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The impact of postnatal environment on opioid peptides in young and adult male Wistar rats
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. (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)
2008 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 42, no 2, 177-191 p.Article in journal (Refereed) Published
Abstract [en]

Early environmental influences can change the neuronal development and thereby affect behavior in adult life. The aim in the present study was to thoroughly examine the impact of early environmental factors on endogenous opioids by using a rodent maternal separation (MS) model. The endogenous opioid peptide system is not fully developed at birth, and short- and/or long-term alterations may occur in these neural networks in animals exposed to manipulation of the postnatal environment. Rat pups were subjected to one of five rearing conditions; 15 min (MS15) litter (l) or individual (i), 360 min (MS360) l or i daily MS, or housed under normal animal facility rearing (AFR) conditions during postnatal days 1-21. Measurements of immunoreactive (ir) Met-enkephalin-Arg(6)Phe(7) (MEAP) and dynorphin B (DYNB) peptide levels in the pituitary gland and in a number of brain areas, were performed at three and 10 weeks of age, respectively. MS-induced changes were more pronounced in ir MEAP levels, especially in individually separated rats at three weeks of age and in litter-separated rats at 10 weeks of age. The enkephalin and dynorphin systems have different developmental patterns, dynorphin appearing earlier, which may point at a more sensitive enkephalin system during the early postnatal weeks. The results provide evidence that opioid peptides are sensitive for early environmental factors and show that the separation conditions are critical and also result in changes manifesting at different time points. MS-induced effects were observed in areas related to stress, drug reward and dependence mechanisms. By describing effects on opioid peptides, the study addresses the possible role of a deranged endogenous opioid system in the previously described behavioral consequences of MS.

Place, publisher, year, edition, pages
2008. Vol. 42, no 2, 177-191 p.
Keyword [en]
handling, maternal separation, maternal deprivation, isolation, MEAP, dynorphin B
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-15880DOI: 10.1016/j.npep.2007.10.006ISI: 000254779400006PubMedID: 18082882OAI: oai:DiVA.org:uu-15880DiVA: diva2:43651
Available from: 2008-03-12 Created: 2008-03-12 Last updated: 2017-12-08Bibliographically 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
2. Maternal Separation in the Rat: The Short- and Long-term effects of Early-life Experience on Neuropeptides, Monoamines and Voluntary Ethanol Consumption
Open this publication in new window or tab >>Maternal Separation in the Rat: The Short- and Long-term effects of Early-life Experience on Neuropeptides, Monoamines and Voluntary Ethanol Consumption
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Early-life experience has profound effects on the individual’s neurobiology and behaviour later in life. The rodent animal experimental model maternal separation (MS) was used to study this more in detail. The MS model involves short and prolonged postnatal separations simulating an emotionally safe and stressful environment, respectively. The aims of the thesis were to examine the impact of individual MS on ethanol consumption and on brain dopamine and serotonin systems in adult male rats. Furthermore, the influence of separation conditions on the short- and long-term consequences of MS on several neurotransmitter systems was examined.

Rat pups were assigned to either litter-wise MS for 15 or 360 minutes (MS15l or MS360l) or individual MS for 15 or 360 minutes (MS15i or MS360i). Control rats were subjected to conventional animal facility rearing (AFR). Ethanol intake was assessed in a two-bottle free-choice paradigm. Neuropeptides were analyzed with radioimmunoassay, monoamines and metabolites with electrochemical detection and gene expression with qPCR.

Using the MSi paradigm, minor effects on voluntary ethanol consumption were observed. However, the monoaminergic responses elicited by ethanol were dependent on the early-life environment.

Furthermore, short- and long-term consequences of MS on serotonin, opioid, oxytocin and vasopressin systems were studied. Multiple neurobiological measurements in one and the same rat offered a unique possibility to examine the effects of duration (MS15 versus MS360) and condition (l versus i) of MS. Time-, region-, sex- and transmitter-specific effects were observed. More pronounced differences were seen in serotonin measures and oxytocin in young rats. In adults these differences in basal levels were normalized. Opioid peptides differed in stress-related brain areas in young rats and in limbic areas in adults. Rats subjected to the MS15l environment that relates to natural conditions generally exhibited a different neurobiological profile than other groups. AFR rats, i.e. conventional control rats, were more similar to the putative most stressful condition MS360. Taken together, the networks examined in the present thesis are important for the establishment of normal social behaviour and derangements in these systems may result in neurobiological changes leading to the susceptibility for psychopathological conditions later in life.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 87 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 106
Keyword
Early-life stress, Handling, Serotonin, Dopamine, Oxytocin, Vasopressin, Enkephalin, Dynorphin, Two-bottle free choice, Maternal deprivation
National Category
Pharmacology and Toxicology
Research subject
Pharmaceutical Pharmacology
Identifiers
urn:nbn:se:uu:diva-108678 (URN)978-91-554-7615-1 (ISBN)
Public defence
2009-11-07, B41, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2009-10-16 Created: 2009-09-25 Last updated: 2011-05-11Bibliographically approved

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