| 1. |
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| 2. |
- Ackermann, Paul, et al.
(författare)
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An opioid system in connective tissue : A study of Achilles tendon in the rat
- 2001
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Ingår i: Journal of Histochemistry and Cytochemistry. - : SAGE Publications. - 0022-1554 .- 1551-5044. ; 49:11, s. 1387-1395
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Tidskriftsartikel (refereegranskat)abstract
- The occurrence of endogenous opioids and their receptors in rat achilles tendon was analyzed by immunohistochemistry (IHC), radioimmunoassay (RIA), and in vitro binding assays. The investigation focused on four enkephalins, dynorphin B, and nociceptin/orphanin FQ. Nerve fibers immunoreactive to all enkephalins (Met-enkephalin, Leu-enkephalin, Met-enkephalin-Arg-Gly-Lys, Met-enkephalin-Arg-Phe) were consistently found in the loose connective tissue and the paratenon, whereas dynorphin B and nociceptin/orphanin FQ could not be detected. The majority of enkephalin-positive nerve fibers exhibited varicosities predominantly seen in blood vessel walls. Measurable levels of Met-enkephalin-Arg-Phe and nociceptin/orphanin FQ were found in tendon tissue using RIA, whereas dynorphin B could not be detected. In addition to the endogenous opioids identified, delta -opioid receptors on nerve fibers were also detected by IHC. Binding assays to characterize the opioid binding sites showed that they were specific and saturable for [H-3]-naloxone (K-d 7.01 +/- 0.98 nM; B-max 23.52 +/- 2.23 fmol/mg protein). Our study demonstrates the occurrence of an opioid system in rat achilles tendon, which may be assumed to be present also in other connective tissues of the locomotor apparatus. This system may prove to be a useful target for pharmacological therapy in painful and inflammatory conditions by new drugs acting selectively in the periphery.
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| 3. |
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| 4. |
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| 5. |
- Bendre, Megha, et al.
(författare)
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Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
- 2019
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Ingår i: Alcohol. - : Elsevier BV. - 0741-8329 .- 1873-6823. ; 79, s. 7-16
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Tidskriftsartikel (refereegranskat)abstract
- Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.
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| 6. |
- Bendre, Megha, et al.
(författare)
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Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation. : Maoa,ELS and alcohol
- 2015
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.
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| 7. |
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| 8. |
- Bendre, Megha
(författare)
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Predictors of Alcohol Misuse : Role of MAOA Genotype, Methylation, Transcription, and Negative and Positive Environmental factors
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alcohol misuse is a risk factor for alcohol use disorder (AUD). Gene-environment interactions contribute to the risk or resilience for AUD. A functional polymorphism in the promoter of the monoamine oxidase A gene (MAOA-uVNTR), in interaction with negative environment (Eneg), is associated with alcohol misuse and AUD. Men carrying short (MAOA-S), and women carrying long (MAOA-L), MAOA-uVNTR alleles who experienced maltreatment or poor parent-child relationships are at increased susceptibility to alcohol misuse and AUD. This thesis assessed whether the association of MAOAxEneg with the risk of AUD is moderated by MAOA methylation or positive environment and whether MAOA methylation-associated changes in MAOA expression in the stress- and reward-related brain regions is an underlying mechanism.The thesis reveals that the association of MAOAxEneg with alcohol misuse is moderated by MAOA methylation in men, but not in women. In the clinical sample, men carrying MAOA-S allele who experienced maltreatment and had low MAOA methylation displayed higher alcohol-related problems than those without maltreatment or MAOA-L carriers with and without maltreatment. Furthermore, the quality of the parent–child relationship moderated the association of MAOAxEneg with alcohol misuse in a sex- and AUD stage-dependent manner. In the non-clinical sample of adolescents, girls carrying MAOA-L allele who experienced maltreatment and poor parent–child relationship displayed higher alcohol consumption, whereas those with average or good parent–child relationship had lower alcohol consumption. In the clinical sample of adolescents, however, no such association was observed. These results suggest that a good parent–child relationship protects MAOA susceptibility genotype carriers exposed to maltreatment during the early stages of alcohol use. The preclinical studies revealed that the male rats exposed to Eneg and alcohol had higher CpG-specific Maoa promoter methylation, which was associated with lower Maoa expression in the nucleus accumbens than the control rats. Thus, MAOA methylation-associated changes in MAOA expression in the nucleus accumbens might mediate the effect of environment on alcohol use.The thesis contributes to the understanding of biological mechanisms underlying MAOAxEnvironment effect and the critical role of MAOA methylation and positive environment in moderating risk and resilience for AUD. Also, the identification of subgroups may benefit from personalised interventions for AUD.
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| 9. |
- Bergström, Jonas, et al.
(författare)
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Purification and quantification of opioid peptides in bone and joint tissues : a methodological study in the rat
- 2003
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Ingår i: Journal of Orthopaedic Research. - 0736-0266 .- 1554-527X. ; 21:3, s. 465-469
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Tidskriftsartikel (refereegranskat)abstract
- The occurrence of methionine-enkephalin-Arg(6)-Phe(7) (MEAP) and dynorphin B (DYNB) representing two main precursors of opioids was analyzed in specimens from rat cortical bone, periosteum, bone marrow and joint tissue by radioimmunoassay (RIA). MEAP and DYNB were extracted in a solution of 4% EDTA in 2 M acetic acid previously proven suitable for extraction of sensory and autonomic neuropeptides in bone and joints. In crude extracts of cortical bone, the immunoreactive (ir) levels of both opioids were under the detection limit of RIA. As for DYNB this also applied to crude extracts of joints and periosteum. Therefore, two purification methods were tested and compared, i.e. reverse phase C 18 and ion exchange chromatography. RIA of the elution fraction disclosed a significant difference between the two methods in terms of recovery, i.e. <5% and 50%, respectively. Thus, purification by ion exchange chromatography prior to RIA appeared to be the most suitable by providing measurable levels of both MEAP and DYNB in all tissues analyzed (highest in bone marrow, lowest in cortical bone). The described method offers a means of quantifying opioid peptides in bone and joints, which may be utilized in the analysis of regulatory mechanisms of nociception, growth and immune responses in different conditions.
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| 10. |
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Beroendemedicin
- 2015. - 2
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)
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| 11. |
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Beroendemedicin
- 2011
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)
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| 12. |
- Broberger, Christian, et al.
(författare)
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Differential effects of intrastriatally infused fully and endcap phosphorothioate antisense oligonucleotides on morphology, histochemistry and prodynorphin expression in rat brain
- 2000
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Ingår i: Brain Research. Molecular Brain Research. - : Elsevier BV. - 0169-328X .- 1872-6941. ; 75:1, s. 25-45
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, we investigated the selectivity and specificity associated with continuous intrastriatal treatment with antisense oligonucleotides. Rats were given intrastriatal infusions for 72 h with phosphodiester, and fully and endcap phosphorothioated oligonucleotide probes complementary to prodynorphin mRNA. Dynorphin (Dyn) peptide levels were measured by radioimmunoassay. The integrity of three other striatal transmitter systems, the neuropeptide Y (NPY)-ergic interneurons, the cholinergic interneurons and the dopaminergic afferent innervation, was assessed histochemically. The gross morphology of the striatum and the distribution of fluorescently labelled antisense probes were also investigated. Brains infused with phosphodiester probes had tissue Dyn levels not different from control. They also showed little or no change in staining for NPY, acetylcholinesterase (AChE) and tyrosine hydroxylase (TH) and essentially normal striatal gross morphology. In contrast, brains treated with fully phosphorothioated oligonucleotides showed significant decreases in striatal Dyn levels but also severe tissue damage accompanied by massive cell infiltration and decreases in immunoreactivities for the striatal neurochemical markers. Fluorescently labelled phosphorothioate probes were observed widely in the striatum and adjacent structures and, presumably retrogradely transported, in the dopamine cell bodies in the substantia nigra, also revealing the presence of abnormal cellular structures within the striatum. By comparison, endcap probes significantly reduced striatal Dyn levels and showed good tissue penetration without inducing major changes in tissue morphology or histochemistry of non-dynorphinergic systems, except for cell infiltration. The deleterious tissue effects of fully phosphorothioated oligonucleotides and the ineffectiveness of phosphodiester oligonucleotides in inhibiting protein synthesis suggest that, of the probes examined in this study, endcap oligonucleotides are the most useful for in vivo studies in the central nervous system.
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| 13. |
- Bytner, Beta, et al.
(författare)
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Nociceptin/orphanin FQ into the rat periaqueductal gray decreases the withdrawal latency to heat and loading, an effect reversed by (Nphe1)nociceptin(1-13)NH2
- 2001
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Ingår i: Brain Research. - 0006-8993 .- 1872-6240. ; 922:1, s. 118-124
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Tidskriftsartikel (refereegranskat)abstract
- The present study investigated the effect of intraperiaqueductal grey injection of nociceptin/orphanin FQ (N/OFQ) and an antagonist (Nphe(1))nociceptin(1-13)NH(2) on the hindpaw withdrawal response to thermal and mechanical stimulation in rats. N/OFQ (5 nmol) significantly decreased the nociceptive thresholds in both tests and 1, 5 and 10 nmol of (Nphe(1))nociceptin(1-13)NH(2) significantly reversed this effect in a dose dependent way. Our results demonstrate, that N/OFQ has a nociceptive action, possibly through inhibition of PAG neurons. This effect is blocked by the antagonist (Nphe(1))nociceptin(1-13)NH(2) probably via ORL1 receptors in the periaqueductal grey.
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| 14. |
- Cappendijk, Susanne L T, et al.
(författare)
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A heroin-, but not a cocaine expecting, self-administration state preferentially alters brain endogenous peptides
- 1999
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Ingår i: European Journal of Pharmacology. - 0014-2999 .- 1879-0712. ; 365:2-3, s. 175-182
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of the current study was to assess neuropeptidergic alterations during a phase of the drug addiction cycle associated with drug craving as compared to a time period when the drug had been recently self-administered. Male Wistar rats were allowed to self-administer cocaine, heroin or saline for 6 h for 5 consecutive days. Immediately following the last self-administration session ('acute drug on board' state), and just before the next scheduled session ('drug expecting' state), the animals were decapitated and the levels of dynorphin A and B, [Met5]- and [Leu5]-enkephalin and substance P were measured in different brain areas. During the 'acute drug on board' state, peptide levels in animals that self-administered heroin or cocaine were not significantly changed. In contrast, during the 'drug expecting' state, heroin-treated animals had increased levels of dynorphin A, dynorphin B and [Met5]-enkephalin in the caudal striatum as compared to the cocaine- and saline-treated animals, and the level of [Leu5]-enkephalin was increased as compared to the cocaine-treated group. In the septum, an increase of [Met5]-enkephalin and substance P was observed in the animals expecting heroin as compared to the saline- and/or cocaine-treated animals. In the caudal striatum, substance P levels were elevated in the heroin- and cocaine-expecting animals. In conclusion, heroin, as compared to cocaine, appears to have a more pronounced effect on dynorphin, enkephalin and substance P levels in the caudal striatum and septum, especially during periods when self-administration of the drug is expected.
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| 15. |
- Comasco, Erika, et al.
(författare)
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Alpha 2a-Adrenoceptor Gene Expression and Early Life Stress-Mediated Propensity to Alcohol Drinking in Outbred Rats
- 2015
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Ingår i: International Journal of Environmental Research and Public Health. - : MDPI AG. - 1661-7827 .- 1660-4601. ; 12:7, s. 7154-7171
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Tidskriftsartikel (refereegranskat)abstract
- Stressful events early in life, later high alcohol consumption and vulnerability to alcohol use disorder (AUD) are tightly linked. Norepinephrine is highly involved in the stress response and the alpha 2A-adrenoceptor, which is an important regulator of norepinephrine signalling, is a putative target in pharmacotherapy of AUD. The aim of the present study was to investigate the effects of early-life stress and adult voluntary alcohol drinking on the alpha 2A-adrenoceptor. The relative expression and promoter DNA methylation of the Adra2a gene were measured in the hypothalamus, a key brain region in stress regulation. A well-characterized animal model of early-life stress was used in combination with an episodic voluntary drinking in adulthood. Alcohol drinking rats with a history of early-life stress had lower Adra2a expression than drinking rats not exposed to stress. Alcohol intake and Adra2a gene expression were negatively correlated in high-drinking animals, which were predominantly rats subjected to early-life stress. The results provide support for a link between early-life stress, susceptibility for high alcohol consumption, and low Adra2a expression in the hypothalamus. These findings can increase our understanding of the neurobiological basis for vulnerability to initiate risk alcohol consumption and individual differences in the response to 2A-adrenoceptor agonists.
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| 16. |
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| 17. |
- Comasco, Erika, 1982-, et al.
(författare)
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Constitutive serotonin transporter reduction resembles maternal separation with regard to stress-related gene expression
- 2019
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 10:7, s. 3132-3142
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Tidskriftsartikel (refereegranskat)abstract
- Interactive effects between allelic variants of the serotonin transporter (5-HTT) promoter-linked polymorphic region (5-HTTLPR) and stressors on depression symptoms have been documented, as well as questioned, by meta-analyses. Translational models of constitutive 5-htt reduction and experimentally controlled stressors often led to inconsistent behavioral and molecular findings and often did not include females. The present study sought to investigate the effect of 5-htt genotype, maternal separation, and sex on the expression of stress-related candidate genes in the rat hippocampus and frontal cortex. The mRNA expression levels of Avp, Pomc, Crh, Crhbp, Crhr1, Bdnf, Ntrk2, Maoa, Maob, and Comt were assessed in the hippocampus and frontal cortex of 5-htt± and 5-htt+/+ male and female adult rats exposed, or not, to daily maternal separation for 180 min during the first 2 postnatal weeks. Gene- and brain region-dependent, but sex-independent, interactions between 5-htt genotype and maternal separation were found. Gene expression levels were higher in 5-htt+/+ rats not exposed to maternal separation compared with the other experimental groups. Maternal separation and 5-htt+/− genotype did not yield additive effects on gene expression. Correlative relationships, mainly positive, were observed within, but not across, brain regions in all groups except in non-maternally separated 5-htt+/+ rats. Gene expression patterns in the hippocampus and frontal cortex of rats exposed to maternal separation resembled the ones observed in rats with reduced 5-htt expression regardless of sex. These results suggest that floor effects of 5-htt reduction and maternal separation might explain inconsistent findings in humans and rodents.
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| 18. |
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| 19. |
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| 20. |
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| 21. |
- Daoura, Loudin
(författare)
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Early Environment and Adolescent Ethanol Consumption : Effects on Endogenous Opioids and Behaviour in Rats
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Excessive and compulsive ethanol drinking is one of the most serious public health issues. Therefore, it is vital to increase the knowledge about risks and protection for alcohol use disorders (AUD) to optimize prevention and treatment strategies. Ethanol consumption commonly initiates during adolescence when extensive neuronal maturation and development also occurs. Early exposure to ethanol is a risk factor for AUD, but the effects of adolescent drinking and the basis for the individual susceptibility to AUD are not fully understood. The interactions between genotype and environmental factors determine the individual risk for AUD and this thesis aimed to examine the environmental impact. The specific aims were to investigate 1) how early-life conditions affect adolescent voluntary ethanol drinking, behavioural profiles, endogenous opioids and response to treatment with an opioid antagonist (naltrexone), and 2) whether alterations detected in the offspring may be mediated by variations in maternal behaviour. A rodent maternal separation (MS) model was used to mimic a protective and risk-inducing early-life environment, respectively, with the use of 15 min (MS15) or 360 min (MS360) of daily MS. The main findings were 1) the MS360, but not the MS15 rats, responded to naltrexone following adolescent ethanol drinking; all adolescent rats had a high voluntary ethanol intake independent of early environmental conditions whereas in the adult groups the MS360, but not the MS15 rats, increased their ethanol intake and preference over time; adolescent ethanol exposure resulted in higher dynorphin levels in hippocampus and higher Met-enkephalin-Arg6Phe7 in the amygdala, independently of rearing conditions, 2) behavioural profiling using the multivariate concentric square field™ test showed: the young MS360 rats had increased risk assessment and risk taking behaviour compared to the young MS15 rats; the young MS15 rats increased, whereas the young MS360 rats decreased, their risk assessment and risk taking behaviour over time; differences in pup-retrieval strategies where the MS360 dams retrieved some pups into a safe area but as compared to MS15 rats they left more pups in a risk area; increased risk assessment behaviour in the MS360 dams immediately after weaning. Taken together, early-life environmental conditions alter adult but not adolescent drinking, the response to naltrexone, and behaviour in dams and offspring. Adolescent rats consumed more ethanol independent of rearing conditions and displayed increased opioid levels in brain areas related to cognition and addiction.
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| 22. |
- Daoura, Loudin, et al.
(författare)
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Early Environmental Factors Differentially Affect Voluntary Ethanol Consumption in Adolescent and Adult Male Rats
- 2011
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Ingår i: Alcoholism. - : Wiley. - 0145-6008 .- 1530-0277. ; 35:3, s. 506-515
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies using the maternal separation (MS) model have shown that environmental factors early in life affect adult ethanol consumption. Prolonged MS is related to enhanced propensity for high adult ethanol intake when compared to short MS. Less is known about the environmental impact on adolescent ethanol intake. In this study, the aim was to compare establishment of voluntary ethanol consumption in adolescent and adult rats subjected to different rearing conditions. Methods: Wistar rat pups were separated from their mother 0 minutes (MS0), 15 minutes (MS15), or 360 minutes (MS360) daily during postnatal days (PNDs) 1 to 20. After weaning, the male rats were divided into two groups; rats were given free access to water, 5 and 20% ethanol at either PND 26 or 68. Ethanol was provided in 24-hour sessions three times per week for 5 weeks. Results: MS resulted in altered ethanol consumption patterns around the pubertal period but otherwise the rearing conditions had little impact on ethanol consumption in adolescents. In adults, the establishment of ethanol consumption was dependent on the rearing condition. The adult MS0 and MS15 rats had a stable ethanol intake, whereas the MS360 rats increased both their ethanol intake and preference over time. Conclusions: With the use of intermittent access to ethanol, new data were provided, which confirm the notion that MS360 represents a risk environment related to higher ethanol intake compared to MS15. The adolescent rats had higher ethanol intake than adult rats but the consumption was independent of rearing condition. Experiences during the first three postnatal weeks thus affect the establishment of voluntary ethanol consumption differently in adolescent and adult rats. Further studies are now warranted to examine the consequences of a combination of early environmental influence and high adolescent ethanol intake.
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| 23. |
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| 24. |
- Daoura, Loudin, et al.
(författare)
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Postpartum Behavioral Profiles in Wistar Rats Following Maternal Separation : Altered Exploration and Risk-Assessment Behavior in MS15 Dams
- 2010
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Ingår i: Frontiers in Behavioral Neuroscience. - : Frontiers Media SA. - 1662-5153. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- The rodent maternal separation (MS) model is frequently used to investigate the impact of early environmental factors on adult neurobiology and behavior. The majority of MS studies assess effects in the offspring and few address the consequences of repeated pup removal in the dam. Such studies are of interest since alterations detected in offspring subjected to MS may, at least in part, be mediated by variations in maternal behavior and the amount of maternal care provided by the dam. The aim of this study was to investigate how daily short (15 min; MS15) and prolonged (360 min; MS360) periods of MS affects the dam by examining postpartum behavioral profiles using the multivariate concentric square field (MCSF) test. The dams were tested on postpartum days 24-25, i.e., just after the end of the separation period and weaning. The results reveal a lower exploratory drive and lower risk-assessment behavior in MS15 dams relative to MS360 or animal facility reared dams. The present results contrast some of the previously reported findings and provide new information about early post-weaning behavioral characteristics in a multivariate setting. Plausible explanations for the results are provided including a discussion how the present results fit into the maternal mediation hypothesis.
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| 25. |
- Daoura, Loudin, et al.
(författare)
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Qualitative differences in pup-retrieval strategies in a maternal separation paradigm
- 2013
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Ingår i: Journal of Behavioral and Brain Science. - : Scientific Research Publishing, Inc.. - 2160-5866 .- 2160-5874. ; 3, s. 603-616
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Tidskriftsartikel (refereegranskat)abstract
- The rodent maternal separation (MS) paradigm is frequently used to investigate the impact of early-life conditions in the offspring. One critical issue is whether the effects seen in the offspring are a result of maternal contact deprivation and/or altered pup-directed maternal behavior. To address this question we used an innovative approach with a qualita-tive analysis of pup-retrieval strategies in a test situation related to risk for the pups. The dams were separated from their litters for 0 (MS0) or 360 (MS360) min, respectively. The pups were placed in a risk area in the multivariate con-centric square field™ test at two test occasions and the pup-retrieval strategies were recorded. No significant evident differences between MS0 and MS360 dams were found. However, there were clearly two different strategies, either removing the pups out of potential danger or into safety, and these strategies were represented in both MS groups. As compared to the MS0 dams, the MS360 dams did not change their strategies and left more pups in the risk area in both pup-retrieval tests. This implies different pup-retrieval strategies depending on early-life conditions.
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| 26. |
- Daoura, Loudin, et al.
(författare)
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The response to naltrexone in ethanol-drinking rats depends on early environmental experiences
- 2011
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Ingår i: Pharmacology, Biochemistry and Behavior. - : Elsevier BV. - 0091-3057 .- 1873-5177. ; 99:4, s. 626-633
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Tidskriftsartikel (refereegranskat)abstract
- The opioid receptor antagonist naltrexone is currently used in the treatment of alcohol addiction. However, substantial individual differences have been reported for the efficacy of naltrexone. Genetic factors are known to contribute to these differences; however, little is known about the impact of early environmental influences. Based on previous findings that have suggested a link between ethanol, endogenous opioids and the early environment, it was hypothesised that early environmental factors affect naltrexone efficacy later in life. A population of Wistar rats was subjected to three different rearing conditions where the pups experienced a daily separation from the dam, for either 15 min or 360 min, or were just briefly handled. On postnatal day 26, the rats were given intermittent access to ethanol (5% and 20%) and water for six weeks before naltrexone (0.3mg/kg or 3.0mg/kg) or saline treatment using a randomised injection schedule with a one-week washout period between injections. Naltrexone reduced ethanol consumption, but there was high variability in the efficacy. In addition, there was an association between the rearing condition and the effectiveness of naltrexone. Naltrexone reduced ethanol intake in rats experiencing postnatal conditions that contrasted normal wildlife conditions, i.e., prolonged absence or continuous presence of the dam, and naltrexone had no effect on the total ethanol consumption in rats reared under naturalistic conditions, i.e., short absences of the dam. These rats reduced their intake of 5% ethanol but increased their preference for 20% ethanol. We conclude that rats with a history of early adversity responded well to naltrexone treatment, whereas rats reared in a social context similar to that found in nature did not benefit from treatment. The present study highlights the importance of not only considering genetics but also environmental factors when identifying individual responses to naltrexone.
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| 27. |
- 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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| 28. |
- Engel, Jörgen, 1942, et al.
(författare)
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A ghrelin receptor (GHS-R1A) antagonist attenuates the rewarding properties of morphine and increases opioid peptide levels in reward areas in mice
- 2015
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Ingår i: European Neuropsychopharmacology. - : Elsevier BV. - 0924-977X .- 1873-7862. ; 25:12, s. 2364-2371
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Tidskriftsartikel (refereegranskat)abstract
- Gut-brain hormones such as ghrelin have recently been suggested to have a role in reward regulation. Ghrelin was traditionally known to regulate food intake and body weight homoeostasis. In addition, recent work has pin-pointed that this peptide has a novel role in drug-induced reward, including morphine-induced increase in the extracellular levels of accumbal dopamine in rats. Herein the effect of the ghrelin receptor (GHS-R1A) antagonist, JMV2959, on morphine-induced activation of the mesolimbic dopamine system was investigated in mice. In addition, the effects of JMV2959 administration on opioid peptide levels in reward related areas were investigated. In the present series of experiment we showed that peripheral JMV2959 administration, at a dose with no effect per se, attenuates the ability of morphine to cause locomotor stimulation, increase the extracellular levels of accumbal dopamine and to condition a place preference in mice. JMV2959 administration significantly increased tissue levels of Metenkephalin-Arg(6)Phe(7) in the ventral tegmental area, dynorphin B in hippocampus and Leuenkephalin-Arg(6) in striatum. We therefore hypothesise that JMV2959 prevents morphine-induced reward via stimulation of delta receptor active peptides in striatum and ventral tegmental areas. In addition, hippocampal peptides that activate kappa receptor may be involved in JMV2959's ability to regulate memory formation of reward. Given that development of drug addiction depends, at least in part, of the effects of addictive drugs on the mesolimbic dopamine system the present data suggest that GIS-R1A antagonists deserve to be elucidated as novel treatment strategies of opioid addiction.
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| 29. |
- Franck, Johan, et al.
(författare)
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Met-enkephalin inhibits 5-hydroxytryptamine release from the rat ventral spinal cord via delta opioid receptors
- 1996
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 35:6, s. 743-749
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of opioid receptor agonists and antagonists on the electrically evoked release of endogenous serotonin (5-hydroxytryptamine, 5-HT) was studied in superfused slices of the rat ventral lumbar spinal cord. Met-ENK (1 x 10(-8)M-1 x 10(-6)M) and DPDPE (1 x 10(-8)M-1 x 10(-6)M) reduced the evoked 5-Ht release in a concentration dependent fashion. DAMGO (1 x 10(-8)-1 x 10(-6)) and (-)-trans-(1S,2S)-U-50488 (1 x 10(-6)M) had no effect on the 5-HT release. The inhibitory effect of met-ENK was completely abolished by ICI-174,864, but neither by naloxonazine nor nor-binaltorphimine. Following i.c.v. treatment with 5,7-dihydroxytryptamine (5,7-DHT), the tissue concentration of 5-HT was reduced by 97%, whereas the concentration of noradrenaline was reduced by only 5%. The tissue concentration of met-ENK, as measured by radioimmunoassay, was not significantly altered. The results suggest that met-ENK is present in the rat ventral spinal cord mainly in non-serotonergic nerve terminals and exerts an inhibitory action on 5-HT release via delta opioid receptors.
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| 30. |
- Granholm, Linnea, et al.
(författare)
-
Episodic Ethanol Exposure in Adolescent Rats Causes Residual Alterations in Endogenous Opioid Peptides
- 2018
-
Ingår i: Frontiers in Psychiatry. - : FRONTIERS MEDIA SA. - 1664-0640. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Adolescent binge drinking is associated with an increased risk of substance use disorder, but how ethanol affects the central levels of endogenous opioid peptides is still not thoroughly investigated. The aim of this study was to examine the effect of repeated episodic ethanol exposure during adolescence on the tissue levels of three different endogenous opioid peptides in rats. OutbredWistar rats received orogastric (i.e., gavage) ethanol for three consecutive days per week between 4 and 9 weeks of age. At 2 h and 3 weeks, respectively, after the last exposure, beta-endorphin, dynorphin B and Met-enkephalin-Arg(6)Phe(7) (MEAP) were analyzed with radioimmunoassay. Beta-endorphin levels were low in the nucleus accumbens during ethanol intoxication. Remaining effects of adolescent ethanol exposure were found especially for MEAP, with low levels in the amygdala, and high in the substantia nigra and ventral tegmental area three weeks after the last exposure. In the hypothalamus and pituitary, the effects of ethanol on beta-endorphin were dependent on time from the last exposure. An interaction effect was also found in the accumbal levels of MEAP and nigral dynorphin B. These results demonstrate that repeated episodic exposure to ethanol during adolescence affected opioid peptide levels in regions involved in reward and reinforcement as well as stress response. These alterations in opioid networks after adolescent ethanol exposure could explain, in part, the increased risk for high ethanol consumption later in life.
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| 31. |
- Granholm, Linnea, et al.
(författare)
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Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats
- 2015
-
Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 232:24, s. 4421-4431
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Tidskriftsartikel (refereegranskat)abstract
- Adolescent binge drinking is common and associated with increased risk of substance use disorders. Transition from recreational to habitual ethanol consumption involves alterations in dorsal striatal function, but the long-term impact of adolescent ethanol exposure upon this region remains unclear. This study aimed to characterise and describe relationships between adolescent ethanol exposure, amphetamine self-administration and adult dopamine dynamics in dorsal striatum, including response to amphetamine challenge, in male Wistar rats. Ethanol (2 g/kg) or water was administered intragastrically in an episodic binge-like regimen (three continuous days/week) between 4 and 9 weeks of age (i.e. post-natal days 28-59). In adulthood, animals were divided into two groups. In the first, dorsal striatal potassium-evoked dopamine release was examined via chronoamperometry, in the basal state and after a single amphetamine challenge (2 mg/kg, i.v.). In the second, amphetamine self-administration behaviour was studied (i.e. fixed and progressive ratio) before chronoamperometric analysis was conducted as described above. Adolescent ethanol exposure suppressed locally evoked dopamine response after amphetamine challenge in adulthood, whereas in the basal state, no differences in dopamine dynamics were detected. Ethanol-exposed animals showed no differences in adult amphetamine self-administration behaviour but an abolished effect on dopamine removal in response to a single amphetamine challenge after self-administration. Amphetamine challenges in adult rats revealed differences in in vivo dopamine function after adolescent ethanol exposure. The attenuated drug response in ethanol-exposed animals may affect habit formation and contribute to increased risk for substance use disorders as a consequence of adolescent ethanol.
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| 32. |
- Granholm, Linnea
(författare)
-
Neurobiological Consequences of Social Conditions and Alcohol Exposure in Adolescent rats
- 2015
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adolescence represents a time of extensive reorganisation and maturation of brain circuits involved in emotions, motivation and cognition and it is a period particular sensitive for external stimuli. External stimuli can be both socio-environmental factors and exposure to exogenous compounds such as drugs of abuse (e.g. alcohol). If these stimuli are of an adverse nature the probability of develop neuropsychiatric diseases or addiction is increased. To study the neurobiological consequences of adverse events during adolescence animal models are crucial since they give the opportunity of providing an environment where the exposure of the stimuli is controlled and also enable a detailed analysis of the effects in the brain. The overall aim of in this thesis was to investigate how environmental factors, social conditions or alcohol exposure, during adolescence affect the brain and/or drug-taking in rats. Rats are very sensitive for dis- turbances in their social conditions and to induce an adverse social environment, early adolescent rats where single-housed for either a short or prolonged time. A short period of single housing induced an acute stress response and increased levels of nociceptin/orphanin FQ in brain areas associated with stress. Prolonged single housing reduced the levels of Met-enkephalin-Arg6Phe7 in several brain areas. Rats exposed to alcohol during adolescence had an altered dopamine response in dorsal striatum after an am- phetamine challenge but displayed similar amphetamine intake-behaviour as water controls. However, animals exposed to a combination of adolescent alcohol exposure and subsequent amphetamine intake had a more efficient removal of dopamine in dorsal striatum after an amphetamine challenge. This thesis demonstrates how two different environmental stimuli are able to alter the neurobiology in adolescent rats. The results further support the notion that environmental conditions are of importance for normal brain maturation and provide new evidence that endogenous opioids are severely affected by social dis- turbances during adolescence. Furthermore, additional information is provided to the existing literature of how alcohol exposure during adolescence affects dopamine dynamics and drug-taking behaviour. In the literature, the majority of the studies of adolescent alcohol exposure have focused on the nucleus accum- bens, a brain area important in the processing of rewards. The results herein provide evidence that dorsal striatum, a brain area involved in the transition into habitual drug use is also affected by adolescent alco- hol exposure. An altered drug response in dorsal striatum may affect habit formation and contribute to a heightened susceptibility for high drug consumption later in life.
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| 33. |
- Granholm, Linnea, et al.
(författare)
-
Single housing during early adolescence causes time-, area- and peptide-specific alterations in endogenous opioids of rat brain
- 2015
-
Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 172:2, s. 606-614
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: A number of experimental procedures require single housing to assess individual behaviour and physiological responses to pharmacological treatments. The endogenous opioids are closely linked to social interaction, especially early in life, and disturbance in the social environment may affect opioid peptides and thereby confound experimental outcome. The aim of the present study was to examine time-dependent effects of single housing on opioid peptides in rats.EXPERIMENTAL APPROACH: Early adolescent Sprague Dawley rats (post-natal day 22) were subjected to either prolonged (7 days) or short (30 min) single housing. Several brain regions were dissected and immunoreactive levels of Met-enkephalin-Arg(6) Phe(7) (MEAP), dynorphin B and nociception/orphanin FQ, as well as serum corticosterone were measured using RIA.KEY RESULTS: Prolonged single housing reduced immunoreactive MEAP in hypothalamus, cortical regions, amygdala, substantia nigra and periaqueductal grey. Short single housing resulted in an acute stress response as indicated by high levels of corticosterone, accompanied by elevated immunoreactive nociceptin/orphanin FQ in medial prefrontal cortex, nucleus accumbens and amygdala. Neither short nor prolonged single housing affected dynorphin B.CONCLUSIONS AND IMPLICATIONS: Disruption in social environmental conditions of rats, through single housing during early adolescence, resulted in time-, area- and peptide-specific alterations in endogenous opioids in the brain. These results provide further evidence for an association between early life social environment and opioids. Furthermore, the results have implications for experimental design; in any pharmacological study involving opioid peptides, it is important to distinguish between effects induced by housing and treatment.
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| 34. |
- Granholm, Linnea, 1986-
(författare)
-
Stress, Drugs and Neuroscience : Neurobiological Effects of Social Stressors and Drug Exposure in Young and Adolescent Rats
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Experiences early in life or during adolescence modulate neuronal networks in the immature brain and consequently lay the foundation for future susceptibility or resilience towards psychiatric disorders. The objective in this thesis is to understand, in part, how the surrounding environment shapes the brain of a young individual. Three types of negative life events were studied, in an animal model, for their effects on the brain reward system (i.e., endogenous opioids and dopamine) and voluntary drug intake. These were: disruption of maternal care, disruption of interaction with peers, and exposure to drugs. Stress, in the form of maternal separation, altered expression of opioid genes in the dorsal striatum and amygdala, and the response to subsequent alcohol intake on these genes was dependent on early life conditions. Basal levels of endogenous opioids were also dependent on how the animals were housed in early adolescence. Short single housing (30 minutes) caused an acute stress response as evidenced by increased serum corticosterone and nociceptin/orphanin FQ in brain areas associated with stress. A prolonged single housing resulted in a marked decrease of Met-Enk-Arg6-Phe7 (i.e., a marker of enkephalins) in several brain areas. The endogenous opioids were also affected by repeated exposure of ethanol during adolescence; ethanol intoxication increased the accumbal levels of Met-Enk-Arg6-Phe7 and decreased those of β-endorphin. Residual effects of the adolescent ethanol exposure were found in Met-Enk-Arg6-Phe7 levels in the amygdala, ventral tegmental area, and substantia nigra. Furthermore, rats exposed to ethanol as adolescents had alterations in the dopamine dynamics in the dorsal striatum. Both endogenous opioids and dopamine are essential in mediating rewarding properties. Alterations of these systems, caused by environmental disturbances and alcohol exposure, presented herein could explain, in part, the increased susceptibility for alcohol- and substance use disorders later in life.
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| 35. |
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| 36. |
- Granholm, Linnea, et al.
(författare)
-
The expression of opioid genes in non-classical reward areas depends on early life conditions and ethanol intake
- 2017
-
Ingår i: Brain Research. - : Elsevier BV. - 0006-8993 .- 1872-6240. ; 1668, s. 36-45
-
Tidskriftsartikel (refereegranskat)abstract
- The young brain is highly sensitive to environmental influences that can cause long-term changes in neuronal function, possibly through altered gene expression. The endogenous opioid system continues to mature after birth and because of its involvement in reward, an inadequate maturation of this system could lead to enhanced susceptibility for alcohol use disorder. Recent studies show that the classical reward areas nucleus accumbens and ventral tegmental area are less affected by early life stress whereas endogenous opioids in non-classical areas, e.g. dorsal striatum and amygdala, are highly responsive. The aim was to investigate the interaction between early life conditions and adult voluntary ethanol intake on opioid gene expression. Male Wistar rats were exposed to conventional rearing, 15, or 360min of daily maternal separation (MS) postnatal day 1-21, and randomly assigned to ethanol or water drinking postnatal week 10-16. Rats exposed to early life stress (MS360) had increased opioid receptor gene (Oprm1, Oprd1 and Oprk1) expression in the dorsal striatum. Ethanol drinking was associated with lower striatal Oprd1 and Oprk1 expression solely in rats exposed to early life stress. Furthermore, rats exposed to early life stress had high inherent Pomc expression in the amygdala but low expression after ethanol intake. Thus, adverse events early in life induced changes in opioid gene expression and also influenced the central molecular response to ethanol intake. These long-term consequences of early life stress can contribute to the enhanced risk for excessive ethanol intake and alcohol use disorder seen after exposure to childhood adversity.
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| 37. |
- Grönbladh, Leif, et al.
(författare)
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Heroinberoende
- 2015. - 2
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Ingår i: Beroendemedicin. - 9789144099859 ; , s. 211-223
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 38. |
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| 39. |
- Gustafsson, Lisa, 1975-
(författare)
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Endogenous Opioids and Voluntary Ethanol Drinking : Consequences of Postnatal Environmental Influences in Rats
- 2007
-
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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| 40. |
- 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
-
Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 146:3, s. 1137-1149
-
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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| 41. |
- 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
-
Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 42:2, s. 177-191
-
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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| 42. |
- 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
-
Ingår i: Alcoholism. - : Wiley. - 0145-6008 .- 1530-0277. ; 30:12, s. 2008-2016
-
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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| 43. |
- 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
-
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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| 44. |
- Herrera-Marschitz, M, et al.
(författare)
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On the origin of extracellular glutamate levels monitored in the basal ganglia of the rat by in vivo microdialysis
- 1996
-
Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042 .- 1471-4159. ; 66:4, s. 1726-1735
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Tidskriftsartikel (refereegranskat)abstract
- Several putative neurotransmitters and metabolites were monitored simultaneously in the extracellular space of neostriatum, substantia nigra, and cortex and in subcutaneous tissue of the rat by in vivo microdialysis. Glutamate (Glu) and aspartate (Asp) were at submicromolar and gamma-aminobutyric acid (GABA) was at nanomolar concentrations in all brain regions. The highest concentration of dopamine (DA) was in the neostriatum. Dynorphin B (Dyn B) was in the picomolar range in all brain regions. Although no GABA, DA, or Dyn B could be detected in subcutaneous tissue, Glu and Asp levels were 5 and approximately 5 and approximately 0.4 microM, respectively. Lactate and pyruvate concentrations were approximately 200 and approximately 10 microM in all regions. The following criteria were applied to ascertain the neuronal origin of substances quantified by microdialysis: sensitivity to (a) K+ depolarization, (b) Na+ channel blockade, (c) removal of extracellular Ca2+, and (d) depletion of presynaptic vesicles by local administration of alpha-latrotoxin. DA, Dyn B, and GABA largely satisfied all these criteria. In contrast, Glu and Asp levels were not greatly affected by K+ depolarization and were increased by perfusing with tetrodotoxin or with Ca2+-free medium, arguing against a neuronal origin. However, Glu and Asp, as well as DA and GABA, levels were decreased under both basal and K+-depolarizing conditions by alpha-latrotoxin. Because the effect of K+ depolarization on Glu and Asp could be masked by reuptake into nerve terminals and glial cells, the reuptake blocker dihydrokainic acid (DHKA) or L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) was included in the microdialysis perfusion medium. The effect of K+ depolarization on Glu and Asp levels was increased by DHKA, but GABA levels were also affected. In contrast, PDC increased only Glu levels. It is concluded that there is pool of releasable Glu and Asp in the rat brain. However, extracellular levels of amino acids monitored by in vivo microdialysis reflect the balance between neuronal release and reuptake into surrounding nerve terminals and glial elements.
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| 45. |
- Immenschuh, Jana, et al.
(författare)
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Long-term effects of early life stress on Cyp19a1 mRNA expression and DNA methylation levels in male rats
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Early life stress (ELS) raises the risk of developing mental disorders later in life by inducing lasting epigenetic changes that can impact gene expression. Aromatase, the enzyme responsible for the synthesis of estrogen, is highly expressed in the limbic brain, a key circuit in mental wellbeing. Its neuroprotective role has been investigated in relation to brain trauma but not emotional stress. The present study aimed to investigate the effect of ELS on the expression of the aromatase gene (Cyp19a1), and whether a relation can be observed with the methylation of the gene, in the limbic brain of young adult male rats. ELS was modelled by daily maternal separation for 360 minutes (MS360) in the first three postnatal weeks and compared to a control group (MS15). Cyp19a1 mRNA levels in the cingulate cortex (CCX), medial prefrontal cortex (mPFC), hypothalamus, hippocampus, and amygdala, were quantified by real-time qPCR. Additionally, CpG methylation levels in the Cyp19a1 gene were assessed via targeted next generation bisulfite sequencing. Lower levels of Cyp19a1 were found in the mPFC in MS360 rats compared to MS15, while the opposite trend was observed in the amygdala. Additionally, higher methylation levels were observed in CpGs of intron 2 in the mPFC of MS360 compared with MS15 rats. The methylation levels of intron 2 were negatively correlated with gene expression in the mPFC of MS15 rats, while the correlation was positive for MS360 rats. These findings suggest that ELS might exert a region-specific, long-term effect on both gene expression and methylation of Cyp19a1, especially in the mPFC, a key regions in stress response regulation.
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| 46. |
- Lager, Susanne, et al.
(författare)
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Alcohol consumption habits and associations with anxiety or depressive symptoms postpartum in women with high socioeconomic status in Sweden.
- 2022
-
Ingår i: Archives of Women's Mental Health. - : Springer Nature. - 1434-1816 .- 1435-1102.
-
Tidskriftsartikel (refereegranskat)abstract
- Postpar tum depression and anxiety are common among new mothers. It is well-established that in the general population alcohol use is associated with depression and anxiety. Linking alcohol consumption to symptoms of postpartum depression (PPDS) or postpartum anxiety (PPAS) is presently less established. This study aims to determine if alcohol consumption pre-pregnancy, 6 weeks postpartum, 6 months postpartum, or changes in alcohol consumption are associated with PPDS or PPAS. Longitudinal data on 3849 women from a Swedish perinatal cohort were analyzed using logistic regression analyses for associations between alcohol consumption and symptoms of anxiety or depression, as assessed with the Edinburgh Postnatal Depression Scale. There was no association between pre-pregnancy drinking habits and PPDS (p = 0.588, n = 2479) or PPAS (p = 0.942; n = 2449) at 6 weeks postpartum. Similarly, no associations were observed between concurrent drinking habits at 6 weeks postpartum and PPAS (p = 0.070, n = 3626), 6 months postpartum and PPDS (0.647, n = 3461) or PPAS (p = 0.700, n = 3431). However, there was an association between drinking habits at 6 weeks postpartum and concurrent PPDS (p = 0.047, n = 3659). In conclusion, robust associations were not found between postpartum alcohol consumption and mood symptoms. This lack of association between poor mental health and risk behaviors in new mothers could be interpreted as a result of long-term policy work and high participation in Swedish maternity care. Future studies need to address these research questions in more diverse socio-cultural contexts.
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| 47. |
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| 48. |
- Landgren, Ellen, et al.
(författare)
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“Mastering a New Life Situation” – Patients’ Preferences of Treatment Outcomes in Early Rheumatoid Arthritis – A Longitudinal Qualitative Study
- 2020
-
Ingår i: Patient Preference and Adherence. - : Dove Medical Press Ltd.. - 1177-889X. ; 14, s. 1421-1433
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To explore patients’ preferred treatment outcomes during their first two years with rheumatoid arthritis (RA). Patients and Methods: A qualitative, longitudinal, multicenter study with interviews at two time points was performed in Sweden. Individual interviews were conducted at time point 1 with 31 patients with RA, defined as disease duration of ≤1 year and treatment for 3–7 months. Seven focus group interviews and five individual interviews were conducted at time point 2 with 22 patients 12–20 months after treatment initiation. The interviews were analyzed using the Qualitative Analysis Guide of Leuven. A core category with four related concepts emerged. Results: The core finding of patient-preferred treatment outcomes was “mastering a new life situation”. Patients preferred to experience control of the disease by controlling the symptoms and by experiencing absence of disease. To experience autonomy by regaining former activity level, experiencing independence, and being empowered was another preferred outcome. Patients preferred to regain identity through being able to participate, experience well-being, and regain former self-image. To experience joy in everyday life through vitality and believing in the future was another preferred outcome. Patients’ preferences developed over time from the acute phase of controlling the symptoms and wanting to return to the life they lived prior to diagnosis, to a more preventive way of self-management and empower-ment to master the new life situation. Conclusion: The patients’ preferred treatment outcomes during the first two years with RA were to master their new life situation and changed from a preference to return to a life lived prior disease onset, to a preference of living with quality of life, despite RA. This study increases the understanding of patients’ preferred treatment outcomes in the early disease course and can be a foundation for tailoring interventions to be more person-centered and to improve long-term treatment outcomes. © 2020 Landgren et al.
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| 49. |
- Landgren, E., et al.
(författare)
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Patients' Perceptions of Person-Centred Care in Early RA : A Qualitative Study
- 2021
-
Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80:Suppl. 1, s. 1024-1024
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Tidskriftsartikel (refereegranskat)abstract
- Data on patients’ experience can identify strengths and weaknesses with given care, why a person-centred care will improve health care quality. In rheumatology care, most research on patient preferences for and experiences of RA care is performed in patients with established RA and less often in patients with early RA. In the early course of RA patients often struggle to manage their new life situation with a chronic disease and its treatment. Expectations and experiences of health care may change over time why it is important to understand how newly diagnosed patients perceive person-centred care.Objectives:To explore patients’ perceptions of person-centred care early in the RA disease course within the framework of person-centred care.Methods:In this qualitative study 31 patients with early RA from four rheumatology specialist outpatient clinics were interviewed. An abductive qualitative content analysis was conducted based on the framework of McCormack and McCance (2006, 2016). The four constructs; prerequisites, care environment, person-centred processes, and person-centred outcomes constituted the four categories in the deductive part of the study. An inductive analysis revealed eleven sub-categories exploring the content of person-centred care for patients with early RA.Results:For patients with early RA person-centred care was described as; 1. Prerequisites were to be treated with respect, to meet dedicated healthcare professionals, and to meet professional competence. 2. The care environment was to have access to a multidisciplinary team, to have access to health care, and a supportive organization. 3. Person-centred processes were to be listened to, to be supported, and to be involved in decision-making. 4. The person-centred outcomes were to be satisfied with received health care and to achieve optimal health.Conclusion:A true person-centred care is important to patients early in the RA disease course, supporting the relevance to implement person-centred approach at all stages in the health care system. This study contributes to information about how to further develop person-centredness in rheumatology care also early in the disease course.References:[1]McCormack, B., & McCance, T. V. (2006). Development of a framework for person-centred nursing. J Adv Nurs, 56(5), 472-479. doi:10.1111/j.1365-2648.2006.04042.x[2]McCormack, B., & McCance, T. V. (2016). Person-centred practice in nursing and health care: theory and practice (2nd edition ed.): John Wiley & Sons.Disclosure of Interests:None declared
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- Landgren, Ellen, et al.
(författare)
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Patients’ Perceptions of Person‐Centered Care in Early Rheumatoid Arthritis : A Qualitative Study
- 2021
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Ingår i: ACR Open Rheumatology. - Hoboken, NJ : John Wiley & Sons. - 2578-5745. ; 3:11, s. 788-795
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Most research on patient experiences of rheumatoid arthritis (RA) care is performed with patients who have established RA and less often with patients with early RA. Experiences of and expectations about health care may change over time, which is why the aim was to explore patients’ perceptions of person-centered care (PCC) early in the RA disease course.Methods: Thirty-one patients with early RA were interviewed in this qualitative study. An abductive qualitative content analysis was conducted based on the framework of McCormack and McCance (1,2). The four constructs, prerequisites, care environment, person-centered processes, and person-centered outcomes, constituted the four categories in the deductive part of the study. An inductive analysis generated 11 subcategories exploring the content of PCC.Results: For patients with early RA, PCC was described in terms of 1) prerequisites including being treated with respect, meeting dedicated health care professionals, and meeting professional competence; 2) care environment including having access to a multidisciplinary team, having access to health care, and encountering a supportive organization; 3) person-centered processes including being listened to, being supported, and being involved in decision-making; and 4) person-centered outcomes including being satisfied with received health care and achieving optimal health.Conclusion: Genuine PCC is important for patients early in the RA disease course, supporting the implementation of a person-centered approach during all stages in the health care system. This study contributes to information about how to further develop person-centeredness in rheumatology care. © 2021 The Authors.
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