Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-... more Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-induced steatosis. Reducing IL-10 expression increases proinflammatory activity in the steatotic liver and worsens insulin resistance. As the transcriptional coactivator proliferator-activated receptor γ coactivator–1α (PGC-1α) plays a central role in dysfunctional hepatocytic activity in diet-induced steatosis, we hypothesized that at least part of the action of PGC-1α could be mediated by reducing the transcription of the IL-10 gene. Here, we used immunoblotting, real-time polymerase chain reaction, immunocytochemistry, and chromatin immunoprecipitation assay to investigate the role of PGC-1α in the control of IL-10 expression in hepatic cells. First, we show that, in the intact steatotic liver, the expressions of IL-10 and PGC-1α are increased. Inhibiting PGC-1α expression by antisense oligonucleotide increases IL-10 expression and reduces the steatotic phenotype. In cultured hepatocytes, the treatment with saturated and unsaturated fatty acids increased IL-10 expression. This was accompanied by increased association of PGC-1α with c-Maf and p50–nuclear factor (NF) κB, 2 transcription factors known to modulate IL-10 expression. In addition, after fatty acid treatment, PGC-1α, c-Maf, and p50-NFκB migrate from the cytosol to the nuclei of hepatocytes and bind to the IL-10 promoter region. Inhibiting NFκB activation with salicylate reduces IL-10 expression and the association of PGC-1α with p50-NFκB. Thus, PGC-1α emerges as a potential transcriptional regulator of the inflammatory phenomenon taking place in the steatotic liver.
The defensive withdrawal test (DWT) is used to model anxiety-like behaviour in rats. The aim of t... more The defensive withdrawal test (DWT) is used to model anxiety-like behaviour in rats. The aim of this study was to investigate whether an aversive stimulus, bright light, affects the behaviour in this test. Additionally, the effect of habituation to the apparatus was studied. Both male and female Wistar rats were used to study whether sex differences exist in the DWT, as reported for other tests of anxiety. On day 1 half of the rats were tested under low light and half under bright light. Two to seven days after trial one the same rats were repeatedly tested under the same light condition for five consecutive days. The male rats showed a higher degree of anxiety-like behaviour when tested under bright light than under low light. In contrast, the behaviour of the female rats was not affected by changes in illumination. Male rats also exhibited elevated anxiety-like behaviour compared to female rats under bright light, whereas under low light conditions no sex difference was seen. Males in low light habituated much faster than males tested under bright light, whereas in females there was little difference in habituation between low and bright light. In summary, we found that bright light is aversive for male but not female Wistar rats in the DWT. Whether this is due to sex differences in light sensitivity or if females respond with a different behavioural strategy in response to bright light, which could not be detected in the DWT, remains to be elucidated.
The present investigation continues previous behavioral profiling studies of selectively bred alc... more The present investigation continues previous behavioral profiling studies of selectively bred alcohol-drinking and alcohol non-drinking rats. In this study, alcohol-naïve adult Sardinian alcohol-preferring (sP) and non-preferring (sNP) rats were tested in the multivariate concentric square field™ (MCSF) test. The MCSF test has an ethoexperimental approach and measures general activity, exploration, risk assessment, risk taking, and shelter seeking in laboratory rodents. The multivariate design enables behavioral profiling in one and the same test situation. Age-matched male Wistar rats were included as a control group. Five weeks after the first MCSF trial, a repeated testing was done to explore differences in acquired experience. The results revealed distinct differences in exploratory strategies and behavioral profiles between sP and sNP rats. The sP rats were characterized by lower activity, lower exploratory drive, higher risk assessment, and lower risk taking behavior than in sNP rats. In the repeated trial, risk-taking behavior was almost abolished in sP rats. When comparing the performance of sP and sNP rats with that of Wistar rats, the principal component analysis revealed that the sP rats were the most divergent group. The vigilant behavior observed in sP rats with low exploratory drive and low risk-taking behavior is interpreted here as high innate anxiety-related behaviors and may be related to their propensity for high voluntary alcohol intake and preference. We suggest that the different lines of alcohol-preferring rats with different behavioral characteristics constitute valuable animal models that mimic the heterogeneity in human alcohol dependence.
The aim of the present investigation was to compare the behavioural profiles in alcohol-preferrin... more 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-naïve 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.
Stress-the International Journal on The Biology of Stress, 2005
The combination of genetic and environmental factors determines the individual vulnerability for ... more The combination of genetic and environmental factors determines the individual vulnerability for excessive ethanol intake, possibly leading to dependence. The environmental influences early in life represent examples of determinant factors for adult behaviour and can be protective as well as risk factors. Maternal separation is one model to examine the long-term consequences of early environmental experiences on neurochemistry and behaviour, including drug-taking behaviour in experimental animals. In the present review, findings from studies using repeated short and prolonged periods of maternal separation, with emphasis on effects on voluntary ethanol intake in rats with or without a genetic predisposition for high voluntary ethanol intake, are summarized. Despite some contradictory results, the general picture emerging shows that short periods of maternal separation during the postnatal period result in a lower adult voluntary ethanol intake in male rats. Prolonged periods of maternal separation were found to induce a high voluntary ethanol intake in male rats, including rats with a genetic predisposition for high ethanol intake. Results from the literature also show that changes were not just related to time of separation but were also related to the degree of handling. Interestingly, in terms of voluntary ethanol intake, female rats were generally not affected by postnatal maternal separation. The reasons for these sex differences need further investigation. In terms of neurobiological consequences of maternal separation, conclusive data are sparse and one of the future challenges will, therefore, be to identify and characterize underlying neurobiological mechanisms, especially in the individual animal.
Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the β-group... more Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the β-group of SLCs, are known to transport neutral amino acids. In this paper, we show that these three families were present before the split of the animal lineage and that they are likely to share a common decent. We also show that the APF transporters found in plants are most likely homologous to the mammalian β-group, suggesting that this type of transporters arouse early in the evolution of eukaryotes. We performed detailed tissue expression analysis of all the members of the β-group in rat and found several examples of highly specific expression patterns, with SLC38A7 being exclusively found in liver, SLC38A5 in blood, and SLC38A4 in muscle and liver. Moreover, we found that SLC38A10 is expressed in several endocrine organs. We also found that SLC38A1 is highly up regulated in the cortex from rats treated with diazepam and that SLC38A2 is significantly down regulated in the same tissue. In addition, we performed a detailed expression analysis of SLC38A1 and SLC38A6 in mouse brain using in situ hybridization, which showed that both these transporters are widely expressed in the brain.
Early life experiences are important for the development of neurobiobehavioral mechanisms and sub... more 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.
Environmental manipulations early in life may induce persistent alterations in adult behaviour an... more Environmental manipulations early in life may induce persistent alterations in adult behaviour and physiology. The underlying neural mechanisms of these responses are not yet clear. We have previously reported long-term changes in brain opioid peptide levels in male and female Sprague–Dawley rats after short periods (15 min, known as neonatal handling) of maternal separation (MS) until weaning. To study this further, we investigated behavioural and neurochemical effects of repeated MS in male Wistar rats. The rat pups were separated from their dams in litters for either 360 min (MS360) or 15 min (MS15) daily from postnatal day 1 to 21 or exposed to normal animal facility rearing. Behavioural analysis showed that MS360 rats had increased ultrasonic calls on postnatal day 5 compared to MS15 rats, but not on postnatal day 6. Moreover, the MS360 rats had more animals with higher frequency of calls at day 5 than 6 than the MS15 rats. Analysis of the opioid peptides dynorphin B and Met-enkephalin-Arg6Phe7 with radioimmunoassay 7 weeks after the MS procedure, revealed long-term neurochemical changes in several brain areas and in the pituitary gland. Immunoreactive dynorphin B and Met-enkephalin-Arg6Phe7 levels were affected in the hypothalamus and dynorphin B levels in the neurointermediate pituitary lobe, amygdala, substantia nigra and the periaqueductal gray. Together, these findings show that repeated periods of MS early in life in male Wistar rats affect the development of the ultrasonic call response and induce long-lasting and possibly permanent alterations in the opioid peptide systems.
Animals exposed to short periods of handling during the critical period of development, i.e., the... more Animals exposed to short periods of handling during the critical period of development, i.e., the first 21 days of life in rats, show attenuated neuroendocrine responses to stress in adult life. We have previously reported long-term changes in brain dynorphin (DYN) peptide levels in male Sprague–Dawley rats after neonatal handling. The purpose of this study was to investigate whether neonatal handling, 15-min individual separation from the mother during postnatal days 1–21, can induce long-term changes in DYNB, Met-enkephalin Arg6Phe7 (MEAP) and nociceptin/orphanin FQ (N/OFQ) immunoreactive (ir) levels in female Sprague–Dawley rats. The peptides were measured in brain and pituitary gland 2 months after the handling procedure. The results reveal that handled (H) rats had increased ir levels of N/OFQ, DYNB and MEAP in the periaqueductal gray (PAG) as compared to nonhandled (NH) controls. Furthermore, H rats had decreased ir levels of DYNB in the frontal cortex and in the amygdala. In contrast to previous findings in male rats, DYNB levels were unaffected in areas related to the hypothalamo–pituitary–adrenal (HPA)-axis. The results indicate that a manipulation early in life can induce persistent neurochemical changes in the N/OFQ and opioid peptide system in female Sprague–Dawley rats.
Melanocortin (MC) peptides are suggested to play a role in opiate dependence, where they antagoni... more Melanocortin (MC) peptides are suggested to play a role in opiate dependence, where they antagonise the addictive properties of opiates. To further study the involvement of the MCs in drug dependence, we analysed the effects of the MC(4)-receptor antagonist HS014 (1 nmol/rat), and the non-selective MC-receptor agonist MTII (1 nmol/rat), using i.c.v. administration, on ethanol intake in alcohol-preferring AA rats. The rats had access to ethanol during 40 days, resulting in a mean ethanol intake of 6.6 g/kg/day, before treatment. One group received only artificial cerebrospinal fluid solution. MTII caused a reduction in ethanol intake and ethanol preference, whereas HS014 was without effect. No effect on water intake was observed. A decrease in food intake was detected after MTII, whereas HS014 induced an increase in food intake. Analysis of dynorphin B and Met-enkephalin-Arg(6)Phe(7) immunoreactive levels revealed that MTII and HS014 altered opioid peptide levels in several brain areas and the pituitary gland of the rats with an established ethanol intake. This is the first report showing that manipulation of the MC-receptor system changes ethanol intake in chronically ethanol-drinking AA rats. In addition, manipulation of the MC system modulates ethanol-induced changes in opioid peptide levels.
Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-... more Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-induced steatosis. Reducing IL-10 expression increases proinflammatory activity in the steatotic liver and worsens insulin resistance. As the transcriptional coactivator proliferator-activated receptor γ coactivator–1α (PGC-1α) plays a central role in dysfunctional hepatocytic activity in diet-induced steatosis, we hypothesized that at least part of the action of PGC-1α could be mediated by reducing the transcription of the IL-10 gene. Here, we used immunoblotting, real-time polymerase chain reaction, immunocytochemistry, and chromatin immunoprecipitation assay to investigate the role of PGC-1α in the control of IL-10 expression in hepatic cells. First, we show that, in the intact steatotic liver, the expressions of IL-10 and PGC-1α are increased. Inhibiting PGC-1α expression by antisense oligonucleotide increases IL-10 expression and reduces the steatotic phenotype. In cultured hepatocytes, the treatment with saturated and unsaturated fatty acids increased IL-10 expression. This was accompanied by increased association of PGC-1α with c-Maf and p50–nuclear factor (NF) κB, 2 transcription factors known to modulate IL-10 expression. In addition, after fatty acid treatment, PGC-1α, c-Maf, and p50-NFκB migrate from the cytosol to the nuclei of hepatocytes and bind to the IL-10 promoter region. Inhibiting NFκB activation with salicylate reduces IL-10 expression and the association of PGC-1α with p50-NFκB. Thus, PGC-1α emerges as a potential transcriptional regulator of the inflammatory phenomenon taking place in the steatotic liver.
The defensive withdrawal test (DWT) is used to model anxiety-like behaviour in rats. The aim of t... more The defensive withdrawal test (DWT) is used to model anxiety-like behaviour in rats. The aim of this study was to investigate whether an aversive stimulus, bright light, affects the behaviour in this test. Additionally, the effect of habituation to the apparatus was studied. Both male and female Wistar rats were used to study whether sex differences exist in the DWT, as reported for other tests of anxiety. On day 1 half of the rats were tested under low light and half under bright light. Two to seven days after trial one the same rats were repeatedly tested under the same light condition for five consecutive days. The male rats showed a higher degree of anxiety-like behaviour when tested under bright light than under low light. In contrast, the behaviour of the female rats was not affected by changes in illumination. Male rats also exhibited elevated anxiety-like behaviour compared to female rats under bright light, whereas under low light conditions no sex difference was seen. Males in low light habituated much faster than males tested under bright light, whereas in females there was little difference in habituation between low and bright light. In summary, we found that bright light is aversive for male but not female Wistar rats in the DWT. Whether this is due to sex differences in light sensitivity or if females respond with a different behavioural strategy in response to bright light, which could not be detected in the DWT, remains to be elucidated.
The present investigation continues previous behavioral profiling studies of selectively bred alc... more The present investigation continues previous behavioral profiling studies of selectively bred alcohol-drinking and alcohol non-drinking rats. In this study, alcohol-naïve adult Sardinian alcohol-preferring (sP) and non-preferring (sNP) rats were tested in the multivariate concentric square field™ (MCSF) test. The MCSF test has an ethoexperimental approach and measures general activity, exploration, risk assessment, risk taking, and shelter seeking in laboratory rodents. The multivariate design enables behavioral profiling in one and the same test situation. Age-matched male Wistar rats were included as a control group. Five weeks after the first MCSF trial, a repeated testing was done to explore differences in acquired experience. The results revealed distinct differences in exploratory strategies and behavioral profiles between sP and sNP rats. The sP rats were characterized by lower activity, lower exploratory drive, higher risk assessment, and lower risk taking behavior than in sNP rats. In the repeated trial, risk-taking behavior was almost abolished in sP rats. When comparing the performance of sP and sNP rats with that of Wistar rats, the principal component analysis revealed that the sP rats were the most divergent group. The vigilant behavior observed in sP rats with low exploratory drive and low risk-taking behavior is interpreted here as high innate anxiety-related behaviors and may be related to their propensity for high voluntary alcohol intake and preference. We suggest that the different lines of alcohol-preferring rats with different behavioral characteristics constitute valuable animal models that mimic the heterogeneity in human alcohol dependence.
The aim of the present investigation was to compare the behavioural profiles in alcohol-preferrin... more 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-naïve 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.
Stress-the International Journal on The Biology of Stress, 2005
The combination of genetic and environmental factors determines the individual vulnerability for ... more The combination of genetic and environmental factors determines the individual vulnerability for excessive ethanol intake, possibly leading to dependence. The environmental influences early in life represent examples of determinant factors for adult behaviour and can be protective as well as risk factors. Maternal separation is one model to examine the long-term consequences of early environmental experiences on neurochemistry and behaviour, including drug-taking behaviour in experimental animals. In the present review, findings from studies using repeated short and prolonged periods of maternal separation, with emphasis on effects on voluntary ethanol intake in rats with or without a genetic predisposition for high voluntary ethanol intake, are summarized. Despite some contradictory results, the general picture emerging shows that short periods of maternal separation during the postnatal period result in a lower adult voluntary ethanol intake in male rats. Prolonged periods of maternal separation were found to induce a high voluntary ethanol intake in male rats, including rats with a genetic predisposition for high ethanol intake. Results from the literature also show that changes were not just related to time of separation but were also related to the degree of handling. Interestingly, in terms of voluntary ethanol intake, female rats were generally not affected by postnatal maternal separation. The reasons for these sex differences need further investigation. In terms of neurobiological consequences of maternal separation, conclusive data are sparse and one of the future challenges will, therefore, be to identify and characterize underlying neurobiological mechanisms, especially in the individual animal.
Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the β-group... more Members of the solute carrier families (SLC) 32, 36, and 38, together also designated the β-group of SLCs, are known to transport neutral amino acids. In this paper, we show that these three families were present before the split of the animal lineage and that they are likely to share a common decent. We also show that the APF transporters found in plants are most likely homologous to the mammalian β-group, suggesting that this type of transporters arouse early in the evolution of eukaryotes. We performed detailed tissue expression analysis of all the members of the β-group in rat and found several examples of highly specific expression patterns, with SLC38A7 being exclusively found in liver, SLC38A5 in blood, and SLC38A4 in muscle and liver. Moreover, we found that SLC38A10 is expressed in several endocrine organs. We also found that SLC38A1 is highly up regulated in the cortex from rats treated with diazepam and that SLC38A2 is significantly down regulated in the same tissue. In addition, we performed a detailed expression analysis of SLC38A1 and SLC38A6 in mouse brain using in situ hybridization, which showed that both these transporters are widely expressed in the brain.
Early life experiences are important for the development of neurobiobehavioral mechanisms and sub... more 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.
Environmental manipulations early in life may induce persistent alterations in adult behaviour an... more Environmental manipulations early in life may induce persistent alterations in adult behaviour and physiology. The underlying neural mechanisms of these responses are not yet clear. We have previously reported long-term changes in brain opioid peptide levels in male and female Sprague–Dawley rats after short periods (15 min, known as neonatal handling) of maternal separation (MS) until weaning. To study this further, we investigated behavioural and neurochemical effects of repeated MS in male Wistar rats. The rat pups were separated from their dams in litters for either 360 min (MS360) or 15 min (MS15) daily from postnatal day 1 to 21 or exposed to normal animal facility rearing. Behavioural analysis showed that MS360 rats had increased ultrasonic calls on postnatal day 5 compared to MS15 rats, but not on postnatal day 6. Moreover, the MS360 rats had more animals with higher frequency of calls at day 5 than 6 than the MS15 rats. Analysis of the opioid peptides dynorphin B and Met-enkephalin-Arg6Phe7 with radioimmunoassay 7 weeks after the MS procedure, revealed long-term neurochemical changes in several brain areas and in the pituitary gland. Immunoreactive dynorphin B and Met-enkephalin-Arg6Phe7 levels were affected in the hypothalamus and dynorphin B levels in the neurointermediate pituitary lobe, amygdala, substantia nigra and the periaqueductal gray. Together, these findings show that repeated periods of MS early in life in male Wistar rats affect the development of the ultrasonic call response and induce long-lasting and possibly permanent alterations in the opioid peptide systems.
Animals exposed to short periods of handling during the critical period of development, i.e., the... more Animals exposed to short periods of handling during the critical period of development, i.e., the first 21 days of life in rats, show attenuated neuroendocrine responses to stress in adult life. We have previously reported long-term changes in brain dynorphin (DYN) peptide levels in male Sprague–Dawley rats after neonatal handling. The purpose of this study was to investigate whether neonatal handling, 15-min individual separation from the mother during postnatal days 1–21, can induce long-term changes in DYNB, Met-enkephalin Arg6Phe7 (MEAP) and nociceptin/orphanin FQ (N/OFQ) immunoreactive (ir) levels in female Sprague–Dawley rats. The peptides were measured in brain and pituitary gland 2 months after the handling procedure. The results reveal that handled (H) rats had increased ir levels of N/OFQ, DYNB and MEAP in the periaqueductal gray (PAG) as compared to nonhandled (NH) controls. Furthermore, H rats had decreased ir levels of DYNB in the frontal cortex and in the amygdala. In contrast to previous findings in male rats, DYNB levels were unaffected in areas related to the hypothalamo–pituitary–adrenal (HPA)-axis. The results indicate that a manipulation early in life can induce persistent neurochemical changes in the N/OFQ and opioid peptide system in female Sprague–Dawley rats.
Melanocortin (MC) peptides are suggested to play a role in opiate dependence, where they antagoni... more Melanocortin (MC) peptides are suggested to play a role in opiate dependence, where they antagonise the addictive properties of opiates. To further study the involvement of the MCs in drug dependence, we analysed the effects of the MC(4)-receptor antagonist HS014 (1 nmol/rat), and the non-selective MC-receptor agonist MTII (1 nmol/rat), using i.c.v. administration, on ethanol intake in alcohol-preferring AA rats. The rats had access to ethanol during 40 days, resulting in a mean ethanol intake of 6.6 g/kg/day, before treatment. One group received only artificial cerebrospinal fluid solution. MTII caused a reduction in ethanol intake and ethanol preference, whereas HS014 was without effect. No effect on water intake was observed. A decrease in food intake was detected after MTII, whereas HS014 induced an increase in food intake. Analysis of dynorphin B and Met-enkephalin-Arg(6)Phe(7) immunoreactive levels revealed that MTII and HS014 altered opioid peptide levels in several brain areas and the pituitary gland of the rats with an established ethanol intake. This is the first report showing that manipulation of the MC-receptor system changes ethanol intake in chronically ethanol-drinking AA rats. In addition, manipulation of the MC system modulates ethanol-induced changes in opioid peptide levels.
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Papers by Erika Roman