Neoadjuvant androgen deprivation therapy for prostate volume reduction, lower urinary tract symptom relief and quality of life improvement in men with intermediate- to high-risk prostate cancer: a randomised non-inferiority trial of degarelix versus goserelin plus bicalutamide.

AIMS: The treatment of intermediate- to high-risk prostate cancer with radical radiotherapy is usually in combination with neoadjuvant androgen deprivation therapy. The aim of the present trial was to investigate whether degarelix achieves comparable efficacy with that of goserelin plus bicalutamide as neoadjuvant therapy before radiotherapy. MATERIALS AND METHODS: The study was a randomised, parallel-arm, active-controlled, open-label trial in 244 men with a UICC prostate cancer TNM category T2b-T4, N0, M0, Gleason score ≥7, or prostate-specific antigen ≥10 ng/ml and a total prostate volume >30 ml, who were scheduled to undergo radical radiotherapy and in whom neoadjuvant androgen deprivation therapy was indicated. Eligible patients received treatment with either monthly degarelix (240/80 mg) or goserelin (3.6 mg) for 12 weeks, the latter patients also receiving bicalutamide (50 mg) for 17 days initially. The primary efficacy measure was the mean percentage reduction in total prostate volume from baseline at week 12 measured by transrectal ultrasound. The severity and relief of lower urinary tract symptoms were assessed by the International Prostate Symptom Score questionnaire. Quality of life was assessed by the eighth question of the International Prostate Symptom Score. About 50% of the patients had moderate to severe lower urinary tract symptoms at baseline. RESULTS: The total prostate volume decreased significantly from baseline to week 12 in both treatment groups, reaching -36.0 ± 14.5% in degarelix-treated patients and -35.3 ± 16.7% in goserelin-treated patients (adjusted difference: -0.3%; 95% confidence interval: -4.74; 4.14%). At the end of the therapy, more degarelix- than goserelin-treated patients reported International Prostate Symptom Score decreases of ≥3 points (37% versus 27%, P = 0.21). In addition, in patients with a baseline International Prostate Symptom Score of ≥13, the magnitude of the decrease was larger in degarelix- (n = 53) versus goserelin-treated patients (n = 17) (6.04 versus 3.41, P = 0.06). CONCLUSIONS: The efficacy of degarelix in terms of prostate shrinkage is non-inferior to that of goserelin plus bicalutamide. The added benefits of degarelix in terms of more pronounced lower urinary tract symptom relief in symptomatic patients could be the reflection of differences in the direct effects on extra-pituitary receptors in the lower urinary tract [Clinicaltrials.gov ID: NCT00833248].

Re-utilization of germinal centers in multiple Peyer's patches results in highly synchronized, oligoclonal, and affinity-matured gut IgA responses.

Whereas gut IgA responses to the microbiota may be multi-centered and diverse, little is known about IgA responses to T-cell-dependent antigens following oral immunizations. Using a novel approach, gut IgA responses to oral hapten (4-hydroxy-3-nitrophenyl)acetyl-cholera toxin (NP-CT) conjugates were followed at the cellular and molecular level. Surprisingly, these responses were highly synchronized, strongly oligoclonal, and dominated by affinity matured cells. Extensive lineage trees revealed clonal relationships between NP-specific IgA cells in gut inductive and effector sites, suggesting expansion of the same B-cell clone in multiple Peyer's patches (PPs). Adoptive transfer experiments showed that this was achieved through re-utilization of already existing germinal centers (GCs) in multiple PPs by previously activated GC GL7(+) B cells, provided oral NP-CT was given before cell transfer. Taken together, these results explain why repeated oral immunizations are mandatory for an effective oral vaccine.

Gene expression profiling identifies STAT3 as a novel pathway for immunomodulation by cholera toxin adjuvant.

Earlier studies have reported on both proinflammatory and anti-inflammatory activities of cholera toxin (CT). As CT is a powerful adjuvant, we were interested in identifying genes with a possible involvement in these functions. A global gene expression analysis in mouse B cells showed that CT regulated <100 annotated genes, which encoded transcription factors, G proteins, cell-cycle regulators, and immunoregulating molecules. Interestingly, CT regulated the expression of the signal transducer and activator of transcription (STAT)3 gene and influenced the level and activation of both isoforms STAT3 alpha and STAT3 beta, in vitro in a B-cell line and in Peyer's patch (PP) B cells and in vivo in freshly isolated splenic B cells from CT-treated mice. This effect was cAMP dependent and was not seen with CTB. B cells pre-exposed to CT were significantly more susceptible to the activation of STAT3 by interleukin (IL)-6 and IL-10. This exerted a stronger inhibitory effect of IL-10 on lipopolysaccharide (LPS)-stimulated B-cell proliferation and cytokine production (IL-6). Moreover, IgG1 and IgA production induced by LPS and IL-10 were enhanced by the addition of CT to cultures of PP or splenic B cells. This is the first study to provide a molecular mechanism that can reconcile previous findings of proinflammatory and anti-inflammatory effects by CT adjuvant.

Bioaccumulation of PCB congeners in marine benthic infauna.

Field concentrations of polychlorinated biphenyls (PCBs) were measured in sediment and nine marine soft bottom invertebrate species. Lipid- and organic carbon normalised biota-sediment accumulation factors (BSAFs) were determined for 29 nonplanar and 11 coplanar congeners. To investigate whether the bioaccumulation was in thermodynamic equilibrium with the sediment, the determined BSAFs were compared to theoretically calculated ones to obtain a BSAFdet./BSAFtheor-ratio. Large interspecific variations were found: one suspension feeding and one deposit feeding species of brittle stars (Amphiura filiformis and A. chiajei), and one predatory polychaete (Glycera rouxii) had ratios>1 for congeners with logKow>6.5. In these species there was also a linear relationship between logKow and BSAF, both for coplanar and for planar congeners but with lower values for coplanar ones. For other species the pattern was more scattered. Only the deposit feeding polychaete Melinna cristata had BSAFdet./BSAFtheor-ratios<1 for all congeners. Thus, the interspecific variations in bioaccumulation did not correlate with differences in feeding strategies, but may be caused by differences in biotransformation, and in age and size of the analysed specimens.

One-year safety and efficacy of budesonide/formoterol in a single inhaler (Symbicort Turbuhaler) for the treatment of asthma.

BACKGROUND: A budesonide/formoterol single inhaler has been developed for convenient treatment of patients whose asthma is inadequately controlled by inhaled glucocorticosteroids alone. OBJECTIVES: To compare long-term safety and efficacy of budesonide/formoterol single inhaler with budesonide plus formoterol via separate inhalers in adults with asthma. METHODS: In this open, randomized, parallel-group 6-month extension conducted in a subset of centres from a previous 6-month study, patients (n=321) received two inhalations bid of budesonide/formoterol (Symbicort Turbuhaler) 160/4.5 microg delivered dose or corresponding doses of budesonide (Pulmicort Turbuhaler) plus formoterol (Oxis Turbuhaler) via separate inhalers. RESULTS: Significantly fewer patients receiving budesonide/formoterol single inhaler withdrew compared with budesonide plus formoterol (9 vs. 19%, P=0.008). Incidence and severity of AEs were low and similar in both groups. No clinically important differences between groups, or changes, were identified in laboratory measurements, vital signs or ECG. Treatments produced similar improvements in lung function, ACQ scores and Mini AQLQ domains that were maintained throughout 12 months. CONCLUSIONS: Budesonide/formoterol in a single inhaler is as safe and effective in the long-term treatment of asthma as budesonide plus formoterol via separate inhalers. The lower number of withdrawals with budesonide/formoterol may reflect better adherence to treatment compared with budesonide plus formoterol.

Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities.

OBJECTIVE: The pharmacological profile of escitalopram, the S-(+)-enantiomer of citalopram, was studied and compared with citalopram and the R-(-)-enantiomer, R-citalopram. METHODS: Inhibition of the serotonin transporter (5-HTT) was studied in COS-1 cells expressing the human 5-HTT (h-5-HTT) and in rat brain synaptosomes. In vitro selectivity was studied relative to noradrenaline transporter (NAT) and dopamine transporter (DAT) function in rat brain synaptosomes, and affinities for other binding sites were determined. In vivo 5-HT activity was measured as inhibition of neuronal firing rate in rat dorsal raphe nucleus (DRN) and enhancement of 5-hydroxytryptophan (5-HTP)-induced behaviour (mouse and rat). Furthermore, studies were conducted in models of antidepressant (mouse forced-swim test), anxiolytic [foot-shock-induced ultrasonic vocalization (USV) in adult rats and mouse black and white box] and anti-aggressive activity (socially isolated mice). RESULTS: Escitalopram inhibited 5-HTT functions approximately 2 times more potently than citalopram and at least 40 times more potently than R-citalopram. Escitalopram showed insignificant activity at other monoamine transporters and 144 other binding sites. Escitalopram inhibited 5-HT neuronal firing in DRN and potentiated 5-HTP-induced behaviours more potently than citalopram; R-citalopram was inactive. Escitalopram and citalopram, but not R-citalopram, reduced forced-swimming-induced immobility and facilitated exploratory behaviour in the black and white box. Escitalopram and citalopram inhibited USV potently; R-citalopram was several times less potent. Escitalopram, citalopram and R-citalopram inhibited aggressive behaviour weakly. Escitalopram and citalopram had very potent anti-aggressive effects when co-administered with l-5-HTP. CONCLUSION: Escitalopram is a very selective 5-HT reuptake inhibitor. It is more potent than its racemate citalopram and is effective in animal models predictive of antidepressant and anxiolytic activities.

Budesonide/formoterol (Symbicort) is well tolerated and effective in patients with moderate persistent asthma.

The aim of this study was to compare the safety and efficacy of budesonide/formoterol 160/4.5 microg, two inhalations twice daily, with that of the mono-products administered at the same daily doses via separate inhalers. A total of 586 patients (mean age 45 years) was included in this six-month, open, randomised, multicentre study. Patients received either budesonide/formoterol (n=390) or budesonide plus formoterol (n=190). Safety was assessed by adverse events, vital signs and laboratory values. Efficacy was evaluated using spirometry tests, the Mini Asthma Quality of Life Questionnaire and the Asthma Control Questionnaire. Both treatments were well tolerated, with no differences in safety parameters between the groups. Mean FEV1 increased by 5-6% over baseline in both groups. There was no significant difference in the change from baseline between the groups using the disease-specific questionnaires. Asthma exacerbations occurred with low frequency in both groups. Withdrawal rates were also comparable between the groups (p=0.085). Budesonide/formoterol in a single inhaler was as effective and as well tolerated as budesonide plus formoterol via separate inhalers.

Sustained administration of the antidepressant venlafaxine in rats: pharmacokinetic and pharmacodynamic findings.

Rats were administered venlafaxine (10 mg/kg per day) for 14 days by using subcutaneously implanted osmotic minipumps. The present study assessed the distribution of VEN in different compartments, whether the VEN concentration in the compartments correlated, the effect of VEN on dialysate monoamine levels and on the spontaneous open-field behavior, and possible relations between the pharmacokinetic and pharmacodynamic parameters. The venlafaxine level in serum after sustained treatment was about 25% of the concentration in brain parenchyma and much higher than in brain dialysate. There was a clear correlation between venlafaxine concentrations in blood and brain compartments. The sustained venlafaxine challenge resulted in higher neocortical concentration of serotonin and noradrenaline, lower 5-hydroxyindole-3-acetic acid levels and increased locomotor activity in the central part of the test arena as compared to controls. No correlations were found between the venlafaxine concentration and brain monoamine parameters or the open-field behaviors. We conclude that, although species differences in pharmacokinetic properties for venlafaxine between rat and man exist, the pharmacokinetic correlations found after sustained treatment add information to the in vivo nature of the drug. Also, more studies like the present need to be performed to find the pharmacokinetic/pharmacodynamic interrelations for drugs like VEN.

Reactivity of serotonin in whole blood: relationship with drug response in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder responds almost only to potent serotonin reuptake inhibitors. Previous studies have suggested a relation between serotonergic function and clinical outcome in serotonin reuptake inhibitor treatment of obsessive-compulsive disorder. METHODS: In a randomized, double-blind trial, comparing clomipramine, paroxetine, and a placebo in obsessive-compulsive disorder, serotonin levels in whole blood (WB-5-HT) were measured at baseline, after 1 week, and after 4 weeks of treatment and related to clinical outcome in 36 patients. RESULTS: In patients treated with serotonin reuptake inhibitors there was a pronounced decrease of WB-5-HT, variable after 1 week and uniformly maximal after 4 weeks. The decrease of WB-5-HT after 1 week of serotonin reuptake inhibitor treatment correlated negatively with clinical outcome after 12 weeks (r = -.61, p =.0006); hence, patients with slower WB-5-HT reactivity eventually responded better to treatment. Baseline WB-5-HT, but not WB-5-HT reactivity, was related to season. Depression, autistic traits, and previous serotonin reuptake inhibitor treatment predicted nonresponse. CONCLUSIONS: A fast decrease of WB-5-HT was associated with poor clinical outcome. This may be related to faster serotonin efflux from platelets, which has previously been linked to autism. Further studies are necessary to identify the underlying mechanism and discern whether serotonin reuptake inhibitor-induced WB-5-HT decrease is clinically useful.

[Residues of chlordane in fish in the Gulf of Gdansk]. / Pozostalosci chlordanu w rybach w Zatoce Gdanskiej.

Concentrations, composition and spatial variations of the residues of the pesticide Chlordane were determined in several species of fish caught in Gulf of Gdansk. The residues of Chlordane (cis-i trans-chlordane, cis-i trans-nonachlor, oxychlordane, heptachlor, heptachlor epoxide, MC4, MC5, MC6, MC7, U82 and U83) were found in all fish examined, however, the concentrations noted were low, i.e. from 0.40 to 12 ng/g wet weight. Among the Chlordane constituents and metabolites determined trans-naonachlor, cis-chlordane, oxychlordan, heptachlor epoxide, cis-nonachlor, MC5, MC6 and trans-chlordane were dominated, and MC4, MC7, U82 and U83 were minor compounds. No heptachlor residues were found in fish examined. A small concentrations and specific composition of the residues of Chlordane and its metabolites determined in fish from the Gulf of Gdansk do indicate on a distant sources of pollution with that pesticide--mainly transported and deposited via the atmosphere.

Organochlorine compounds in the Gulf of Bothnia: sediment and benthic species.

Surface sediment, amphipods (Monoporeia affinis), isopods (Saduria entomon) and fourhorn sculpins (Oncocottus quadricornis) were collected at two coastal stations in the Gulf of Bothnia, one in the Bothnian Bay and the other in the Bothnian Sea. The objective was to study the concentrations, composition profiles, bioaccumulation features and spatial differences of organochlorine compounds such as hexachlorocyclohexanes (HCHs), DDTs, hexachlorobenzene (HCBz), chlordanes (CHLs), dieldrin, Mirex and polychlorinated biphenyls (PCBs). All groups of compounds were found in every sample investigated, with the exception of Mirex that was not detected in the sediment samples. The concentrations for e.g. PCBs and CHLs ranged from 700 to 2400 and 70 to 400 ng/g lipid in the specimens. For the corresponding sediments the results were 9.0-9.3 ng/g dw for PCBs and 0.54-0.57 ng/g dw for CHLs, respectively. Bioaccumulation differences between the species with regard to both degree of and type of compound were observed. The highest accumulation potential was found for the cyclodiene compounds including CHLs and Mirex in isopod. Finally, there were only small concentration and bioaccumulation differences between the two stations.

Environmental monitoring of the kafue river, located in the Copperbelt, Zambia.

Zambia is a country with an extensive mining industry with the majority of mines located in the Copperbelt province. Through this region of the country, the Kafue River drains and receives effluent water from mining activities as well as from other industrial point sources. In addition, production of agricultural products and pest control requires use of different pesticides in the area. Information on industrial and agricultural pollution has not been clearly identified in Zambia, and little attention has been paid to pollution control and possible impact of metals, pesticides, and other persistent compounds in the environment. The objective of this study was to introduce and to evaluate a few methodologies based on in situ bioassays for environmental assessment to promote sustainable and environmentally sound water resource management of the Kafue River. The results show that caged threespot tilapia exposed downstream of industrial points sources rapidly bioaccumulate several trace elements, i.e., Cd, Co, Cu, Cr, Ni. These elements also occurred in much higher concentrations in water samples downstream of the industrial area compared with a locality upstream. Furthermore, the use of a semipermeable membrane device (SPMD) for passive absorption of lipophilic pollutants in the water showed relatively high concentration of several pesticides, i.e., DDT with major metabolites, PCB, and dieldrin. The present study shows that only 2 weeks of in situ studies in waters contaminated by pollutants affects in situ exposed fish and that the correlation between water and tissue concentrations was relatively good. Both trace elements and persistent organic pollutants occurred in such high concentrations that they must be considered from ecotoxicological aspects and may affect aquatic animal health.

Dynamic and kinetic effects of chronic citalopram treatment in experimental hepatic encephalopathy.

Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome that arises in liver-impaired subjects. Patients with HE display various neuropsychiatric symptoms including affective disturbances and may therefore likely receive treatment with novel thymoleptics like citalopram (CIT). The simultaneous pharmacokinetic and pharmacodynamic outcome of the commonly used serotonin-selective thymoleptic drugs in liver-impaired subjects with pending chronic HE is far from understood today. We therefore investigated the effects of chronic, body-weight-adjusted (10 mg x kg(-1) x day(-1)), treatment with CIT in rats with and without portacaval shunts (PCS). Open-field activity was monitored. The 5-HT, 5-HIAA, noradrenaline (NA), and dopamine (DA) output were assessed in the frontal neocortex. The racemic levels of CIT and its metabolites DCIT and DDCIT, including the S- and R-enantiomers, were determined in serum, brain parenchyma, and extracellular fluid. The rats with PCS showed higher (2-3-fold) levels of CIT than rats undergoing a sham treatment with CIT in all compartments investigated. The PCS rats also showed elevated levels of DCIT and DDCIT. No major differences in the S/R ratios between PCS rats and control rats could be detected. The CIT treatment resulted in neocortical output differences between PCS rats and control rats mainly within the 5-HT and DA systems but not within the NA system. For the 5-HT system, this change was further evidenced by outspoken elevation in 5-HT output after KCI-depolarizing challenges. Moreover, the CIT treatment to PCS rats was shown to "normalize" the metabolic turnover of 5-HT, measured as a profound lowering of a basal elevation in the 5-HIAA levels. The CIT treatment resulted in an increased or "normalized" behavioral activity in the PCS group. Therefore, a dose-equal chronic treatment with CIT in PCS rats produced pharmacokinetic and pharmacodynamic changes not observed in control rats. The results further support the contention of an altered 5-HT neurotransmission prevailing in the chronic HE condition. However, the tentatively beneficial behavioral response also seen following chronic CIT treatment to PCS rats in this study has to be viewed in relation to both the pharmacokinetic and pharmacodynamic changes observed.

Plasma and brain levels of oxindole in experimental chronic hepatic encephalopathy: effects of systemic ammonium acetate and L-tryptophan.

It has previously been shown that the neurodepressant L-tryptophan metabolite oxindole is increased in the blood and brain of rats with fulminant hepatic failure and in the blood of cirrhotic patients affected by chronic hepatic encephalopathy. In the present investigation, we found that oxindole levels were significantly increased in the blood and brain of portacaval-shunted rats, an animal model of chronic hepatic encephalopathy, compared with sham-operated controls. A further increase in plasma and brain oxindole content was found after oral administration of L-tryptophan (300 mg/kg) to both portacaval-shunted or sham-operated animals, while intraperitoneal injection of the amino acid did not modify oxindole content either in brain or blood. Ammonium acetate administration (4.0 mmol/kg, intraperitoneal) reversibly deteriorated the neurological status of portacaval-shunted animals, but did not modify, in a directly related manner, plasma and brain oxindole content. The present findings are in line with the possibility that oxindole may be an additional L-tryptophan-related candidate in the pathogenesis of chronic hepatic encephalopathy.

[Dieldrin, aldrin, endrin, isodrin, endosulfan 1 and 2 on fish in the Gulf of Gdansk]. / Dieldryna, aldryna, endryna, izodryna, endosulfan 1 i 2 w rybach w Zatoce Gdanskiej.

The residues of dieldrin, aldrin, endrin, isodrin, endosulfan 1 and 2 has been determined in a several species of fish caught in the Gulf of Gdansk in 1992. The method of measurement was capillary gas chromatograph and low resolution mass spectrometry (HRGC/LRMS) after a nondestructive extraction and clean-up step with a further fractionation of the extract on Florisil column. Apart from dieldrin no other cyclodiene pesticides studied were found in fishes in detectable amounts, and for dieldrin concentrations ranged from 0.84 to 6.6 ng/g wet weight.

Persistent Organochlorines in the Effluents from a Chlorine-Bleached Kraft Integrated Pulp and Paper Mill in Southeast Asia.

A bleached sulfate integrated pulp and paper mill producing printing and writing paper from mixed tropical hardwood and bamboo was studied. The mill uses a "conventional bleaching sequence," C-E-H1-H2, with an average molecular chlorine consumption of 50 kg per ton of air-dried pulp (ADP). The content of polychlorinated dibenzofurans (PCDFs) and dibenzo-p-dioxins (PCDDs) in the bleaching filtrate in terms of the nordic toxicity equivalent (N-TEQ) was 33.5, 1.15, 0.56, and 0.014 pg/L for the E, C, H1, and H2 bleaching stages, respectively. The corresponding PCDFs and PCDDs loads in ng/t ADP were in the same ranking, i.e., 670, 69, 11.2, and 0.28, respectively. The congener and isomeric pattern of PCDFs and PCDDs of the bleaching filtrate and the bleached pulp was found to be typical for the chlorine bleaching plant effluent. The obtained dioxin load formed in the mill is in agreement with Western studies for the given multiple chlorine of 0.21-0.23. The load is, however, lower than reported discharges from Scandinavian mills using 1980s bleaching technologies, but substantially higher than the discharges from mills with modern bleaching technologies. Modifications in the bleaching plant to reduce molecular chlorine use are necessary to reduce dioxin formation.http://link.springer-ny.com/link/service/journals/00244/bibs/37n3p303.html

Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges.

RATIONALE: Latent or manifest chronic hepatic encephalopathy (HE) symptomatology often includes affective symptoms. It is therefore warranted to investigate the functional outcome of novel antidepressants when chronic HE prevails. OBJECTIVE: Portacaval shunt (PCS) in rats is a widely used experimental model for chronic HE, a neuropsychiatric syndrome accompanying liver dysfunction. HE is believed to arise from a primary alteration in neurotransmission in the CNS. PCS has been reported to increase the metabolism of serotonin in the brain, and thus the central serotonin nerve of PCS rats may contain more serotonin than normal. However, the functional relevance of this serotonergic alteration in terms of affecting behavioral performance of PCS rats has been only rarely studied. METHODS: Locomotor and rearing activities were recorded in PCS and sham-operated control rats. A single subcutaneous challenge with saline versus either the mixed serotonin/noradrenaline reuptake inhibitor venlafaxine (10 mg x kg(-1)) or the selective serotonin reuptake inhibitor citalopram (5 mg x kg(-1)) were performed. RESULTS: The PCS-saline injected rats showed reduced locomotor and rearing activity compared with sham-saline treated rats. While no significant differences could be observed following the venlafaxine challenge to controls, the PCS-venlafaxine challenged rats displayed reduced behavioral activity as compared to PCS-saline treated rats. The PCS-citalopram rats, however, displayed increased activity compared with the PCS-saline rats while, again, no effect of the citalopram challenge to controls was found. CONCLUSIONS: The present study show altered but opposite behavior in PCS rats, when challenged with either venlafaxine or citalopram, compared to PCS control rats. These findings therefore support the contention that caution should be advocated when CNS monoamine active drugs are used in liver-impaired subjects until better delineation of the combined pharmacodynamic and pharmacokinetic outcome for each such drug in this condition has been made.

Effect of atypical antipsychotic drugs on 5-HT2 receptors in the rat orbito-frontal cortex: an in vivo electrophysiological study.

Low doses of the atypical antipsychotic drug risperidone are effective in patients with obsessive compulsive disorder (OCD) not responding to serotonin (5-HT) reuptake inhibitors, although higher doses have been reported to induce OCD symptoms in psychotic patients. Since such atypical antipsychotics exert, in addition to dopamine, 5-HT2 receptor antagonistic properties, it was deemed essential to investigate the electrophysiological effect of these agents on 5-HT2 receptors in the rat orbito-frontal cortex (OFc), a brain region implicated in OCD. Microiontophoretic application of the GABAA receptor antagonist bicuculline had no effect on the suppressant effect of neuronal activity in the OFc induced by microiontophoretic application of the preferential 5-HT2A and 5-HT2C receptor agonists (+)-1-(4-iodo-2, 5-dimethoxyphenyl)-2-aminopropane (DOI) and m-chlorophenyl-piperazine (mCPP), respectively, but it antagonized the effect of GABA on the same neurons. These results indicate a lack of involvement of GABA interneurons in the suppressant effect of DOI and mCPP. While the 5-HT2 receptor antagonist ritanserin (2 mg/kg, i.v.) attenuated the inhibitory effect of DOI and mCPP in the medial prefrontal cortex (mPFc), the inhibition was unaffected in the OFc. In the mPFc, the effect of DOI and mCPP was blocked by both clozapine (1.0 and 10 mg/kg, i.v.) and risperidone (0.1 and 1.0 mg/kg, i.v.). In the OFc, only the suppressant effect of mCPP was attenuated by both doses of clozapine but only by the high dose of risperidone. These results suggest that the 5-HT2 response in the OFc is more akin to the 5-HT2C subtype and that the deleterious effect sometimes observed with high doses of risperidone and clozapine may be due to a decrease in 5-HT neurotransmission. In contrast, the beneficial effect of low doses of risperidone may be due, in part, to the antagonism of dopamine receptors.

Effect of long-term administration of antidepressant treatments on serotonin release in brain regions involved in obsessive-compulsive disorder.

BACKGROUND: Among all antidepressant treatments, including electroconvulsive shock (ECS) therapy and monoamine oxidase inhibitors (MAOIs), only the selective serotonin (5-HT) reuptake inhibitors (SSRIs) exert a clear therapeutic effect in obsessive-compulsive disorder (OCD). An 8-week, but not a 3-week treatment with the SSRI paroxetine results in an increased electrically evoked [3H]5-HT release and a desensitization of 5-HT autoreceptors in the guinea pig orbitofrontal cortex, a brain region implicated in OCD. METHODS: In the present study, the effect of long-term treatment with the SSRI fluoxetine, ECS, and the reversible type A MAOI moclobemide was investigated on evoked [3H]5-HT release from preloaded guinea pig brain slices prepared from the hypothalamus, cingulate cortex, and orbitofrontal cortex. RESULTS: Fluoxetine treatment yielded an enhanced [3H]5-HT release in the three brain areas, but a desensitization of the 5-HT autoreceptor only in the hypothalamus and orbitofrontal cortex. ECS treatment did not result in any alteration of the electrically evoked [3H]5-HT release or of 5-HT autoreceptor sensitivity in any of the brain regions. Moclobemide increased [3H]5-HT release only in the orbitofrontal cortex without any alteration in the 5-HT autoreceptor sensitivity. CONCLUSIONS: These findings indicate that only treatments effective in OCD have the capacity to desensitize the terminal 5-HT autoreceptor in the orbitofrontal cortex.