| 1. |
- Drakenberg, Katarina, et al.
(författare)
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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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Ingår i: 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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Tidskriftsartikel (refereegranskat)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-
(författare)
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Endogenous Opioids and Voluntary Ethanol Drinking : Consequences of Postnatal Environmental Influences in Rats
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
(författare)
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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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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 146:3, s. 1137-1149
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Tidskriftsartikel (refereegranskat)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.
(författare)
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The impact of postnatal environment on opioid peptides in young and adult male Wistar rats
- 2008
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Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 42:2, s. 177-191
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Alcoholism. - : Wiley. - 0145-6008 .- 1530-0277. ; 30:12, s. 2008-2016
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Tidskriftsartikel (refereegranskat)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.
(författare)
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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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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1305:Suppl., s. S2-S6
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Tidskriftsartikel (refereegranskat)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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| 8. |
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Oreland, Sadia, et al.
(författare)
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Two repeated maternal separation procedures differentially affect brain 5-hydroxytryptamine transporter and receptors in young and adult male and female rats
- 2009
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Ingår i: Brain Research. - : Elsevier. - 0006-8993 .- 1872-6240. ; 1305:Suppl. 1, s. S37-S49
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Tidskriftsartikel (refereegranskat)abstract
- Early environment is a known determinant for individual differences in vulnerability for adult psychopathology, e.g. ethanol addiction. One underlying mechanism could be dysfunction in serotonergic neurotransmission. This study focused on the methodological considerations regarding an animal model for studying effects of early environment, maternal separation (MS), using two different paradigms. Age- and sex-specific effects on brain stem 5-hydroxytryptamine (5-HT) transporter and receptors were examined. Male and female 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) daily during postnatal days 1-21. Normal animal facility reared rats were used as controls. Analyses were performed in young and adult rats. As compared to the other males, MS15l males had lower 5-HT1A and 5-HT2C receptor mRNA expression at both ages, lower 5-HT2A receptor mRNA when young and lower 5-HTT mRNA expression when adult. In contrast, adult MS15l females had higher 5-HT2C receptor mRNA expression than the other females. The strong impact of MS15l on 5-HT-related genes was either transient or persistent depending on sex and fewer effects on gene expression were observed in females than in males. This study shows the importance of tactile contact for the consequences of short, but not long MS, as evidenced by major differences between MS15l and MS15i. The results suggest that MS15i is less suitable than MS15l to simulate a protective environment in studies of for instance ethanol addiction processes.
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| 16. |
- Pickering, Chris, et al.
(författare)
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Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex
- 2006
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1099:1, s. 101-108
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Tidskriftsartikel (refereegranskat)abstract
- Stress early in life puts the individual at a greater risk for developing mental disorders in adulthood. The animal model of maternal separation involves daily removal of pups from their mother over the early postnatal period and leads to several behavioral deficits in adults. Since this period corresponds to a time of extensive developmental changes in the glutamatergic system, glutamate receptor mRNA expression was studied in the hippocampus and prefrontal cortex. Male Wistar rats were either separated from their mother for 15 min (MS15 or 'handling') or 360 min (MS360) once a day from pnd 1-21 and glutamate receptor expression levels were measured at 25 weeks of age using real-time RTPCR analysis. A third group of animal facility reared (AFR) rats was included as a control for the handling group. In the hippocampus, mRNA expression of NMDA NR2B and AMPA GluR1 and GluR2 receptors was significantly lower in MS360 rats relative to MS15. In addition, expression of the glutamate transporter GLAST was increased in MS360 relative to MS15. No differences were observed for AFR rats relative to MS15, which indicates that the hippocampal effects were not a result of handling or maternal care. For the prefrontal cortex, no difference in mRNA expression was observed for NMDA NR2A and NR2B or AMPA GluR1 and GluR2. These findings suggest that prolonged maternal separation produces neuroadaptive changes in the hippocampus that may, at least partially, account for the behavioral deficits previously observed in this animal model.
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| 17. |
- Roman, Erika, et al.
(författare)
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Behavioral profiles and stress-induced corticosteroid secretion in male Wistar rats subjected to short and prolonged periods of maternal separation
- 2006
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Ingår i: Hormones and Behavior. - : Elsevier BV. - 0018-506X .- 1095-6867. ; 50:5, s. 736-747
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Tidskriftsartikel (refereegranskat)abstract
- Early life experiences are important for the development of neurobiobehavioral mechanisms and subsequent establishment of mental functions. In experimental animals, early life experiences can be studied using the maternal separation model. Maternal separation has been described to induce neurobiological changes and thus affect brain function, mental state and behavior. We have established a protocol in order to study the effects of repeated short and prolonged periods of maternal separation during the postnatal period on adult neurochemistry, voluntary ethanol intake and behavior. In the present experiment, we focus on the long-term effects of maternal separation on exploration and risk assessment behavior as well corticosteroid secretion. Rat pups were assigned to 15 min (MS15) or 360 min (MS360) of daily maternal separation and normal animal facility rearing (AFR) during postnatal days 1-21. To establish the adult behavioral profile in male rats, three tests were used: the Concentric Square Field (CSF), the Open Field (OF) and the Elevated Plus-maze (EPM). No differences between the three experimental groups were found in the traditional OF and EPM tests. The CSF test indicated that the MS360 rats were more explorative and expressed an altered risk assessment and risk-taking profile. In response to a restraint stress, MS360 rats had a blunted corticosterone release in contrast to MS15 and AFR rats. In contrast to previous results, the outcome of the present investigation does not support the notion that a prolonged period of maternal separation results in an adult phenotype characterized by an increased emotional reactivity.
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| 18. |
- Roman, Erika, et al.
(författare)
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Short and prolonged periods of maternal separation and voluntary ethanol intake in male and female ethanol-preferring AA and ethanol-avoiding ANA rats
- 2005
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Ingår i: Alcoholism. - 0145-6008 .- 1530-0277. ; 29:4, s. 591-601
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetic as well as environmental factors can affect the propensity for psychopathology and/or drug dependence. Maternal separation represents an animal experimental model that is useful in studies of effects of early life experiences. The authors have established a protocol for short and prolonged periods of maternal separation to study adult neurochemistry, behavior, and ethanol intake and have previously reported alterations in ethanol intake in Wistar rats and ethanol-preferring rats. The aim of the current study was to more thoroughly study how early life experiences affect an inherited propensity for high and low ethanol intake, respectively, in male and female ethanol-preferring AA (Alko alcohol) and ethanol-avoiding ANA (Alko, Non-Alcohol) rats. METHODS: AA and ANA pups were assigned to one of three different rearing conditions: 15 min (MS15) or 360 min (MS360) of daily maternal separation in litters or normal animal facility rearing (AFR) during postnatal days 1 to 21. In adulthood, voluntary ethanol intake was investigated using the two-bottle free choice paradigm. RESULTS: In male ethanol-preferring AA rats, MS15 resulted in a lower intake and fewer high-preferring animals at 8% and 10% ethanol compared with MS360 rats. The male MS360 rats had a higher ethanol intake at 8% and 10% ethanol in comparison with AFR rats. In contrast, the female AA MS15 and MS360 rats had a lower ethanol intake and a lower preference for the 10% ethanol solution compared with the female AA AFR rats. In male and female ANA rats, no major separation-induced effects were found. CONCLUSIONS: The current results show that genetic inheritance can be affected by environmental manipulations in AA rats with an inherent high ethanol intake. The findings in female ethanol-preferring AA rats give further evidence of a differential outcome of maternal separation in male and female rats, as previously shown.
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| 19. |
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| 21. |
- Roman, Erika, et al.
(författare)
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The multivariate concentric square field test reveals different behavioural profiles in male AA and ANA rats with regard to risk taking and environmental reactivity
- 2007
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 183:2, s. 195-205
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present investigation was to compare the behavioural profiles in alcohol-preferring AA (Alko, alcohol) and alcohol-avoiding ANA (Alko, non-alcohol) rats. Twelve adult, alcohol-naive male AA and ANA rats were tested in the recently established multivariate concentric square field (MCSF) test. The more traditional open field and elevated plus-maze tests were used as reference tests. Six weeks after the initial MCSF test, a repeated testing was used to explore differences in acquired recognition after a previous experience. The results revealed distinct differences between the two lines. The ANA rats were generally more active in the three tests. In the MCSF, parameters of risk taking and shelter seeking indicated differences between the two lines. The ANA rats had higher shelter seeking behaviour and less risk taking behaviour than the AA rats. Repeated exposure to the MCSF caused a general decrease in activity and reduction in the number of visits to the various zones, especially evident in the ANA rats. The ANA rats showed more shelter seeking than the AA rats and also more shelter seeking than in the first trial, supporting an "anxiety-like" profile in these rats. In conclusion, the parameters related to risk taking and shelter seeking revealed obvious differences between AA and ANA rats. The higher risk taking behaviour seen in the AA rats might relate to their innate propensity for high voluntary alcohol intake. The results are discussed in relation to the reported neurobiological differences and in relation to other alcohol-preferring and alcohol-avoiding rat lines.
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| 22. |
- Roman, Erika, et al.
(författare)
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Variations in opioid peptide levels during the estrous cycle in Sprague-Dawley rats
- 2006
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Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 40:3, s. 195-206
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Tidskriftsartikel (refereegranskat)abstract
- The estrous cycle, with its various hormonal conditions, may provide us with the means of understanding how endocrine states relate to opioid mechanisms. There has been increasing experimental support for interaction between sex steroids and opioid peptides in the central nervous system. Here, we describe fluctuations in endogenous brain immunoreactive (ir) peptide levels during various phases of the estrous cycle in the female Sprague-Dawley rat. Ir levels of dynorphin A, dynorphin B, Leu-enkephalin-Arg(6), Met-enkephalin-Arg(6)Phe(7) and nociceptin/orphanin FQ were measured in the pituitary gland and in 10 areas of the brain during the diestrus, proestrus and estrus phase. In several areas of the brain, basal levels of endogenous opioid peptides showed variation during the course of the estrous cycle. Significant differences were found between the diestrus state and the proestrus and/or estrus conditions, particularly in the nucleus accumbens, caudate putamen and the substantia nigra. The ir levels of the endogenous peptide nociceptin/orphanin FQ became altered in only one of the areas measured, indicating less variance during the estrous cycle. Correlation analyses revealed that significant associations between dynorphin A or dynorphin B and Leu-enkephalin-Arg(6) were found more often during estrus than during the diestrus and proestrus conditions. The ratio between the ir levels of Leu-enkephalin-Arg(6), a cleavage product of the enzymatic conversion of dynorphin peptides into shorter peptides in vivo, and dynorphin peptides was calculated. The significantly lower ratio between Leu-enkephalin-Arg(6) and dynorphin B in diestrus than in proestrus and estrus also indicates cyclic fluctuations in the enzymatic cleavage of dynorphin. These findings are discussed in relation to the possible role of interactions between sex steroids and opioid peptide mechanisms during the normal estrous cycle.
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