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.

One of the neurological alterations in patients with minimal or overt hepatic encephalopathy is cognitive impairment. This impairment is reproduced in rats with chronic liver failure due to portacaval shunt (PCS). These rats show decreased ability to learn a conditional discrimination task in a Y‐maze, likely due to reduced function of the glutamate–nitric oxide (NO)–cyclic guanosine monophosphate (cGMP) pathway in brain. It has been proposed that inflammation exacerbates the neuropsychological alterations induced by hyperammonemia, suggesting that inflammation‐associated alterations may contribute to cognitive impairment in hepatic encephalopathy. This study assessed whether treatment with an anti‐inflammatory drug, ibuprofen, is able to restore the function of the glutamate‐NO‐cGMP pathway in cerebral cortex in brain in vivo and/or learning ability in PCS rats. We show that PCS rats have increased levels of interleukin‐6 and increased activities of cyclooxygenase and of inducible NO synthase in cerebral cortex, indicating the presence of inflammation. Chronic treatment with ibuprofen normalizes cyclooxygenase and inducible NO synthase activities but not interleukin‐6 levels. Moreover, ibuprofen normalizes the function of the glutamate‐NO‐cGMP pathway in cerebral cortex in vivo and completely restores the ability of rats with chronic liver failure to learn the Y‐maze task. This supports that inflammation contributes to the cognitive impairment in hepatic encephalopathy. Conclusion: the results reported point to the possible therapeutic utility of decreasing inflammation in the treatment of the cognitive deficits in patients with minimal or overt hepatic encephalopathy. (HEPATOLOGY 2007.)

The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7 μg and 1 μg of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or the striatum.