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.

In vivo steady-state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats.

The thymoleptic drug citalopram (CIT) belongs to the selective serotonin reuptake inhibitors (SSRIs) and is today extensively used in psychiatry. Further clarification of the enantiomer-selective distribution of racemic CIT in both clinical and toxic doses is highly warranted. By a steady-state in vivo paradigm, rats underwent chronic systemic exposure for 10 days by using osmotic pumps and the total as well as the individual distributions of the S- and R-enantiomers of CIT, and its metabolites in serum and two different brain regions, were analysed. In serum, the S/R ratios in the groups treated with 10, 20, or 100 mg kg(-1) day(-1) were 0.94, 0.83, and 0.34, respectively. The ratios were almost the same in the brain regions. In the group treated with 100 mg kg(-1) day(-1), the serum and brain total CIT levels were found to be 20 times and 6 - 8 times higher than in the rats treated with 10 or 20 mg kg(-1) day(-1), respectively. In all groups, the CIT levels were higher in brain tissue as compared to serum. In a spontaneous open-field behavioural test, a correlation between clinical and toxic drug concentrations was observed. In conclusion, the R-enantiomer was present in an increased proportion compared with the S-enantiomer when higher steady-state CIT concentration was prevailing. This is of particular interest, since the S-enantiomer is responsible for the inhibition of serotonin reuptake in vitro. The present data may be of importance, as full understanding on where different racemic or enantiomeric drug effects of CIT and its main metabolites are unravelled.

Effect of halving the dose of venlafaxine to adjust for putative pharmacokinetic and pharmacodynamic changes in an animal model of chronic hepatic encephalopathy.

Patients with chronic hepatic encephalopathy display monoaminergic perturbations together with affective symptoms. Thus, these patients belong to a group with a probability of receiving antidepressant drug treatment. The liver impairment may result in pharmacokinetic alterations of the antidepressant drug, which in turn may affect the already perturbed monoaminergic function. Venlafaxine (VEN) was administered as a single subcutaneous challenge to portacaval shunted (experimental hepatic encephalopathy model) rats (5 mg/kg) and sham-operated rats (5 and 10 mg/kg). The aims were to investigate whether a reduced dose in portacaval shunted rats resulted in higher concentrations of VEN and serotonin as compared to control rats, which had been demonstrated earlier when the rats received the same dose (10 mg/kg). A 50% reduction of the dose of VEN administered to portacaval shunted rats resulted in elevated levels of VEN in serum, brain parenchyma, and brain dialysate about 300 minutes after the injection. The VEN challenge increased the serotonin and noradrenaline concentrations in dialysate in portacaval shunted rats and both sham groups, but the three VEN groups did not differ in any major way in serotonin and noradrenaline output. Therefore, when the dose of VEN administered to experimental hepatic encephalopathy was reduced 50% as compared to control rats, mainly pharmacokinetic, and possibly also monoaminergic, alterations were observed.

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.

Altered adaptive behaviour expressed in an open-field paradigm in experimental hepatic encephalopathy.

Chronic hepatic encephalopathy (HE) encounters a neuropsychiatric syndrome arising as a complication to liver dysfunction. Patients with chronic HE display a great variety of neuropsychiatric symptoms including such mental derangements as adaptational difficulty, and deteriorated learning and memory capacity. The portacaval shunt (PCS) in the rat is a widely used model for experimental chronic HE. In the present study, the adaptive capacity of unhabituated PCS rats and sham-operated control rats were studied by measuring two exploratory behaviours (locomotion and rearing) during 5 or 60 min, at four consecutive days or nights with 24 h between sessions. The results revealed that PCS and sham-operated control rats showed parallel behavioural outcome over the four sessions in the 5-min trial. However, at the four consecutive test sessions in the 60-min trials, the sham-controls displayed a continuing decrease in overall activity between sessions whereas the PCS rats evidenced a repeated and stable activity level. These results indicate a presence of a long-term habituation deficiency as exhibited by the PCS rats. Additionally, the results indicate that differences in normal open-field motor behaviour between PCS rats and controls may not be found if such tests are conducted repeatedly during night-time but may emerge when tested repeatedly during daytime. The results may also be interpreted as a possible impaired learning/memory capacity in PCS rats. However, further investigations of how the PCS procedure affects entities of adaptation and learning ability are needed before any conclusions may be drawn since this is the first report of such an impairment in experimental chronic HE when represented by the PCS rat.

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.

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.

Quantitative studies of testicular atrophy following portacaval shunt in rats.

To evaluate the differential effects of portacaval shunting (PCS) on the morphological changes that occur in humans with portal-systemic encephalopathy, male rats underwent either PCS (13) or sham operations (10). Normal adult rats (6) were used as controls. All animals were killed 5 to 7 weeks after the surgery. The wet weight of the testes was obtained. Hematoxylin-eosin (HE)-stained sections at 5-micrometers thickness were used for stereological analysis using an image analysis system. Apoptosis was assessed quantitatively in HE and in in situ end-labeling (ISEL)-stained slides, while mitotic activity and mast cell numbers were assessed in 20 high-power fields. There was a significant reduction in the testicular mass (664 mg) in PCS rats in comparison with sham (2,199 mg) and control (1,937 mg) rats (P <.00001). The thickness of germinal epithelium was significantly reduced in PCS rats (64 micrometers) compared with sham (126 micrometers) and control groups (108 micrometers). The number of tubules per square millimeter and the mean curvature were significantly increased in PCS rats (P <.00001). There was a 112-fold increase in apoptosis in PCS rats (112) in comparison with the control and sham-operation groups (1.2 and 0.7, respectively). Mitosis was significantly reduced in the PCS group (P =.0089), but mast cells were unchanged. The results suggest that PCS in the absence of liver dysfunction produces testicular atrophy by reduction in mitosis, maturation arrest, and increased apoptosis of the germinal epithelium. PCS may therefore be responsible for gonadal atrophy that occurs with advanced liver disease in humans.

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.

Diurnal and gender effects by chronic portacaval shunting in rats on spontaneous locomotor and rearing activities in an open-field.

Behavioural disturbances in chronic experimental hepatic encephalopathy (HE) have been investigated for several decades, but only in recent years, the possibility for gender-dependent reduction of spontaneous locomotor activity has come under attention. Unfortunately though, the results of such gender dependency have been discrepant. We therefore performed an open-field behavior study in unhabituated female and male portacaval shunted (PCS) rats during both day- and night-time, monitoring locomotor as well as rearing activity for a 60 min period. The results revealed lower locomotor and rearing activities in both male and female PCS rats during night-time, compared to sham-operated controls. Daytime differences could only be detected in the rearing activity of female PCS versus control rats. Female PCS rats also spent less cumulated time rearing, compared to controls but no differences regarding the overall locomotor/rearing activity ratio or portion of the behaviours exerted in the central area of the open-field could be detected between PCS and controls, or between the sexes. Diurnal activity differences were found between control groups of both sexes but not between the female versus male PCS rats. Thus, our results are not supportive of any major gender-dependent behavioural disturbance between PCS and control rats.

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.

Central vs. peripheral spontaneous behavioral abnormalities in experimental hepatic encephalopathy.

The most common behavioral disturbance reported in experimental chronic hepatic encephalopathy (HE) refers to changes in spontaneous activities in an open field in the portacaval-shunted (PCS) rat. A major problem at present is that not all of these findings of abnormal PCS behavior are in agreement. We, therefore, investigated the total, central, and peripheral locomotor and rearing activities in an open field 2 and 6 months after PCS surgery. The results revealed that, 2 months after surgery, locomotor and rearing activities were lower in PCS rats compared to controls. At 6 months, a partial remission of the behaviors had occurred. Clearly though, as pointed out by the peripheral behavioral recordings, the hypoactivity persisted and, interestingly, central locomotor activity as higher in PCS rats than in controls. This novel finding may be attributed to the special study of central vs. peripheral components of the spontaneous open-field behavior in experimental chronic HE. Our observations may also help explain some of the seemingly discrepant results available in the literature.

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.

Gender and diurnal effects on specific open-field behavioral patterns in the portacaval shunted rat.

Hepatic encephalopathy (HE) is a frequently observed neuropsychiatric syndrome with unknown pathogenesis in patients suffering from chronic liver failure. The portacaval shunted (PCS) rat has been extensively used as an experimental model for HE and for studying the effects of portal-systemic shunting. Previous behavioral studies on PCS rats have shown a number of abnormalities but there is no consensus about which abnormalities are characteristic. We therefore made a thorough descriptive study of 100 male and female PCS rats and sham-operated controls four to six weeks after the shunting procedure in an open field. The frequency, duration and average time sequence of various kinds of defined spontaneous behavioral patterns were investigated during both night and day in order to assess behavioral differences between PCS rats and sham-operated controls. The results indicate differences especially regarding motor exploratory behaviors such as forward locomotion and rearing. There were also differences in eating and sniffing behaviors. Our results show that the overall behavioral alteration seen in PCS rats compared to sham-operated controls is that of hypoactivity.

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.