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Background Many patients lack a clear recollection from their stay in the intensive care unit (ICU). Diaries have been introduced as a tool to complete memories and reduce the risk of posttraumatic stress disorder (PTSD). Aims To describe and compare patients' memories and PTSD in relation to having received and read or not received a diary and patients' experiences of having received and read their diary, without having discussed the contents with ICU staff. Design Descriptive and comparative. Methods Patients received their diaries at ICU discharge. After 2 months patients answered the ICU Memory Tool, a screening instrument for PTSD (PTSS-14) and a questionnaire including space for own comments about the diaries. Results Of 96 patients, 52(54%) received a diary, 44 did not. Patients with diaries had significantly longer stay and more mechanical ventilation. Of these, 40 patients responded to PTSS-14 and had evaluated and read the diary and 34 patients served as controls. No significant differences were found in presence/absence of memories between these groups. In the diary-group patients with emotional memories had lower APACHE. Feelings of being anxious or frightened were more common in the diary-group. At 2 months, 12% scored above cut-off on the PTSS14 with no difference between groups. The diaries were helpful for understanding the ICU-stay. Conclusions Diaries seem valuable in understanding what happened, as an act of caring and as a tool for discussion with relatives and friends. Patients valued reading their diaries. None expressed the wish to have read the diary together with a member of staff. The diary and non-diary groups however reported similar memories. Relevance to clinical practice Diaries seem to be valuable in understanding what happened, giving a feeling of trust and for talking about their ICU-stay. As many patients described stressful memories, sessions should be offered with ICU staff.

Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and sham-operated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S- and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups.

Patients with chronic hepatic encephalopathy (HE) may present affective symptoms and antidepressant drug treatment in this condition is not uncommon. The present microdialysis study investigated treatment with the chronic antidepressant venlafaxine (VEN) in experimental HE with regard to tentative changes in pharmacokinetic and/or pharmacodynamic parameters. Three weeks after portacaval shunt (PCS) or sham operation in rats, VEN (10 mg/kg daily) was administered by implanted osmotic minipumps. VEN treatment for 14 days resulted in higher concentrations of VEN in PCS rats than in sham controls in serum and brain compartments, and the VEN levels in serum and brain were strongly inter-correlated. The serum N-desmethylvenlafaxine concentration did not differ between the groups, but correlated with the serum VEN levels. The other VEN metabolites were below the quantification limits. VEN treatment for 9-12 days significantly stimulated locomotion and rearing in the open field in sham controls, but failed to do so in the PCS rats. The concentrations of noradrenaline, dopamine, 5-HT, and 5-HIAA in neocortical dialysates were higher in PCS than in sham rats after 14 days of VEN treatment, but the elevations reached statistical significance only in the case of dopamine and 5-HIAA. In summary, there were significant pharmacokinetic and pharmacodynamic alterations in rats with experimental HE as compared to controls. The described experimental HE model may be useful for continued pharmacokinetic/pharmacodynamic interaction studies to unravel the pathophysiological consequences of HE on the CNS.

The spontaneous open-field behavioural effects of 10 days of chronic treatment with two clinical doses (10 and 20 mg/kg daily) and one high/toxic dose (100 mg/kg daily) of the selective serotonin reuptake inhibitor citalopram (delivered subcutaneously by implanted osmotic pumps) were examined in rats. Central and peripheral arena locomotor and rearing activities were recorded simultaneously, and the data were assessed during the first hour as well as during the following 24 hr (the latter for effects on the diurnal rhythm). Rats treated with 100 mg/kg daily exhibited lower peripheral locomotor and rearing activities than the other groups during the first test hour. The ratio between central and peripheral activity increased in a dose-dependent non-proportional manner during the first test hour, indicating a general increase in the central arena activity exerted by the rats when treated with citalopram. No major differences were observed between any of the four groups in overall behavioural activities over the 24-hr period. This study indicated that the open-field locomotor and rearing behaviours in normal rats were affected by increasing doses of racemic citalopram, particularly during the first hour of adaptation.

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.

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 behaviour 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.

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.

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

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.

Portal-systemic encephalopathy (PSE) is associated with increased brain turnover of serotonin (5-hydroxytryptamine; 5-HT). Despite this metabolic increase, neuronal release of 5-HT is unaltered in neocortex of portacaval shunted (PCS) rats. In the present study, frontal neocortical extracellular 5-HT and 5-hydroxyindole-3-acetic acid (5-HIAA) levels were determined in PCS rats and sham-operated controls prior to, as well as, after acute challenge with L-tryptophan (L-TRP; a bolus dose of 280 mg/kg i.p. followed by 5 consecutive hourly doses of 50 mg/kg). Neither basal 5-HT nor 5-HIAA extracellular levels were significantly altered in PCS rats compared to controls. L-TRP administration resulted in unaltered extracellular 5-HT but elevated 5-HIAA levels in PCS and sham rats. These findings do not suggest that changes in brain neuronal 5-HT release play any major functional role in the pathogenesis of chronic PSE. The present data also emphasize the importance of distinguishing between brain 5-HT metabolism and brain 5-HT release.

Patients with chronic liver impairment often display symptoms of affective psychiatric nature where the choice for antidepressant treatment is rational. Since caution is recommended when these drugs are used in such patients, a dose reduction is usually performed. We have previously reported that a dose reduction to liver-impaired portacaval shunted rats has resulted in similar brain concentrations of venlafaxine as compared to sham-operated control rats that received a two times higher dose. The main aim of the present study was therefore to investigate if this "normalisation" in pharmacokinetics of the portacaval-shunted rats also was true for the pharmacodynamic response in terms of drug effect on spontaneous open-field behaviour. Thus, portacaval-shunted rats received a single reduced dose (5 mg/kg) of venlafaxine or saline, whereas sham-operated rats received either 10 mg/kg or saline. Thereafter, central and peripheral arena locomotor and rearing activities were recorded during 60 min. The venlafaxine-treated portacaval-shunted and sham rats displayed reduced and unchanged overall behavioural activities compared with corresponding controls, respectively. However, the ratios between centrally and peripherally performed behavioural activities were higher in the venlafaxine-treated sham rats, indicating an increase in central arena activity as compared to the sham-saline and portacaval-shunted rats. The present study indicates that, despite a 50% dose reduction, caution still is necessary when antidepressants are used in liver insufficient subjects. This study also shows the importance of detailed open-field behavioural studies in which both central and peripheral activities are recorded for measurement of open-field behavioural drug effects.

Background. It is well known that portacaval shunting ultimately leads to a decrease in liver volume and hepatic function, but the mechanism is uncertain. The aim of the present study was to evaluate the effect of portacaval shunting (PCS) upon the morphological changes that occur in the liver in rats after port caval. anastomosis. Materials and methods. Sixty-six male rats underwent either PCS (n = 35) or sham operations (n = 31). Hormone levels were determined in blood samples taken just before removal and weighing of the livers. Hematoxylin and eosin-stained sections were used for quantitative morphometric analysis. Apoptosis, mitosis, and cellular organelles also were assessed quantitatively. Results. There was a significant reduction in the liver mass together with testosterone levels in PCS rats in comparison with sham rats. The distance between presinusoidal and postsinusoidal vessels was reduced from 500 mu m in the sham rats to 299 mu m in the PCS rats (P = 0.000001). Within the same group, there was a significant reduction in the area of hepatocyte nuclei in zone 3 in comparison with zone 1. Electron microscopy revealed a highly significant (P = 0.0007) reduction in the membrane-bound cytoplasmic organelles of zone 3 hepatocytes in PCS rats in comparison with the sham rats. Apoptosis was increased in zone 3 in PCS rats (P = 0.00001), whereas in zone 1 of the same group, there was an associated increased in mitosis (P = 0.000001). Overall, the degree of apoptosis was in excess of mitosis, resulting in a general loss of liver mass. Conclusion. Morphometric analysis at cellular and subcellular levels confirms the morphological findings of liver atrophy in PCS rats. The mechanism of atrophy is a complex one. Portacaval shunting leads to hepatic atrophy that, in turn, results in microcirculatory and hormonal changes that further contribute to liver cell loss in this animal model. (C) 2006 Elsevier Inc. All rights reserved.

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.

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.

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.

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 × kg–1) or the selective serotonin reuptake inhibitor citalopram (5 mg × 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.

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

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.

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.

The syndromes encountered within the term metabolic encephalopathy may be defined as “any metabolic disease that disrupts normal cerebral function” (Conn and Bircher, 1988). In the case of liver dysfunction, the terms hepatic encephalopathy (HE) or portal-systemic encephalopthy (PSE) are frequently used. In the human and clinical situation, these HE/PSE disorders are recognized as acute, chronic or, most commonly, acute-on-chronic events. The central nervous system (CNS) processes accompanying the patient suffering from HE/PSE probably include a mixture of reversible as well as irreversible changes of euronal function (Victor et al. 1965; Victor 1974, 1979; see also Conn and Lieberthal, 1979). Thus, clinical HE/PSE, which almost inexclusively have included previous or even ongoing exposure to e.g. liver affecting agents, like those related to a variety of acute or chronic infectious or immunological processes, as well as intake of liver toxins such as ethanol. Since the chronic abuse of alcohol is not an uncommon major cause for a subsequently appearing liver cirrhosis, in turn related to the etiology chronic PSE in many clinical cases by blood vessel collateral development bypassing the liver parenchyma, it should be kept in mind that this type of abuse will most certainly exert effects of its own on the CNS in patients with chronic PSE involving aspects of acute, chronic as well as acute-on-chronic CNS effects of ethanol concomitantly to the encephalopathy component provided by the “isolated” PSE per se. Of course, in the clinical setting the isolated effects on the brain of chronic PSE is almost impossible to purify in scientific terms whereas, however, this pure type of chronic PSE may be identified in experimental in vivo models available such as most prominently evidenced by the advent of the surgically induced end-to-side portacaval shunt (PCS) in the rat (Lee and Fisher, 1961).

Hepatic encephalopathy (HE) refers to a neuropsychiatric syndrome observed in patients with chronic liver failure. The pathogenesis for this important, but clinically often neglected, syndrome is still unknown. A profound perturbation in the handling of ammonia as well as of the essential aromatic amino acid L-tryptophan (L-TRP) has been shown to be associated with HE. This incapacity for normal L-TRP processing accompanying HE in vivo encompasses disturbances in L-TRP kinetics and metabolism both in brain tissue (1, for overview, see 2) as well as in the brain extracellular compartment (3,4).

Increased brain quinolinic acid (QUIN) levels have been suggested to play a role in hepatic encephalopathy (HE). Previous brain tissue studies have been unable to confirm this hypothesis. Because QUIn is a potent NMDA-receptor agonist, it also is relevant to determine brain extracellular QUIN levels in HE. For this purpose, we assessed frontal neocortical extracellular QUIN levels by in vivo microdialysis in rats subjected to a portacaval shunt (PCS). We also evaluated the acute effects of altered L-tryptophan (L-TRP) availability on brain extracellular QUIN levels. The basal extracellular L-TRP levels were significantly (p < .001) higher in the PCS rats than in the sham-operated controls. However, the QUIN level (p < .05) and the QUIN to L-TRP ratio (p < .01) were significantly lower in the PCS rats. Elevated L-TRP availability increased the QUIN levels to a similar degree in both sham and PCS rats. This study, in conjunction with our previous results, does thereby not support a major involvement of QUIN in the pathogenesis of HE.

Chronic hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with a substantial increase in the brain L-tryptophan (L-TRP) level. Moreover, a supranormal L-TRP hydroxylating activity in the brain suggests an induced enzymatic process in chronic HE. GTP-cyclohydrolase I (GTPCHI) and tetrahydrobiopterin (BH4) are two major factors besides L-TRP that are involved in regulating the brain L-TRP hydroxylating activity. We therefore determined the GTPCHI activity, the total biopterin and the BH4 concentrations in the neocortex and mesencephalon-pons of portacaval shunted (PCS) rats. The encephalopathic component in PCS rats was accounted for by studying open field behaviour. The acute effects of a single parenteral L-TRP challenge were also evaluated. The basal GTPCHI activities in PCS rats were decreased bu 50% (p