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].

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.

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.

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.

Pharmacokinetic and pharmacodynamic responses to chronic administration of the selective serotonin reuptake inhibitor citalopram in rats.

The number of drugs used to treat affective disorders such as depression is rapidly increasing. Citalopram (CIT), an antidepressant, is a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI). In the present study, rats were treated with 10 mg/kg/d racemic CIT for two weeks with use of osmotic pumps, and the following were monitored: open-field behavior, racemic and enantioselective concentrations of CIT and metabolites in blood, brain parenchyma, and extracellular space, and the brain extracellular monoamine levels. The racemic CIT concentration in serum was estimated about tenfold lower than in brain parenchyma but much higher than in brain extracellular fluid. The major CIT metabolites, demethylcitalopram (DCIT) and didemethylcitalopram (DDCIT) were 20% and 30%, respectively, of the amounts of CIT in serum and even lower in the brain parenchyma. The S-enantiomer/R-enantiomer ratios for CIT and DCIT were about 1.01 and 0.31, respectively, in blood and brain. There was a clear correlation between the different drug components within and between blood and brain compartments. Citalopram had no measured effect on open-field behavior, but it elevated extracellular 5-HT and decreased 5-HIAA levels. No correlations between any of the drug components and the brain monoamines were found. In summary, the drug components after chronic dosing correlated well between the periphery and the brain, but not with the brain monoamine concentrations. Further studies investigating the combined pharmacokinetic/dynamic effects could take advantage of blood drug monitoring for the commonly used novel antidepressant drugs.

Brain monoamine output alterations after a single venlafaxine challenge in experimental hepatic encephalopathy.

Venlafaxine (VEN) pharmacokinetics and effects on the brain monoamine output were investigated in the context of experimental hepatic encephalopathy (HE). Systemic VEN (10 mg/kg; subcutaneous) was administered to chronic portacaval shunted (PCS) and sham-operated rats. Their neocortical extracellular levels of 5-HT, 5-HIAA, NA, and DA were then assessed using microdialysis. Serum, brain extracellular, and brain tissue levels of racemic VEN and its main metabolites were also investigated. In a dose-equipotent manner, the VEN challenge increased the 5-HT levels in PCS rats compared with VEN-treated controls, whereas the 5-HIAA levels decreased similarly with time after the challenge in PCS and controls. Brain extracellular NA levels increased similarly in PCS and controls after VEN, but DA increased predominantly in controls. A similar single dose challenge resulted in clearly higher VEN levels in serum, brain extracellular fluid, and brain tissue in the PCS rats compared with controls. However, the VEN brain tissue/serum ratios were in the same order of magnitude for the two groups. Of the main VEN metabolites, only O-desmethylvenlafaxine (ODV) could be detected in pharmacologically significant amounts. The ODV concentration was also elevated in all three investigated biomatrices of the PCS rats versus control rats. The authors concluded that a typical novel brain monoamine-acting drug, such as VEN, exhibits both pharmacokinetic and pharmacodynamic alterations in experimental HE. Accordingly, the results of this study suggest that this frequently used type of drug should be further studied for its potential combined kinetic/dynamic actions in compromised patients with liver impairment.

Regional brain serotonin receptor changes in portacaval shunted rats.

The pathogenesis of hepatic encephalopathy is unknown, but metabolic perturbations, including hyperammonaemia and increased brain turnover of serotonin (5-HT), have been identified. Possible alterations of 5-HT receptors in the brain have been rudimentarily studied. We therefore investigated the 5-HT1A, 5-HT1B and 5-HT2A receptor density in 18-22 different regions in the brain of portacaval shunted rats by means of radioligand binding with autoradiographical evaluation. The results revealed a decreased 5-HT1A receptor binding in seven serotonergic projection areas of the brain, and an increase in the nucleus accumbens, hypothalamus and subiculum. No changes in the raphe nuclei were observed. An increased 5-HT1B receptor binding was seen in five brain regions: basal ganglia, olfactorial regions, hippocampus, mid brain and thalamus. However, decreased binding was seen in three regions of cortical areas and hippocampus. The 5-HT2A receptor binding site density was essentially unaltered. These findings suggest that perturbations in the central serotonergic neurotransmission may play a functional role in chronic hepatic encephalopathy.

Effect of citalopram on brain serotonin release in experimental hepatic encephalopathy: implications for thymoleptic drug safety in liver insufficiency.

In the present study, effects of citalopram (CIT) on brain 5-hydroxytryptamine (5-HT) release in experimental chronic hepatic encephalopathy (HE) were investigated. Neocortical administration of CIT (1.0 microM) increased the brain 5-HT output to a similar extent in portacaval shunted (PCS) rats and sham-operated controls, indicating that a previous described mismatch between increased 5-HT turnover and unchanged release in PCS rats is not explained by an accelerated brain 5-HT reuptake. Subsequent systemic administration of CIT (5 mg/kg subcutaneously) resulted in a more pronounced attenuation of the brain 5-HT release in PCS rats than in sham-operated controls, possibly indicating a higher susceptibility to indirect mid-brain 5-HT1A autoreceptor activation in experimental portal-systemic encephalopathy (PSE). A KCl (60 mM) challenge in the presence of locally administered CIT (1 microM) induced a more marked neocortical 5-HT response in PCS rats than in sham-operated controls, confirming previous results of a higher than normal amount of 5-HT available for depolarization-induced release in PCS rats. Although the pharmacodynamic parameters in this study was investigated for CIT, the likelihood of a parallel pharmacokinetic alteration existing for this drug in the PCS condition also was indicated. It is thus suggested that otherwise generally safe central nervous system 5-HT-active drugs may represent a potential hazard in patients with liver failure with or without PSE.

Potassium-evoked neuronal release of serotonin in experimental chronic portal-systemic encephalopathy.

Portal-systemic encephalopathy (PSE) is associated with an increased brain tissue turnover of serotonin (5-HT). Despite increased 5-HT metabolism, brain 5-HT release in rats with a portacaval shunt (PCS) seems to be unaltered. Although this may indicate that the overall 5-HT output is unaltered in PSE, it is also possible that the 5-HT release pattern might be altered in some way. In the present study, the potassium-evoked frontal neocortical release of 5-HT was studied in experimental chronic PSE. KCI (60 mM) produced marked increases in the 5-HT output compared with basal values both in PCS and sham rats. Simultaneously, the KCI challenge resulted in significant elevations in the 5-HT release of PCS compared with sham. In Ca2+-free medium, the difference between PCS and sham rats in the KCl-evoked release of 5-HT was abolished. In the presence of TTX (1 mM), both groups displayed increased extracellular 5-HT levels. Again, a difference with higher amplitude of the 5-HT release in PCS compared with sham was evident. It is concluded that in experimental chronic PSE an augmented neocortical 5-HT release compared with the normal in vivo situation is available. The possible mechanism(s) responsible for the difference in neocortical 5-HT output between PCS and sham-operated rats in response to the KCl-challenge is discussed.

p-Chloroamphetamine- and d-fenfluramine-induced brain serotonin release in experimental portal-systemic encephalopathy.

Portal-systemic encephalopathy (PSE) is associated with increased brain turnover of serotonin (5-HT) in vivo but the brain 5-HT output seems to be unaltered. Recent results suggest, however, that an augmented neocortical 5-HT release in experimental chronic PSE may prevail under certain conditions. In the present study, neocortical extracellular 5-HT and 5-hydroxyindoleacetic-3-acid (5-HIAA) levels were measured in portacaval shunted (PCS) rats and sham-operated controls following local administration of p-chloroamphetamine (pCA) and d-fenfluramine (dFEN), two specific 5-HT releasing agents. The basal neocortical extracellular 5-HT concentrations were unaltered and the 5-HIAA levels were elevated in experimental PSE, supporting an unchanged brain 5-HT output despite elevated brain 5-HT metabolism. Perfusion with pCA or dFEN (5 microM; one 20-min pulse) produced marked increases in brain 5-HT release both in PCS and sham-operated rats compared with corresponding basal values. While no difference in the 5-HT response to dFEN administration was seen between sham (5-HT levels increased by 330%) and PCS (500%) rats, a clear difference (p<0.05) in the brain 5-HT output was observed between the two experimental groups following pCA perfusion (sham, 1100% versus PCS, 1470%). These results support our previous contention of an enhanced neocortical 5-HT output in experimental chronic PSE under certain pharmacological conditions.

Elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy.

Brain tissue levels of the two serotonin metabolites 5-hydroxytryptophol and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured in porta-caval shunted rats, an in vivo model of portal-systemic encephalopathy. An intraperitoneal challenge of L-tryptophan (280 mg/kg body weight) to sham-operated rats was also instituted to increase the brain serotonin metabolism in these rats. The results revealed significant increases in 5-hydroxytryptophol (by 31% and 5-HIAA (by 87%) brain levels in porta-caval shunted rats as compared to sham-operated controls. The brain 5-hydroxytryptophol-to-5-HIAA ratio was lower in the porta-caval shunted rats. The 5-hydroxytryptophol levels in sham rats after the L-tryptophan challenge were intermediate between the porta-caval shunted and sham rats but not statistically significant for either group. These results suggest that increased brain 5-hydroxytryptophol levels might be associated with the pathogenesis of portal-systemic encephalopathy. Further, the elevated brain 5-hydroxytryptophol levels in experimental portal-systemic encephalopathy are probably a result of the increased brain serotonin metabolism prevailing in this condition rather than changes in the brain redox potential.

Ammonium acetate challenge in experimental chronic hepatic encephalopathy induces a transient increase of brain 5-HT release in vivo.

Ammonia has been shown to cause release of neurotransmitters such as serotonin (5-hydroxytryptamine; 5-HT) from synaptosomal preparations in vitro. In the present study, frontal neocortical extracellular levels of 5-HT and its major metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA), were determined in vivo by the use of microdialysis in portacaval shunted (PCS) rats, an experimental model of chronic hepatic encephalopathy (HE), prior to and after an acute coma-inducing administration of ammonium acetate (NH4Ac; 5.2 mmol/kg, i.p.). PCS rats displayed elevated (P < 0.01) 5-HIAA but unaltered 5-HT extracellular levels compared with controls, supporting the contention of an increased neocortical 5-HT metabolism but unaltered neuronal 5-HT output in chronic HE. However, a transient elevation of extracellular 5-HT levels was observed when PCS-NH4Ac rats were in coma. Increased brain ammonia may thus augment neuronal 5-HT release in chronic HE, which in turn could be a causative for precipitation of more severe stages of HE.