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Fin Stolze Larsen - One of the best experts on this subject based on the ideXlab platform.

  • cerebral blood flow autoregulation in experimental liver failure
    Journal of Cerebral Blood Flow and Metabolism, 2008
    Co-Authors: Thomas Dethloff, Gitte M Knudsen, Fin Stolze Larsen
    Abstract:

    Patients with acute liver failure (ALF) display impairment of cerebral blood flow (CBF) autoregulation, which may contribute to the development of fatal intracranial hypertension, but the pathophysiological mechanism remains unclear. In this study, we examined whether loss of liver mass causes impairment of CBF autoregulation. Four rat models were chosen, each representing different aspects of ALF: galactosamine (GIN) intoxication represented liver necrosis, 90% hepatectomy (PH×90) represented reduction in liver mass, Portacaval Anastomosis (PCA) represented shunting of blood/toxins into the systemic circulation thus mimicking intrahepatic shunting in ALF, PCA + NH3 provided information about the additional effects of hyperammonemia Rats were intubated and sedated with pentobarbital. We measured CBF with laser Doppler, intracranial pressure (ICP) was measured in the fossa posterior and registered with a pressure transducer, brain water was measured using the wet-to-dry method, and cerebral glutamine/gluta...

  • cerebral hyperemia and nitric oxide synthase in rats with ammonia induced brain edema
    Journal of Hepatology, 2001
    Co-Authors: Jeanne Gottstein, Fin Stolze Larsen, Andres T Blei
    Abstract:

    Abstract Background/Aim : Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS). Methods : Male rats received an end-to-side Portacaval Anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 μ M/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210′). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N -omega-nitro- l -arginine ( l -NNA, 2 μ g/kg per min intravenously) Results : At 90′, brain water was significantly increased ( P r =0.88, n =36, P l -NNA did not prevent the development of cerebral hyperperfusion and edema. Conclusion : We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.

  • pathophysiology of cerebral edema in fulminant hepatic failure
    Journal of Hepatology, 1999
    Co-Authors: Andres T Blei, Fin Stolze Larsen
    Abstract:

    F ULMINANT hepatic failure (FHF) is a devastating disease and is still associated with a high mortality (1). FHF results in progressive multi-organ failure with a dramatic impact on the brain. Indeed, development of intracranial hypertension (IH) is a leading cause of death in FHE During this decade two theories have independently emerged to explain the pathogenesis of cerebral edema and intracranial pressure in FHE The glutamine hypothesis is based on the fact that ammonia is detoxified in the brain to glutamine, whose osmotic effects in astrocytes may account for the development of brain edema (2). Astrocyte swelling is a prominent neuropathological feature in FHF (3). In humans, hyperammonemia induces brain edema in several medical conditions (4). Experimentally, inhibition of glutamine synthesis with methionine-sulfoximine (MSO) prevents the development of ammoniainduced brain edema in normal rats (5), decreases astrocyte swelling (6) and ameliorates brain edema in rats after Portacaval Anastomosis (PCA) receiving an ammonia infusion (7). A second hypothesis suggests that cerebral edema arises as a consequence of cerebral vasodilatation (8). Physiological studies in patients with FHF (9,lO) and in experimental models (11) indicate that cerebral arterioles are dilated. Furthermore, patients with signs of cerebral edema and IH have a higher cerebral blood flow (CBF) compared to patients without brain swelling (12,13). Two recent experimental studies suggest that development of brain edema may depend both on glutamine accumulation in astrocytes and changes in CBE First, Cordoba et al. (14) found in PCA rats receiving an ammonia infusion that an increase in brain glutamine was associated with a marked rise in CBF at the time of an increase in brain water and intracranial pressure.

Andres T Blei - One of the best experts on this subject based on the ideXlab platform.

  • Cerebral Blood Flow in Acute Liver Failure: A Finding in Search of a Mechanism
    Metabolic Brain Disease, 2004
    Co-Authors: Javier Vaquero, Chuhan Chung, Andres T Blei
    Abstract:

    In the last few years, several abnormalities of cerebral blood flow (CBF), namely loss of cerebral autoregulation, altered reactivity to carbon dioxide, and development of cerebral hyperemia, have been described in patients as well as experimental models of acute liver failure (ALF) and/or hyperammonemia. The development of cerebral hyperemia seems particularly relevant to the pathogenesis of brain edema in ALF. In addition to the potential increase of brain blood volume causing a rise in intracranial pressure, an increase of CBF could facilitate the movement of water across the blood brain barrier in an osmotically altered brain. Because maneuvers that abrogate the rise of CBF have been shown to prevent or ameliorate brain edema in ALF/hyperammonemia, elucidation of the mechanism by which the rise of CBF occurs is important. In the rat after Portacaval Anastomosis receiving an ammonia infusion, the signal resulting in cerebral hyperemia arises within the brain once maximal glutamine accumulation has occurred in astrocytes. Several mediators potentially involved in the development of cerebral hyperemia in ALF are examined in this review, but further work is needed to assess the role, if any, of each of them.

  • cerebral hyperemia and nitric oxide synthase in rats with ammonia induced brain edema
    Journal of Hepatology, 2001
    Co-Authors: Jeanne Gottstein, Fin Stolze Larsen, Andres T Blei
    Abstract:

    Abstract Background/Aim : Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS). Methods : Male rats received an end-to-side Portacaval Anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 μ M/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210′). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N -omega-nitro- l -arginine ( l -NNA, 2 μ g/kg per min intravenously) Results : At 90′, brain water was significantly increased ( P r =0.88, n =36, P l -NNA did not prevent the development of cerebral hyperperfusion and edema. Conclusion : We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.

  • Stenosis of a Portacaval Anastomosis affects circadian locomotor activity in the rat:a multivariable analysis
    1997
    Co-Authors: Josee ́ Dupuis, Jeanne Gottstein, Andres T Blei
    Abstract:

    sis. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G1218–G1225, 1997.—The study of hepatic encephalopathy is limited by the lack of standardized experimental models to assess behavior. We have shown that rats continuously monitored while running on a wheel show abnormalities of the circadian rhythm of locomotor activity after Portacaval Anastomosis (PCA), such that entrainment of running activ-ity to the light-dark cycle is severely impaired. To identify factors that affect postoperative circadian behavior, we have performed a multivariable analysis of 69 sham-operated controls and 107 rats after PCA. Our results indicate that shunt stenosis, as determined by the pressure gradient from the splenic pulp to the inferior vena cava, ameliorated the postoperative deterioration of the circadian rhythm. In addi-tion, postoperative behavior was affected by preoperativ

  • cerebral blood flow and the hyperdynamic circulation of rats after Portacaval Anastomosis
    Journal of Hepatology, 1993
    Co-Authors: Amit Srivastava, Jeanne Gottstein, Andres T Blei
    Abstract:

    Both increased and decreased values of cerebral blood flow have been reported in liver disease. Furthermore, the relation between the cerebral circulation and the generalized hemodynamic disturbance seen in chronic liver disease with portal-systemic shunting has not been fully characterized. We studied this problem in a well defined model of the hyperdynamic circulation, the rat after Portacaval Anastomosis (PCA). Using the radioactive microsphere technique, cardiac output and regional blood flows were measured; regional vascular resistances were then calculated. While the fraction of cardiac output perfusing the splanchnic bed was significantly increased, the corresponding brain fraction was reduced. Blood flow to the cerebral hemispheres and midbrain was significantly decreased. Arterial vasodilatation was demonstrated by the fall in arterial pressure, systemic vascular resistance as well as splanchnic and renal resistances; cerebrovascular resistance, however, was unchanged. No relation between values of arterial pressure and cerebral blood flow was seen, making a failure of cerebrovascular autoregulation unlikely. The decrease in hemispheric and midbrain perfusion without changes in vascular resistance suggests that a drop in blood flow is appropriately coupled to a reduction in brain metabolism. The cerebral circulation does not participate in the hyperdynamic state that is seen in this model.

Rajkumar Jalan - One of the best experts on this subject based on the ideXlab platform.

  • Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure
    HEPATOLOGY, 2007
    Co-Authors: Rajkumar Jalan
    Abstract:

    We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using die molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by Portacaval Anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brain ammonia correlated with the percent change in ICP (r(2) = 0.511). Increases in brain lactate dehydrogenase activity and mitochondrial complex activity for complex IV were found in ALF compared with those in the sham, which was unaffected by MARS treatment. Brain oxygen consumption did not differ among the study groups. Conclusion: The observation that brain oxygen consumption and mitochondrial complex enzyme activity changed in parallel in both ALF- and MARS-treated animals indicates that the attenuation of increased extracellular brain ammonia (and extracellular brain glutamate) in the MARS-treated animals reduces energy demand and increases supply, resulting in attenuation of increased extracellular brain lactate. The mechanism of how MARS reduces extracellular brain ammonia. requires further investigation.

  • Association of reduced extracellular brain ammonia, lactate, and intracranial pressure in pigs with acute liver failure
    2007
    Co-Authors: Christopher Rose, Lars M. Ytrebø, Nathan A. Davies, Sambit Sen, Geir I. Nedredal, Mireille Belanger, Arthur Revhaug, Rajkumar Jalan
    Abstract:

    This work is part of an international multicenter collaboration studying various end-organ functions in acute liver failure. Different pathophysiological aspects will be dealt with in separate articles. This article does not contain data published or submitted elsewhere. Potential conflict of interest: Nothing to report. We previously demonstrated in pigs with acute liver failure (ALF) that albumin dialysis using the molecular adsorbents recirculating system (MARS) attenuated a rise in intracranial pressure (ICP). This was independent of changes in arterial ammonia, cerebral blood flow and inflammation, allowing alternative hypotheses to be tested. The aims of the present study were to determine whether changes in cerebral extracellular ammonia, lactate, glutamine, glutamate, and energy metabolites were associated with the beneficial effects of MARS on ICP. Three randomized groups [sham, ALF (induced by Portacaval Anastomosis and hepatic artery ligation), and ALF+MARS] were studied over a 6-hour period with a 4-hour MARS treatment given beginning 2 hours after devascularization. Using cerebral microdialysis, the ALF-induced increase in extracellular brain ammonia, lactate, and glutamate was significantly attenuated in the ALF+MARS group as well as the increases in extracellular lactate/pyruvate and lactate/glucose ratios. The percent change in extracellular brai

Jeanne Gottstein - One of the best experts on this subject based on the ideXlab platform.

  • cerebral hyperemia and nitric oxide synthase in rats with ammonia induced brain edema
    Journal of Hepatology, 2001
    Co-Authors: Jeanne Gottstein, Fin Stolze Larsen, Andres T Blei
    Abstract:

    Abstract Background/Aim : Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS). Methods : Male rats received an end-to-side Portacaval Anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 μ M/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210′). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N -omega-nitro- l -arginine ( l -NNA, 2 μ g/kg per min intravenously) Results : At 90′, brain water was significantly increased ( P r =0.88, n =36, P l -NNA did not prevent the development of cerebral hyperperfusion and edema. Conclusion : We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.

  • cerebral blood flow and the development of ammonia induced brain edema in rats after Portacaval Anastomosis
    Hepatology, 1999
    Co-Authors: Sonali Master, Jeanne Gottstein
    Abstract:

    : Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after Portacaval Anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. Four groups received either a continuous ammonium acetate or control infusion; half of the animals had been pretreated with MSO or vehicle. The ammonia group exhibited brain edema (79.97 +/- 0.04 vs. 81.11 +/- 0. 13% water), an increase in cerebrospinal fluid (CSF) glutamine (1.29 +/- 0.21 vs. 2.84 +/- 0.39 mmol/L) and CBF (63 +/- 11 vs. 266 +/- 45 mL/min/100 g brain). When MSO was added to the ammonia infusion, ammonia levels rose further (928 +/- 51 vs. 1,293 +/- 145 mmol/L, P <.05) but CSF glutamine decreased (2.84 +/- 0.39 vs. 1.61 +/- 0.2 mmol/L, P <.01). Brain edema (80.48 +/- 0.11%) and cerebral hyperemia (140 +/- 25 mL/min/100 g brain) were significantly ameliorated in the ammonia plus MSO group. Brain output of circulating nitric oxide (NO(x)) was increased in the ammonia-infused group but normalized in the ammonia plus MSO group. In this model, the rise of CBF reflects intracranial events that occur after glutamine synthesis. Activation of nitric oxide synthase in the brain could account for these findings.

  • Stenosis of a Portacaval Anastomosis affects circadian locomotor activity in the rat:a multivariable analysis
    1997
    Co-Authors: Josee ́ Dupuis, Jeanne Gottstein, Andres T Blei
    Abstract:

    sis. Am. J. Physiol. 273 (Gastrointest. Liver Physiol. 36): G1218–G1225, 1997.—The study of hepatic encephalopathy is limited by the lack of standardized experimental models to assess behavior. We have shown that rats continuously monitored while running on a wheel show abnormalities of the circadian rhythm of locomotor activity after Portacaval Anastomosis (PCA), such that entrainment of running activ-ity to the light-dark cycle is severely impaired. To identify factors that affect postoperative circadian behavior, we have performed a multivariable analysis of 69 sham-operated controls and 107 rats after PCA. Our results indicate that shunt stenosis, as determined by the pressure gradient from the splenic pulp to the inferior vena cava, ameliorated the postoperative deterioration of the circadian rhythm. In addi-tion, postoperative behavior was affected by preoperativ

  • cerebral blood flow and the hyperdynamic circulation of rats after Portacaval Anastomosis
    Journal of Hepatology, 1993
    Co-Authors: Amit Srivastava, Jeanne Gottstein, Andres T Blei
    Abstract:

    Both increased and decreased values of cerebral blood flow have been reported in liver disease. Furthermore, the relation between the cerebral circulation and the generalized hemodynamic disturbance seen in chronic liver disease with portal-systemic shunting has not been fully characterized. We studied this problem in a well defined model of the hyperdynamic circulation, the rat after Portacaval Anastomosis (PCA). Using the radioactive microsphere technique, cardiac output and regional blood flows were measured; regional vascular resistances were then calculated. While the fraction of cardiac output perfusing the splanchnic bed was significantly increased, the corresponding brain fraction was reduced. Blood flow to the cerebral hemispheres and midbrain was significantly decreased. Arterial vasodilatation was demonstrated by the fall in arterial pressure, systemic vascular resistance as well as splanchnic and renal resistances; cerebrovascular resistance, however, was unchanged. No relation between values of arterial pressure and cerebral blood flow was seen, making a failure of cerebrovascular autoregulation unlikely. The decrease in hemispheric and midbrain perfusion without changes in vascular resistance suggests that a drop in blood flow is appropriately coupled to a reduction in brain metabolism. The cerebral circulation does not participate in the hyperdynamic state that is seen in this model.

Butterworth Roger - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Portacaval Anastomosis on glutamine synthetase protein and gene expression in brain, liver and skeletal muscle
    'Springer Science and Business Media LLC', 1999
    Co-Authors: Desjardins Paul, Rao, Rama K., Michalak Adrianna, Rose Christopher, Butterworth Roger
    Abstract:

    The effects of chronic liver insufficiency resulting from end-to-side Portacaval Anastomosis (PCA) on glutamine synthetase (GS) activities, protein and gene expression were studied in brain, liver and skeletal muscle of male adult rats. Four weeks following PCA, activities of GS in cerebral cortex and cerebellum were reduced by 32\% and 37\% (p

  • Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction
    'Elsevier BV', 1999
    Co-Authors: Rose Christopher, Michalak Adrianna, Butterworth Roger, Zayed Joseph, Normandin Louise, Todd Kathryn, Spahr Laurent, Huet Pierre-michel, Pomier-layrargues Gilles
    Abstract:

    BACKGROUND & AIMS: Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. METHODS: Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side Portacaval Anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. RESULTS: Mn content was significantly increased in frontal cortex (by 38\%), occipital cortex (by 55\%), pallidum (by 186\%), putamen (by 66\%), and caudate (by 54\%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and Portacaval-shunted rats, Mn content was increased in pallidum (by 27\% and 57\%, respectively) and in caudate/putamen (by 57\% and 67\%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in Portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. CONCLUSIONS: These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction

  • Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure
    'Elsevier BV', 1997
    Co-Authors: Knecht K., Michalak Adrianna, Rose Christopher, Rothstein, Jane D., Butterworth Roger
    Abstract:

    It has been suggested that reduced astrocytic uptake of neuronally released glutamate contributes to the pathogenesis of hepatic encephalopathy in acute liver failure. In order to further address this issue, the recently cloned and sequenced astrocytic glutamate transporter GLT-1 was studied in brain preparations from rats with ischemic liver failure induced by Portacaval Anastomosis followed 24 h later by hepatic artery ligation and from appropriate sham-operated controls. GLT-1 expression was studied using reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of GLT-1 transcript was significantly decreased in frontal cortex at coma stages of acute liver failure. Western blotting using a polyclonal antibody to GLT-1 revealed a concomitant decrease in expression of transporter protein in the brains of rats with acute liver failure. Reduced capacity of astrocytes to reuptake neuronally released glutamate, resulting from a GLT-1 transporter deficit and the consequently compromised neuron-astrocytic trafficking of glutamate could contribute to the pathogenesis of hepatic encephalopathy and brain edema, two major complications of acute liver failure

  • The Portacaval‐shunted rat : a new model for the study of the mechanisms controlling voluntary ethanol consumption and ethanol preference?
    'Wiley', 1997
    Co-Authors: De Waele Jean‐pascal, Rose Christopher, Audet, Robert M., Butterworth Roger
    Abstract:

    Portacaval Anastomosis (PCA) is a surgical procedure whereby blood from the portal vein is shunted into the inferior vena cava. PCA in the rat results in a significant increase (from 0.77 ± 0.26 to 3.51 ± 0.37 g of ethanol/kg/day) in voluntary ethanol consumption in a free‐choice paradigm between water and 5% ethanol solution. After PCA surgery, increased voluntary ethanol consumption starts abruptly at 6 to 7 days and is maintained for > 28 weeks. Voluntary ethanol consumption in rats after PCA results in blood ethanol levels up to 158 mg%. After PCA, the ethanol preference ratio (defined as the percentage of total fluid intake constituted by ethanol) increased from 19 ± 2% to 78 ± 2% (p < 0.001). Administration of the nonselective opioid receptor antagonist naloxone (5 mg/kg, sc) resulted in a significant 6‐fold attenuation of voluntary ethanol consumption by rats with PCA, an effect that was not mediated by an effect on locomotor activity. These findings, together with previous reports of widespread alterations of the μ‐ and δ‐opioid receptors in the brain after PCA, suggest that increased voluntary ethanol consumption and ethanol preference in PCA rats may result from activation of the endogenous opioid system. Preliminary studies suggest that rats with PCA manifest behavioral signs consistent with the development of dependence. The Portacaval‐shunted rat may provide a useful preparation for the study of mechanisms, in particular those involving the liver, implicated in the development of increased voluntary ethanol consumption and ethanol preference