Involvement of the Opioid System in High Alcohol Consumption : Environmental and Genetic Influences

Sammanfattning: It is well accepted that both inherent and environmental factors influence the pathogenesis of alcohol dependence. This thesis investigates the role of the opioid system in the initiation and maintenance of high ethanol intake. Ethanol-preferring C57BL/6J mice differ from ethanol-avoiding DBA/2J mice in that they exhibit lower basal levels of the opioid peptides dynorphin B and Met-enkephalin-Arg6Phe7 (MEAP) in the nucleus accumbens, which may contribute to their divergent drug-taking behaviour. Chronic ethanol intake in C57BL/6J mice and repeated ethanol administration in Sprague-Dawley rats induce time-specific changes in dynorphin B and MEAP levels in regions, such as the nucleus accumbens and the ventral tegmental area, associated with reinforcing effects of drugs of abuse. Daily neonatal handling for 15 min (H15) and maternal separation for 360 min (MS360) during postnatal day 1-21 were used as models for environmental manipulation early in life. H15 in male rats results in decreased anxiety-like behaviour, whereas MS360 increases anxiety-like behaviour. Both H15 and MS360 induce changes in dynorphin B and MEAP levels especially in regions related to the hypothalamic-pituitary-adrenal (HPA) axis. In female rats, regions related to the HPA axis are unaffected by H15. This suggests a gender-specific involvement of opioids in the HPA axis response to stress. More rats in the MS360 group initiate ethanol consumption and have a higher ethanol intake later in life than the H15 group. The H15 group has particularly low ethanol intake and also differs with regard to neurochemistry compared to both MS360 and control groups, suggesting that H15 can induce long-term changes, protective against high ethanol intake. Specific changes in opioid receptor density are observed after chronic ethanol consumption, such as an increased κ-receptor density in several brain areas, as well as changes in δ-receptor density in the frontal cortex and the nucleus accumbens. Altogether, these results suggest that the opioid system plays an important role in the mechanisms underlying the initiation and maintenance of high ethanol intake.