| 1. |
- Brolin, Erika, et al.
(författare)
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Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
- 2018
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Ingår i: Pharmacology, Biochemistry and Behavior. - : Elsevier BV. - 0091-3057 .- 1873-5177. ; 167, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.
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| 2. |
- Brolin, Erika, 1984-
(författare)
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Growth hormone in the brain : Focus on cognitive function
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.
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| 3. |
- Brolin, Erika, et al.
(författare)
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The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
- 2017
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 646, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.
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| 4. |
- Enhamre-Brolin, Erika, et al.
(författare)
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Growth hormone reverses streptozotocin-induced cognitive impairments in male mice
- 2013
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 238, s. 273-278
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Tidskriftsartikel (refereegranskat)abstract
- In recent decades, growth hormone (GH) replacement therapy in human subjects deficient in the hormone has resulted in a number of beneficial effects on cognitive performance. Studies in hypophysectomised rats report similar effects of GH treatment on learning and memory tasks. The purpose of this study was to investigate the ability of GM to reverse learning impairments in mice with streptozotocin (STZ)-induced diabetes. Diabetic and control mice were given recombinant human GM (rhGH) 0.1 IU/kg/day for ten consecutive days. In the latter phase of the treatment the cognitive abilities of the mice were tested using the Barnes maze (BM). A profound hormonal effect was seen when analysing the search patterns used by the animals in the maze. rhGH treatment significantly counteracted the cognitive disabilities expressed as lack of direct search strategies on the last day in the BM. In addition, the number of primary errors made by diabetic mice during the acquisition phase was reduced by rhGH treatment, although the primary escape latency was unchanged in these animals when compared to saline-treated diabetic animals. These results suggest that specific cognitive impairments induced by STZ, i.e. the disabilities seen in strategic behaviour, could be reversed by exogenous hormone treatment. Our findings highlight the influence of GH on brain function and in particular on cognitive behaviour related to learning and memory.
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| 5. |
- Johansson, Jenny, et al.
(författare)
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Gamma-Hydroxybutyrate (GHB) elevates Met-enkephalin-Arg6Phe7 (MEAP) levels in the frontal cortex of the male rat brain
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Gamma-hydroxybutyrate (GHB) has increased in popularity among adolescents during recent years. Predominantly it is used as a recreational drug, but frequently also as an anabolic agent due to its ability of releasing growth hormone. The fact that GHB has been reported to be highly addictive and can cause cognitive deficiencies has become a major concern. In this study, we investigated the impact of GHB treatment in rats on the levels of the endogenous opioid peptides Met-enkephalin-Arg6Phe7 (MEAP) and Dynorphin B (DYNB) in various regions of the brain and on the levels of insulin-like growth factor 1 (IGF-1) in plasma. Furthermore, spontaneous explorative behavior and locomotor activity after GHB administration was analyzed in an Open field (OF). The results demonstrated that treatment with GHB did not affect the parameters that were assessed in the OF, nor did it affect the plasma levels of IGF-1. Regarding the opioid peptide levels, the GHB treated rats demonstrated increased immunoreactive (ir) MEAP but not DYNB levels in the frontal cortex, while no significant alterations were observed in caudate putamen, hypothalamus, nucleus accumbens, amygdala, hippocampus and periaqueductal grey. Moreover, in control rats the levels of ir MEAP and ir DYNB seemed well-balanced in many regions and the peptide levels correlated in amygdala, hippocampus and hypothalamus. However, in the GHB-treated animals no such correlation was observed. In conclusion, GHB treatment created an imbalance regarding the opioids MEAP/DYNB and increased the levels of MEAP significantly in regions of the brain that are of importance for the development of drug dependence.
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| 6. |
- Jonsson, Anna, 1981-, et al.
(författare)
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Small constrained SP1-7 analogues bind to a unique site and promote anti-allodynic effects following systemic injection in mice
- 2015
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Ingår i: Neuroscience. - : Elsevier BV. - 0306-4522 .- 1873-7544. ; 298, s. 112-119
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Tidskriftsartikel (refereegranskat)abstract
- Previous results have shown that the substance P (SP) N-terminal fragment SP1–7 may attenuate hyperalgesia and produce anti-allodynia in animals using various experimental models for neuropathic pain. The heptapeptide was found to induce its effects through binding to and activating specific sites apart from any known neurokinin or opioid receptor. Furthermore, we have applied a medicinal chemistry program to develop lead compounds mimicking the effect of SP1–7. The present study was designed to evaluate the pharmacological effect of these compounds using the mouse spared nerve injury (SNI) model of chronic neuropathic pain. Also, as no comprehensive screen with the aim to identify the SP1–7 target has yet been performed we screened our lead compound H-Phe-Phe-NH2 toward a panel of drug targets. The extensive target screen, including 111 targets, did not reveal any hit for the binding site among a number of known receptors or enzymes involved in pain modulation. Our animal studies confirmed that SP1–7, but also synthetic analogs thereof, possesses anti-allodynic effects in the mouse SNI model of neuropathic pain. One of the lead compounds, a constrained H-Phe-Phe-NH2 analog, was shown to exhibit a significant anti-allodynic effect.
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