| 1. |
- Drakenberg, Katarina, et al.
(author)
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Mu opioid receptor A118G polymorphism in association with striatal opioid neuropeptide gene expression in heroin abusers
- 2006
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 103:20, s. 7883-7888
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Journal article (peer-reviewed)abstract
- μ Opioid receptors are critical for heroin dependence, and A118G SNP of the μ opioid receptor gene (OPRM1) has been linked with heroin abuse. In our population of European Caucasians (n = 118), ≈90% of 118G allelic carriers were heroin users. Postmortem brain analyses showed the OPRM1 genotype associated with transcription, translation, and processing of the human striatal opioid neuropeptide system. Whereas down-regulation of preproenkephalin and preprodynorphin genes was evident in all heroin users, the effects were exaggerated in 118G subjects and were most prominent for preproenkephalin in the nucleus accumbens shell. Reduced opioid neuropeptide transcription was accompanied by increased dynorphin and enkephalin peptide concentrations exclusively in 118G heroin subjects, suggesting that the peptide processing is associated with the OPRM1 genotype. Abnormal gene expression related to peptide convertase and ubiquitin/proteosome regulation was also evident in heroin users. Taken together, alterations in opioid neuropeptide systems might underlie enhanced opiate abuse vulnerability apparent in 118G individuals.
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| 2. |
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| 3. |
- Gustafsson, Lisa, 1975-
(author)
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Endogenous Opioids and Voluntary Ethanol Drinking : Consequences of Postnatal Environmental Influences in Rats
- 2007
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 4. |
- Gustafsson, Lisa, et al.
(author)
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Ethanol-induced effects on opioid peptides in adult male Wistar rats are dependent on early environmental factors
- 2007
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In: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 146:3, s. 1137-1149
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Journal article (peer-reviewed)abstract
- 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.
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| 5. |
- Gustafsson, Lisa, et al.
(author)
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The impact of postnatal environment on opioid peptides in young and adult male Wistar rats
- 2008
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In: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 42:2, s. 177-191
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Journal article (peer-reviewed)abstract
- 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.
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| 6. |
- Gustafsson, Lisa, et al.
(author)
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Time-dependent alterations in ethanol intake in male wistar rats exposed to short and prolonged daily maternal separation in a 4-bottle free-choice paradigm
- 2006
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In: Alcoholism. - : Wiley. - 0145-6008 .- 1530-0277. ; 30:12, s. 2008-2016
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Journal article (peer-reviewed)abstract
- Background: Previous studies have shown that maternal separation can be used in animal studies of early environmental influence on adult ethanol intake. These studies have shown that short daily separations result in low ethanol intake, whereas prolonged separations relate to an enhanced risk for a high ethanol intake. The aim of the present study was to further examine the long-term effects of early-life events on ethanol intake. Methods: Rat pups were exposed to 15 minutes (MS15) or 360 minutes (MS360) of daily maternal separation during postnatal days 1 to 21 or kept under normal animal facility rearing (AFR) conditions. In adulthood, male rats were given free access to 5, 10, and 20% ethanol, in addition to water, in a 4-bottle-choice paradigm. Results: No differences in total ethanol intake or preference between the 3 experimental groups were found. The 54-day drinking period was divided into acquisition, stabilization, and maintenance phases for analysis of time and group differences. The MS15 rats increased ethanol intake over time; they mostly consumed 5% ethanol and had a low intake of 20% ethanol throughout the experiment. MS360 rats increased ethanol intake, changed preference from 5% to 20% ethanol, and had a higher increase in intake of 20% ethanol over time. The ethanol intake and preference in the AFR rats were more similar to that of the MS360 rats. Conclusions: Time-dependent changes were observed in the preferred choice of low versus high ethanol concentrations in MS15 and MS360 rats. The results support previous findings suggesting that MS15 can be used as a model for environmental protective factors and that MS360 represents a risk environment for acquisition of a high adult ethanol intake.
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| 7. |
- Hammarberg, Anders, et al.
(author)
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The effect of acamprosate on alcohol craving and correlation with hypothalamic pituitary adrenal (HPA) axis hormones and beta-endorphin
- 2009
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In: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1305:Suppl., s. S2-S6
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Journal article (peer-reviewed)abstract
- Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol dependent patients. The mechanism of acamprosate action is hypothesized to be by modulation of craving responses. Previous research has suggested that acamprosate may affect the hypothalamic pituitary adrenal (HPA) axis as well as beta-endorphin. The aim of the present study was to investigate if acamprosate attenuates alcohol craving following a short-term treatment, and if craving and drinking measures are correlated to changes in HPA-axis hormones and beta-endorphin. In a double-blind design, 56 alcohol dependent treatment seeking patients were randomized to 21 days of either acamprosate (1998 mg/day) or placebo treatment. Subjective, physiological and biological measurements were recorded at inclusion and on day 21. The results showed that acamprosate treated patients showed significantly reduced craving compared to placebo. Further, a significant correlation was shown between craving and alcohol consumption during study. No changes in hormonal levels were found in acamprosate treated patients compared to placebo.
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