment with fluvoxamine and paroxetine during adolescence on serotonin-related behavior in adult male rats.

Selective Serotonin Reuptake Inhibitors (SSRIs) are designed to treat adults, but are increasingly prescribed for adolescents. SSRIs might cause permanent changes in serotonin-related behavior in adolescents, since their serotonergic system is still developing. Male Wistar rats were treated with paroxetine (15 mg/kg p.o.) or fluvoxamine (30 mg/kg p.o.) throughout adolescence. After a washout period their behavior in the elevated plus-maze, prepulse inhibition test, Forced swimming test and elevated T-maze were studied. In addition, the effects of the 5-HT(1A) receptor agonist 8-OH-DPAT on sexual behavior and lower lip retraction were measured. Paroxetine mildly inhibited weight gain during treatment. Both SSRIs caused a reduction in ejaculation frequency and in time spent on the open arm of the elevated plus-maze in adult rats. Fluvoxamine slightly increased avoidance latency in the elevated T-maze compared to paroxetine. No differences between the groups were found in the other tests. Apparently, chronic treatment with SSRIs during adolescence may cause mild changes in adult behavior.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of fluvoxamine: role of sigma-1 receptors.

This study was undertaken to examine the effects of the selective serotonin reuptake inhibitors fluvoxamine and paroxetine on cognitive deficits in mice after repeated administration of the N-methyl-D-aspartate receptor antagonist phencyclidine (PCP). In the novel object recognition test, repeated administration of PCP (10 mg/kg/day, 10 days) significantly decreased the exploratory preference in the retention test session, but not in the training test session. PCP-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of fluvoxamine (20 mg/kg/day), but not paroxetine (10 mg/kg/day). Furthermore, the effect of fluvoxamine on PCP-induced cognitive deficits was antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1 mg/kg/day). Moreover, PCP-induced cognitive deficits were also significantly improved by subsequent subchronic (2-week) administration of the selective sigma-1 receptor agonist SA4503 (1 mg/kg/day) or neurosteroid dehydroepiandrosterone 3-sulfate (DHEA-S; 25 mg/kg/day). The effects of SA4503 or DHEA-S were also antagonized by co-administration of NE-100 (1 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of these drugs. In contrast, acute single administration of these drugs (fluvoxamine, paroxetine, SA4503) alone or combination with NE-100 did not alter PCP-induced cognitive deficits. The present study suggests that agonistic activity of fluvoxamine at sigma-1 receptors plays a role in the active mechanisms of fluvoxamine on PCP-induced cognitive deficits in mice. Therefore, sigma-1 receptor agonists such as fluvoxamine would be potential therapeutic drugs for the treatment of the cognitive deficits of schizophrenia.     

Association between tryptophan hydroxylase-2 genotype and the antidepressant effect of citalopram and paroxetine on immobility time in the forced swim test in mice

Tryptophan hydroxylase-2 (TPH2) is the rate limiting enzyme of serotonin synthesis in the brain. The 1473G allele of the C1473G polymorphism in mTPH2 gene is associated with reduced enzyme activity and serotonin synthesis rate in the mouse brain. Here, the influence of the 1473G allele on the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs), citalopram (2.5 or 5.0 mg/kg) and paroxetine (5.0 or 10.0 mg/kg), in the forced swim test was studied using B6-1473G and B6-1473C congenic mouse lines with the 1473G (decreased TPH2 activity) or 1473C (normal TPH2 activity) alleles, respectively, transferred to the genome of C57BL/6 mouse strain. Paroxetine (5.0 or 10.0 mg/kg) and citalopram (2.5 or 5.0 mg/kg) decreased immobility time in B6-1473C mice, while both doses of paroxetine and 2.5 mg/kg of citaloprame did not alter immobility time in B6-1473G mice. However, 5.0 mg/kg of citalopram reduced immobility in B6-1473G mice. The results provided genetic evidence of moderate association between 1473G allele and reduced sensitivity to SSRIs in mice.     

Influence of fluoxetine and paroxetine in behavioral sensitization induced by ethanol in mice

The serotonergic system is involved in depression, anxiety and alcoholism. The rewarding properties of ethanol, mainly its anxiolytic and stimulant effects, as well as the development of dependence on ethanol have been related to the serotonergic system. Consequently, the use of selective serotonergic reuptake inhibitors (SSRI) has been proposed in the treatment of alcoholism. In this study we investigated whether acute administration of the SSRIs fluoxetine or paroxetine is able to (i) reverse the behavioral effects induced by chronic ethanol consumption, and conversely, (ii) to determine whether acute ethanol is able to substitute for the chronically induced behavioral effects of fluoxetine or paroxetine. Four groups of male Swiss mice (n=60/group) received daily i.p. saline, ethanol (2 g/kg), fluoxetine (10 mg/kg) or paroxetine (5 mg/kg) for 27 days. On the 28th day, each group was challenged with saline, ethanol, fluoxetine or paroxetine. The 14 groups (SS, SE, SP, SF, EE, ES, EP, EF, PP, PE, PS, FF, FE, and FS) were then tested in open field, activity cage and plus-maze. EP and EF groups were able to reverse the behavioral sensitization to the psychomotor stimulant effects of chronic ethanol administration. In contrast, a sensitized stimulatory effect was observed in chronically fluoxetine- or paroxetine treated mice challenged with ethanol (PE and FE). An anxiolytic effect was observed whether ethanol was substituted for SSRI or, conversely, SSRI was substituted for ethanol. SSRIs facilitated ethanol-induced locomotor sensitization, although SSRIs by themselves are unable to produce the locomotor stimulation similar to that induced by ethanol. Finally, SSRIs are unable to interfere in the ethanol anxiolytic effect.