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Attenuation of ssri-induced increases in extracellular brain 5-ht by benzodiazepines

Attenuation of SSRI-induced increases in extracellular brain 5-HT by benzodiazepines Chapter 8
Attenuation of SSRI-induced increases in
extracellular brain 5-HT by benzodiazepines.
Enhanced serotonergic neurotransmission is generally thought to be the neurochemical basisof the antidepressant effects of Selective Serotonin Reuptake Inhibitors (SSRIs).
The anxiolytic benzodiazepines, on the other hand, have been shown to decrease serotonergicneurotransmission . Since depressed patients are frequently treated with a combination ofSSRI’s and benzodiazepines, we investigated the effects of co-administration of these drugson extracellular levels of serotonin (5-HT) in guinea pig brain.
Using microdialysis of 5-HT in ventral hippocampus of freely moving guinea pigs, weinvestigated the effects of the typical benzodiazepines oxazepam and temazepam, alone andin combination with the SSRI paroxetine on extracellular levels of 5-HT.
Paroxetine alone increased extracellular 5-HT levels in hippocampus to about 350 % ofcontrol values,whereas oxazepam and temazepam each produced small decreases to 90% and70% of control levels, respectively when administered alone. The combined administration ofparoxetine with oxazepam as well as temazepam significantly attenuated the increase of 5-HT levels induced by paroxetine.
Since the co-administration of SSRIs with benzodiazepines attenuates the serotonergictransmission, but enhances the clinical effects of SSRI’s in depressed patients, it might bequestioned whether the mechanism of the antidepressant action of SSRI’s is completely dueto enhanced serotonergic neurotransmission.
Attenuation of SSRI-induced increases in extracellular brain 5-HT by benzodiazepines 1. Introduction
Selective Serotonin Re-uptake Inhibitors (SSRIs) are generally believed to exert theirantidepressant effects by enhancing serotonergic neurotransmission (Blier et al. 1987). Uponacute administration of SSRIs, extracellular brain 5-HT levels are increased (Fuller 1994), butthese 5-HT enhancing effects are restricted by the counteraction of release modulatingserotonergic autoreceptors . It has been shown that during chronic treatment theseautoreceptors are desensitized, thereby potentiating the effect of SSRIs on brain 5-HT levels(Blier et al.1987; Invernizzi et al. 1994). Since the gradual desensitization of autoreceptors isthought to produce, at least partly, the antidepressant effects of SSRIs, it was hypothesizedthat co-administration of an SSRI with an autoreceptor antagonist would instantaneouslymimic this desensitization, and therefore reduce the time until onset of antidepressant action(Artigas 1993, Hjorth 1993). Indeed, clinical trials investigating the effects of co-administration of an SSRI with the putative 5-HT1A antagonist pindolol have shownpromising results, indicative of the beneficial effects of augmented 5-HT levels in thetreatment of depression (McAskill et al.1998).
Depressed patients are often simultaneously treated with benzodiazepines because ofcomorbidity of depression and anxiety. Although patients who were being treated with otherdrugs are excluded from clinical trials that investigate the effect of SSRIs or combinations ofSSRIs with pindolol , patients on benzodiapines are usually included in these studies (Bordetet al.1998; Perez et al. 1997). Previous preclinical studies had shown that administration ofbenzodiazepines decreases the extracellular levels of 5-HT in a wide variety of brainstructures in rats and guinea pigs (Rex et al.1993; Pei et al.1989,Gibson et al.1996). Sincethis 5-HT decreasing effect could possibly counteract the 5-HT increase produced by SSRI’swe investigated the effect of co-administration of the SSRI paroxetine with two commonlyused benzodiazepines on extracellular 5-HT levels in guinea pig brain.
2. Materials and Methods
2.1 Animals and drug administration Male albino guinea pigs of a Dünkin Hartley strain (300-400 g; Harlan, Zeist, TheNetherlands were housed in cages (32 x 40 x 40 cm), and had free access to food and water.
The experiments are concordant with the declarations of Helsinki and were approved by theanimal care committee of the fbaculty of mathematics and natural science of the University ofGroningen .
The following drugs were used: paroxetine (SKB, West Sussex, UK) , Oxazepam andTemazepam (Bufa, the Netherlands). Paroxetine was dissolved in ultrapure water. Oxazepamand temazepam were dissolved in 10 % v/v solutol and ultrapure water. In experiments witha drug alone, the appropriate vehicle for the combination was injected before or after thedrug.
Preceding surgery, the animals were anaesthetised by means of an intraperitoneal injection ofketamine/xylazine (50/8 mg/kg), after premedication with midazolam (5 mg/kg s.c.).
Lidocaine-HCl, 10 % (m/v) was used for local anaesthesia. The animals were placed in astereotaxic frame (Kopf, USA), and home made I-shaped probes (polyacrylonitrile / sodiummethyl sulphonate copolymer dialysis fibre; 4 mm open surface, i.d. 220 µm, o.d. 310 µm,AN 69, Hospal, Italy) were inserted into the ventral hippocampus (co-ordinates: IA: + 4.9mm, lateral : +/- 6.5 mm, ventral: - 9.0 mm from the dura mater (Luparello, stereotaxic atlas)and secured with dental cement. Postoperative analgesia was accomplished by anintramuscular injection of 0.1 mg/kg buprenorphine.
Guinea pigs were allowed to recover for at least 24 h, after which theprobes were perfusedwith artificial CSF (147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl2, and 1.2 mM MgCl2.) at aflow-rate of 1.5 µl / min (Harvard apparatus, South Natick, Ma., USA). 15 minute sampleswere collected in vials containing 7.5 µl of 0.02 mM acetic acid.
Concentrations of 5-HT in microdialysates were measured by HPLC with electrochemicaldetection. Twenty µl samples were injected onto a reversed phase column (PhenomenexHypersil 3 : 3 µm, 100 x 2.0 mm, C18, Bester, Amstelveen, the Netherlands) by anautoinjector (CMA/200 refrigerated microsampler, Carnegie Medicine, Sweden). The mobile Attenuation of SSRI-induced increases in extracellular brain 5-HT by benzodiazepines phase consisted of 5 g/l di-ammoniumsulfate, 500 mg/l ethylene diamino tetra acetic acid(EDTA), 50 mg/l heptane sulphonic acid, 4 % methanol v/v, and 30 µl/l of triethylamine, at apH of 4.65, and was delivered at aflow-rate of 0.4 ml/min (Shimadzu LC-10 AD liquidchromatograph). 5-HT was detected electrochemically at a glassy carbon electrode set at aworking potential of 500 mV vs. Ag/AgCl (Antec Leyden, Leiden, the Netherlands). Thedetection limit was 0.5 fmol 5-HT per 20 µl sample (signal to noise ratio 3).
2.5 Data presentation and statistics Four consecutive microdialysis samples with less then 20 % variation were taken as controland set at 100 %. Data are presented as percentages of control level (mean + SEM). Statisticalanalysis was performed using Sigmastat for Windows (Jandel Corporation). Treatmenteffects were compared versus saline treatment using two way ANOVA for repeatedmeasurements, followed by Student’s Newman Keuls post-hoc test. Treatment effects werecompared versus basal values using one way ANOVA for repeated measurements on ranks.
Level of significance level was set at p<0.05.
3. Results
Basal levels of 5-HT in dialysates from guinea pig ventral hippocampus were 8.87 + 0.84fmol/sample (mean + S.E.M.) (n= 27). No significant differences were observed between thedifferent treatment groups.
3.2 Oxazepam administration and paroxetine + oxazepam co-administration: Figure 1 shows the effect of administration of oxezepam alone and in combination withparoxetine. Oxazepam alone significantly decreased extracellular levels of 5-HT in guineapig ventral hippocampus to about 90 % of basal values (χ210 = 18.5, p<0.05). Paroxetinealone increased extracellular 5-HT levels to about 350 % of control values (χ210 = 28.9;p<0.05). Injection of oxazepam 30 minutes prior to administration of paroxetine significantlyattenuated the 5-HT produced by paroxetine alone to 250% of basal levels (F(1,151) = 2,73;p<0.05).
Figure 1. Effect of administration of 5 mg/kg paroxetine (■, n = 10, vehicle t=0, paroxetinet=30), oxazepam 1µmol/kg (▲, n = 5 , oxazepam t=0, vehicle t=30), and paroxetine 5 mg/kgtogether with oxazepam (●, n = 4 ,oxazepam t=0, paroxetine t=30). * denote significant vs.
paroxetine alone.
Attenuation of SSRI-induced increases in extracellular brain 5-HT by benzodiazepines Figure 2. Effect of administration of 5 mg/kg paroxetine (■, n = 10, vehicle t=0, paroxetinet=30), temazepam 1µmol/kg (▲, n = 4 , temazepam t=0, vehicle t=30), and paroxetine 5mg/kg together with temazepam oxazepam (●, n = 4 , temazepam t=0, paroxetine t=30). *denote significant vs. paroxetine alone.
3.3 Temazepam administration and paroxetine + temazepam co-administration: Administration of temazepam alone induced a significant decrease of extracellular levels of5-HT levels to about 70 % of basal values (χ210 = 20, p<0.05). Similar to oxazepam, co-administration of temazepam with paroxetine induced a blunted response to paroxetine andextracellular 5-HT levels increased to only 225% (F(1, 150) = 2.10; p<0.05).
4. Discussion
The present data show that co-administration of benzodiazepines and the SSRI paroxetineattenuates the effect of the SSRI on brain extracellular 5-HT levels.
The few studies that investigated the effect of benzodiazepine administration on theserotonergic system showed that these drugs have an inhibitory influence on the firing rate of5-HT neurons and decrease terminal 5-HT release in several brain structures of rats (Pei etal. 1989; Gibson et al., 1996) and guinea pigs (Rex et al.1993). It has been suggested thatthis inhibitory effect of benzodiazepines on the serotonergic system is a consequence ofenhanced GABA-ergic transmission, resulting from the binding of benzodiazepines to thebenzodiazepine/GABAA receptor complex. (Pei et al.1989).
As mentioned in the introduction, SSRIs are believed to exert their clinical effect byenhancing serotonergic neurotransmission. In support of this, clinical and preclinical studieshave indeed shown evidence for the positive effects of enhanced serotonergic levels intreatment of depression. Analysis of literature revealed that patients treated for depression arefrequently also treated with benzodiazepines and that in trials designed to evaluate the effectsof enhanced serotonergic levels by co-administration of SSRIs with the autoreceptorantagonist pindolol, patients on benzodiazepines were included (Bordet et al.1998; Perez etal.1997).
It is clear from the present study that co-administration of benzodiazepines such as oxazepamand temazepam, attenuates the effect of SSRIs on extracellular 5-HT levels and thus the SSRI–induced effect on serotonergic transmission. Therefore if enhanced serotonergicneurotransmission is indeed responsible for the antidepressant action of SSRI’s, one wouldexpect that co-administration of benzodiazepines to patients on SSRIs would also diminishthe antidepressant effects,. This effect however, is not observed in the clinic, in contrast,some authors have suggested that co-administration of an SSRI with a benzodiazepine issuperior to SSRI treatment alone (Smith et al.1998). Co-morbidity of anxiety with depressionin addition to the well-known anxiolytic effect of benzodiazepine could be a feasibleexplanation for this apparent discrepancy (Keller et al.1995). Furthermore, since some potentbenzodiazepines have antidepressant activity of their own, this might further complicate theexplanation of the overall clinical outcome of combined administration of both classes ofcompounds (Petty et al. 1995, Sussman 1998).
Theoretically, the observed pharmacological effects of co-administration of oxazepam andtemazepam with paroxetine might be explained by pharmacokinetic interference (druginteractions) between the compounds. However, since oxazepam and temazepam are directlyconjugated, interference does not seem likely between these specific benzodiazepines andparoxetine (Sproule et al.1997).
Although the present findings seem to be at odds with the idea that enhanced serotonin levelsare associated with an antidepressant response, the situation might be different after chronictreatment. Since chronic benzodiazepine treatment has been shown to result in subsensitivityof GABA-ergic receptors in the dorsal raphe nucleus (Wilson and Gallager 1988), theseeffects might counteract the inhibitory effects of GABA in the DRN and augment the SSRIinduced 5-HT increases (Tao and Auerbach 1996).
Attenuation of SSRI-induced increases in extracellular brain 5-HT by benzodiazepines It would require further preclinical studies to evaluate whether chronic benzodiazepine andSSRI co-administration attenuates the serotonergic effects of SSRI’s (thus questioning therelevance of enhanced 5-HT levels for the antidepressant response), or that this combinationrapidly desensitizes GABA-ergic mechanisms, leading to an augmented response to SSRIs.
Artigas F. (1993). 5-HT and antidepressants: new views from microdialysis studies. TrensPharmacol. Sci. 14(7) :262Blier P., de Montigny C., Chaput Y. (1987). Modifications of the serotonin system byantidepressant treatments: implications for the therapeutic response in major depression. JClin Psychopharmacol 7 : 24S-35SBordet R., Thomas P., Dupuis B. (1998). Effect of pindolol on onset of action of paroxetine inthe treatment of major depression: intermediate analysis of a double-blind, placebo-controlledtrial. Reseau de Recherche et d'Experimentation Psychopharmacologique. Am J Psychiatry155 : 1346-1351Clifford E.M., Gartside S.E., Umbers V., Cowen P.J., Hajos M.,Sharp T. (1998).
Electrophysiological and neurochemical evidence that pindolol has agonist properties at the5-HT1aautoreceptor in vivo. Br J Pharmacol 124 : 206-212Fuller R.W. (1994). Uptake inhibitors increase extracellular serotonin concentration measuredby brain microdialysis. Life Sci 55 : 163-167Gibson E.L., Barnfield A.M.C., Curzon G., (1996) Dissociation of effects of chronicdiazepam treatment and withdrawal on hippocampal dialysate 5-HT and MCPP-inducedanxiety in rats. Behavioral Pharmacology 7: 185-193Hjorth, S. (1993), Serotonin 5-HT1A autoreceptor blockade potentiates the ability of the 5-HT reuptake inhibitor citalopram to increase nerve terminal output of 5-HT in vivo: amicrodialysis study. J. Neurochem. 60(2); 776-779.
Invernizzi R., Bramante M.,Samanin R. (1994). Chronic treatment with citalopram facilitatesthe effect of a challenge dose on cortical serotonin output: role of presynaptic 5-HT1Areceptors. Eur J Pharmacol 260 : 243-246Keller M.B., Hanks D.L. (1995). Anxiety symptom relief in depression treatment outcome. J.
Clin. Psychiatry 57 (suppl. 6) : 22-29McAskill R., Mir S.,Taylor D. (1998). Pindolol augmentation of antidepressant therapy. Br JPsychiatry 173 : 203-208Pei Q., Zetterstrom T., Fillenz M. (1989). Both systemic and local administration ofbenzodiazepine agonists inhibit the in vivo release of 5-HT from ventral hippocampus.
Neuropharmacology 28 : 1061-1066Perez V., Gilaberte I., Faries D., Alvarez E., Artigas F. (1997). Randomised, double-blind,placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment[see comments]. Lancet 349 : 1594-1597Rex A., Marsden C.A., Fink H. (1993). Effect of diazepam on cortical 5-HT release andbehaviour in the guinea-pig on exposure to the elevated plus maze. Psychopharmacology 110: 490-496Petty F., Trivedi M.H., Fulton M., Rush A.J. (1995). Benzodiazepines as antidepressants :Does GABA play a role in depression? Biol. Psychiatry 38 : 578-591Smith W.T., Londborg P.D., Glaudin V., Painter J.R. (1998). Short-term augmentation offluoxetine with clonazepam in the treatment of depression: a double blind study. Am JPsychiatry 155 : 1339-1351 Attenuation of SSRI-induced increases in extracellular brain 5-HT by benzodiazepines Sproule B.A., Naranjo C.A., Bremner K.E., Hassan P.C. (1997). Selective serotonin reuptakeinhibitors and CNS drug interactions. Clin. Pharmacokinet. 33 (6) : 454-471Sussman N. (1998). Anxiolytic antidepressant augmentation, J. Clinical Psychiatry 59 (Suppl5) : 42-48Tao R., Ma Z., Auerbach S.B. (1996). Differential regulation of 5-hydroxytryptamine releaseby GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. BritishJournal of Pharmacology 119 : 1375-1384Wilson M.A., Gallager, D.W. (1988). GABAergic subsensitivity of dorsal raphe neuronsinvitro after chronic benzodiazepine treatment in vivo. Brain Research 473 : 198-202.

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Dominique DETAILLE Born on september 17th, 1969 E-mail: domidet@usal.es or domidet@hotmail.com PhD in Biology Project: Scientific collaborator in a public or private research laboratory on Biomedical topics. Education 2002 - Ph.D. in Biology (Adviser: Professor Pierre Devos) Title: The Xenopus laevis oocyte as experimental tool for the study of an antidiabetic drug,

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