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Ethanol-induced effects on opioid peptides in adult male Wistar rats are dependent on early environmental factors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction & Behaviour)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Neuropharmacology, Addiction & Behaviour)
2007 (English)In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 146, no 3, 1137-1149 p.Article in journal (Refereed) Published
Abstract [en]

The vulnerability to develop alcoholism is dependent on both genetic and environmental factors. The neurobiological mechanisms underlying these factors are not fully understood but individual divergence in the endogenous opioid peptide system may contribute. We have previously reported that early-life experiences can affect endogenous opioids and also adult voluntary ethanol intake. In the present study, this line of research was continued and the effects of long-term voluntary ethanol drinking on the opioid system are described in animals reared in different environmental settings. Rat pups were subjected to 15 min (MS15) or 360 min (MS360) of daily maternal separation during postnatal days 1–21. At 10 weeks of age, male rats were exposed to voluntary ethanol drinking in a four-bottle paradigm with 5%, 10% and 20% ethanol solution in addition to water for 2 months. Age-matched controls received water during the same period. Immunoreactive (ir) Met-enkephalin-Arg6Phe7 (MEAP) and dynorphin B (DYNB) peptide levels were thereafter measured in the pituitary gland and several brain areas. In water-drinking animals, lower ir MEAP levels were observed in the MS360 rats in the hypothalamus, medial prefrontal cortex, striatum and the periaqueductal gray, whereas no differences were seen in ir DYNB levels. Long-term ethanol drinking induced lower ir MEAP levels in MS15 rats in the medial prefrontal cortex and the periaqueductal gray, whereas higher levels were detected in MS360 rats in the hypothalamus, striatum and the substantia nigra. Chronic voluntary drinking affected ir DYNB levels in the pituitary gland, hypothalamus and the substantia nigra, with minor differences between MS15 and MS360. In conclusion, manipulation of the early environment caused changes in the opioid system and a subsequent altered response to ethanol. The altered sensitivity of the opioid peptides to ethanol may contribute to the previously reported differences in ethanol intake between MS15 and MS360 rats.

Place, publisher, year, edition, pages
2007. Vol. 146, no 3, 1137-1149 p.
Keyword [en]
handling, maternal separation, maternal deprivation, dynorphin B, MEAP, alcohol
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95649DOI: 10.1016/j.neuroscience.2007.02.037ISI: 000246584500023PubMedID: 17391858OAI: oai:DiVA.org:uu-95649DiVA: diva2:169949
Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2011-04-28Bibliographically approved
In thesis
1. Endogenous Opioids and Voluntary Ethanol Drinking: Consequences of Postnatal Environmental Influences in Rats
Open this publication in new window or tab >>Endogenous Opioids and Voluntary Ethanol Drinking: Consequences of Postnatal Environmental Influences in Rats
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Genetic and environmental factors interact to determine the individual vulnerability to develop ethanol dependence. The neurobiological mechanisms underlying these processes are not fully understood. Endogenous opioid peptides have been suggested to contribute. Brain opioids mediate ethanol reward and reinforcement via actions on the mesocorticolimbic dopamine system. This thesis focuses on environmental factors and investigates the impact of the early-life environment on adult voluntary ethanol consumption. The possible involvement of opioid peptides in environmental influences on adult ethanol consumption was examined using an experimental animal model.

Maternal separation with short 15 min separations (MS15) was used to simulate a safe environment whereas prolonged 360 min separations (MS360) simulated an unsafe environment. Control rats were subjected to normal animal facility rearing (AFR). The separations were performed daily from postnatal day 1 to 21. Long-term ethanol consumption was registered using a two-bottle or a four-bottle free-choice paradigm in adult male and female ethanol-preferring AA (Alko, Alcohol), ethanol-avoiding ANA (Alko, Non-Alcohol) and non-preferring Wistar rats. In addition, analyses of immunoreactive Met-enkephalin-Arg6Phe7 (MEAP), dynorphin B (DYNB) and nociceptin/orphanin FQ (N/OFQ) peptide levels were performed after maternal separation as well as after voluntary ethanol drinking.

In male rats, MS15 was related to lower ethanol consumption and these rats preferred lower concentrations, whereas MS360 was associated with an increased risk for higher consumption and/or preference for higher ethanol concentrations. Differences in basal opioid levels were observed in MS15 and MS360 rats. Furthermore, the ethanol-induced effects on opioid peptides in adults were dependent on the early environment. Female rats, on the other hand, were less affected or unaffected by maternal separation both in terms of ethanol consumption and neurobiological effects. Taken together, voluntary ethanol drinking, preference for low or high ethanol concentrations and opioid peptides in brain areas related to reward and reinforcement, motivation and stress were influenced by postnatal maternal separation in a sex dependent manner. The early environment thus had profound impact on the adult brain and the individual propensity for high ethanol drinking. A deranged endogenous opioid system contributed to these effects and may act as a mediator for long-term environmental influence on voluntary ethanol consumption.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 51
Keyword
Pharmaceutical pharmacology, Maternal separation, Maternal deprivation, Handling, Isolation, Alcohol, Two-bottle model, Four-bottle model, MEAP, Dynorphin B, Nociceptin/orphanin FQ, Radioimmunoassay, Farmaceutisk farmakologi
Identifiers
urn:nbn:se:uu:diva-7776 (URN)978-91-554-6843-9 (ISBN)
Public defence
2007-04-20, Lecture hall B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2007-03-30 Created: 2007-03-30 Last updated: 2009-06-02Bibliographically approved

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