| 1. |
- Lindberg, Marie K, 1975, et al.
(author)
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Estrogen receptor specificity for the effects of estrogen in ovariectomized mice.
- 2002
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In: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 174:2, s. 167-78
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Journal article (peer-reviewed)abstract
- Estrogen exerts a variety of important physiological effects, which have been suggested to be mediated via the two known estrogen receptors (ERs), alpha and beta. Three-month-old ovariectomized mice, lacking one or both of the two estrogen receptors, were given estrogen subcutaneously (2.3 micro g/mouse per day) and the effects on different estrogen-responsive parameters, including skeletal effects, were studied. We found that estrogen increased the cortical bone dimensions in both wild-type (WT) and double ER knockout (DERKO) mice. DNA microarray analysis was performed to characterize this effect on cortical bone and it identified four genes that were regulated by estrogen in both WT and DERKO mice. The effect of estrogen on cortical bone in DERKO mice might either be due to remaining ERalpha activity or represent an ERalpha/ERbeta-independent effect. Other effects of estrogen, such as increased trabecular bone mineral density, thymic atrophy, fat reduction and increased uterine weight, were mainly ERalpha mediated.
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| 2. |
- Lindholm, Sara
(author)
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Neurochemical and behavioral studies on ethanol and brain opiod interactions in the brain
- 2001
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Doctoral thesis (other academic/artistic)abstract
- Substance dependence is a devastating disorder that produces enormous socio-economic costs, personal tragedies and health related problems. The brain mesolimbic dopamine pathway originating in the ventral tegmental area (VTA) with projections to limbic brain structures such as the nucleus accumbens has been implicated in the reinforcing effects of different drugs of abuse. The basal and drug-induced activity of mesolimbic dopamine neurons is modulated by endogenous opioids. Non-selective opioid receptor antagonists are increasingly used in the treatment of alcohol dependence, and ligands selective for the different opioid receptor types have recently been suggested to be effective in the treatment of cocaine and heroin addiction in humans. The present thesis examined the neurobiological and behavioral interactions between ethanol and endogenous opioids, with specific focus on the dynorphin/kappa-opioid receptor system. In addition, the effects of concurrent ethanol and cocaine administration on kappa-opioid receptor mRNA and dopamine transmission in the mesolimbic pathway were studied. Repeated ethanol administration significantly increased the dynorphin B levels in the nucleus accumbens at 30 min and at 21 days after the last dose. The kappa-receptor mRNA levels were significantly reduced in both the VTA and the nucleus accumbens after separate as well as concurrent administration of ethanol and cocaine. These results suggest that repeated exposure to ethanol may lead to neuroadaptive changes in the dynorphin/kappa-receptor system associated with the mesolimbic pathway, some of which may be long lasting. Following repeated ethanol administration, extracellular dopamine concentrations in the nucleus accumbens were significantly increased in rats pre-treated with ethanol, but not in the controls. Conversely, the inibitory effect of the kappa-receptor agonist U50,488H on dopamine levels was more pronounced in saline- than in ethanol -pre-treated rats. This suggests that repeated ethanol changes the sensitivity of the dynorphin/kappa-receptor system, and/or enhances the activity of the endogenous agonist dynorphin. Pre-treatment with ethanol increased the effect of cocaine on dopamine levels in the nucleus accumbens. Cocaine-induced stereotypic behavior was unaffected by ethanol pre-treatment. The enhanced dopamine release in the nucleus accumbens may be related to the heightened experience produced by concurrent intake of ethanol and cocaine in humans, and could influence the probability of co- abuse. Naltrexone and the selective delta-receptor antagonists ICI-174,864 and naltrindole significantly decreased voluntary ethanol intake, whereas the mu1-antagonist naloxonazine had no significant effect. The kappa-receptor agonist U50,488H decreased ethanol intake, whereas the kappa-receptor antagonist nor-BNI lacked effect by itself, but reduced the effect of U50,488H. This suggests that not only the mu-/delta-receptor systems, but also the kappa-receptor systems modulate volitional ethanol intake in the rat. In summary, repeated exposure to ethanol andlor cocaine produces alterations in the brain dynorphin/kappa-opioid receptor system. Further, voluntary ethanol intake is reduced by selective opioid receptor ligands. It is suggested that the dynorphinergic system is involved in the pathophysiology of alcohol dependence, and may represent a potential pharinacotherapeutic target in the treatment of this disorder.
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| 3. |
- Lindholm, Sara, et al.
(author)
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Nociceptin/orphanin FQ tissue concentration in the rat brain : Effects of repeated ethanol administration at various post-treatment intervals
- 2002
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In: Progress in Neuro-psychopharmacology and Biological Psychiatry. - 0278-5846 .- 1878-4216. ; 26:2, s. 303-306
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Journal article (peer-reviewed)abstract
- The aim of this study was to study short- and long-term effects of repeated ethanol administration on nociceptin/orphanin FQ (N/OFQ) tissue concentrations in rat brain with radioimmunoassay. Animals were given either ethanol (intraperitoneal) or saline for 13 consecutive days. N/OFQ levels were examined at 30 min, 5 days and 21 days after the last dose on day 13. Ethanol-treated rats had significantly decreased N/OFQ tissue concentration in the hippocampus at 30 min after the last dose. N/OFQ levels were decreased in the cingulate cortex at 5 days after cessation of ethanol administration whereas no significant changes were found at 21 days. There were no significant changes in N/OFQ tissue concentrations at any time point studied in the mesolimbic dopamine (DA) system, a brain area associated with ethanol-induced activation. However, the results indicate that repeated ethanol administration may induce short- and long-term changes in N/OFQ tissue concentrations in other brain regions innervated with dopaminergic neurons.
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| 4. |
- Lindholm, Sara, et al.
(author)
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Repeated ethanol administration induces short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat brain
- 2000
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In: Alcohol. - 0741-8329 .- 1873-6823. ; 22:3, s. 165-171
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Journal article (peer-reviewed)abstract
- Recently, we have shown that rats repeatedly treated with ethanol and/or cocaine have decreased kappa-opioid receptor mRNA levels in the mesolimbic system. The aim of the present study was to investigate the short- and long-term effects of repeated ethanol administration on opioid peptide concentrations in brain tissue of male Sprague-Dawley rats. Dynorphin B (1-13) (Dyn B) and Met-enkephalinArg(6)Phe(7) (MEAP), endogenous ligands to kappa- and delta-opioid receptors, respectively, were measured using radioimmunoassays. The rats were given either ethanol [intraperitoneal (ip), twice daily, 2 g/kg bw/dose] or saline for 13 consecutive days. Thirty minutes after the last ethanol dose on Day 13, the Dyn B tissue concentration was significantly decreased in the cingulate cortex. The MEAP tissue concentration was decreased in the hippocampus 5 days after the last ethanol injection as compared to saline-treated controls. Furthermore, the Dyn B and the MEAP concentrations were increased in the periaqueductal grey area (PAG) at this time point. Of particular interest were the significant increases in Dyn B tissue concentrations found in the nucleus accumbens (NAcc) at 30 min and at 21 days after the last ethanol dose. The results suggest that repeated ethanol administration induces both short- and long-term changes in the tissue concentrations of opioids in certain brain regions associated with motivation and reward.
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