Adolescence is a developmental period which the risk of drug and alcohol abuse increases. Since mesolimbic dopaminergic system undergoes developmental changes during adolescence, and this system is involved in rewarding effects of drugs of abuse, we addressed the hypothesis that ethanol exposure during juvenile/adolescent period over‐activates mesolimbic dopaminergic system inducing adaptations which can trigger long‐term enduring behavioural effects of alcohol abuse. We treated juvenile/adolescent or adult rats with ethanol (3 g/kg) for two‐consecutive days at 48‐h intervals over 14‐day period. Here we show that intermittent ethanol treatment during the juvenile/adolescence period alters subsequent ethanol intake.In vivomicrodialysis demonstrates that ethanol elicits a similar prolonged dopamine response in the nucleus accumbens of both adolescent and adult animals pre‐treated with multiple doses of ethanol, although the basal dopamine levels were higher in ethanol‐treated adolescents than in adult‐treated animals. Repeated ethanol administration also down‐regulates the expression of DRD2 and NMDAR2B phosphorylation in prefrontal cortex of adolescent animals, but not of adult rats. Finally, ethanol treatment during adolescence changes the acetylation of histones H3 and H4 in frontal cortex, nucleus accumbens and striatum, suggesting chromatin remodelling changes. In summary, our findings demonstrate the sensitivity of adolescent brain to ethanol effects on dopaminergic and glutamatergic neurotransmission, and suggest that abnormal plasticity in reward‐related processes and epigenetic mechanisms could contribute to the vulnerability of adolescents to alcohol addiction.

Minimal hepatic encephalopathy (MHE) is mainly diagnosed using psychometric tests such as the psychometric hepatic encephalopathy score (PHES). Despite the clinical and social relevance of MHE, psychometric testing is not widespread in routine clinical care. We assessed the usefulness of the critical flicker frequency (CFF), for the diagnosis of MHE and for the prediction of the development of overt episodes of HE. The normal range of PHES in the Spanish population was evaluated in a control group. Subsequently, 114 patients with cirrhosis and 103 healthy controls underwent both PHES and CFF tests. A diagnosis of MHE was made when the PHES was lower than −4 points. Patients were followed‐up every 6 months for a total of 1 year. CFF did not correlate with age, education, or sex in the control group. The mean CFF was significantly lower in patients with MHE versus non‐MHE or controls. Mean CFF correlated with individual psychometric tests as well as PHES (r = 0.54; P < 0.001). CFF <38 Hz was predictive of further bouts of overt HE (log‐rank: 14.2; P < 0.001). There was a weak correlation between mean CFF and Child‐Pugh score but not with model for end‐stage liver disease score. In multivariate analysis using Cox regression, CFF together with Child‐Pugh score was independently associated with the development of overt HE. Conclusion: CFF is a simple, reliable, and accurate method for the diagnosis of MHE. It is not influenced by age or education and could predict the development of overt HE. (HEPATOLOGY 2007;45:879–885.)

Objectives of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Commission were to identify well‐characterized animal models of hepatic encephalopathy (HE) and to highlight areas of animal modelling of the disorder that are in need of development. Features essential to HE modelling were identified. The best‐characterized animal models of HE in acute liver failure, the so‐called Type A HE, were found to be the hepatic devascularized rat and the rat with thioacetamide‐induced toxic liver injury. In case of chronic liver failure, surgical models in the rat involving end‐to‐side portacaval anastomosis or bile duct ligation were considered to best model minimal/mild (Type B) HE. Unfortunately, at this time, there are no satisfactory animal models of Type C HE resulting from end‐stage alcoholic liver disease or viral hepatitis, the most common aetiologies encountered in patients. The commission highlighted the urgent need for such models and of improved models of HE in chronic liver failure in general as well as a need for models of post‐transplant neuropsychiatric disorders. Studies of HE pathophysiology at the cellular and molecular level continue to benefit from in vitro and or ex vivo models involving brain slices or exposure of cultured cells (principally cultured astrocytes) to toxins such as ammonia, manganese and pro‐inflammatory cytokines. More attention could be paid in the future to in vitro models involving the neurovascular unit, microglia and neuronal co‐cultures in relation to HE pathogenesis.