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1

Lucocorticoid receptor stimulation modulates morphine addiction-like symptoms

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Marut L., Skupio U., Przewlocki R.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
2

Glucocorticoid receptor stimulation modulates morphine addiction-like symptoms

100%
Marut L., Skupio U., Przewlocki R.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Morphine is widely used painkiller, however misuse of morphine may lead to the addiction. Stress system and glucocorticoids are thought to be involved in various aspects of addiction-like behavior. In animal models stressors and glucocorticoids facilitate acquisition of drug self-administration, increase their rewarding potential and promote relapse. AIM(S): The involvement of stress system in addiction is widely studied however the specific role of glucocorticoid receptor (GR) is still not fully understood. The aim of this study was to evaluate effects of GR stimulation on addiction-like symptoms induced by morphine. METHOD(S): We used dexamethasone (DEX), selective glucocorticoid receptor agonist, in self-administration (SA) and conditioned place preference (CPP) paradigms in mice. Mice were allowed to self-administer increasing doses of morphine. To test the influence of GR stimulation on morphine intake, we administered DEX (4 mg/kg). Also effects of DEX on morphine place preference was evaluated. 1 hour before morphine conditioning mice were pretreated with either DEX (4 mg/kg) or saline (SAL). RESULTS: DEX treatment resulted in significant increase in morphine intake. This effect seems to be specific for the drug, as at the same time, DEX treatment caused decrease in water intake. Interestingly, in CPP paradigm DEX pretreatment resulted in significant decrease of time spent in morphine-paired compartment of the apparatus. In control conditions SAL pretreatment did not affect morphine place preference. CONCLUSIONS: In CPP paradigm DEX attenuate morphine place preference that is a measure of drug rewarding properties. GR stimulation led to enhanced morphine SA. This result may indicate that after DEX mice need more drug to achieve the same reward. Taking together our result may suggest that GR stimulation decrease rewarding potential of morphine. FINANCIAL SUPPORT: Funding for this study was provided by Polish National Science Centre Grants: 2013/08/A/ NZ3/00848.
3

The role of astrocytic glucocorticoid receptor in behavioral effects of opioids

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Kudla L., Skupio U., Marut L., Tertil M., Wawrzczak-Bargiela A., Przewlocki R.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Glucocorticoid receptor (GR)-dependent mechanisms are considered to affect behavioral effects of multiple drugs of abuse, including opioids. Recent evidence points to the important role of astrocytes in mediating GR-dependent effects in the brain. However, the exact mechanisms of astrocytic GR contribution to behavioral response to opioids remain unknown. AIM(S): Here, we aimed to evaluate effects of opioid receptors ligands in astrocytic GR knockout mice. We assessed the animals in nociception and addiction assays. METHOD(S): We used transgenic mice in which GR is selectively ablated in astrocytes expressing connexin 30 (C×30×GR flox/flox) and non‑transgenic littermates. To investigate nociceptive sensitivity and morphine-induced analgesia, animals were assessed in tail flick test. To evaluate addiction-like behavior, morphine tolerance and naloxone-precipitated morphine withdrawal symptoms were measured. Moreover, sensitivity to opioid reward was tested in conditioned place preference (CPP) paradigm and response to aversive properties of naloxone was measured using conditioned place aversion (CPA) test. RESULTS: Mutant and control mice presented similar nociceptive sensitivity, did not differ in morphine analgesia, developed similar opioid tolerance and morphine-induced CPP. However, when subjected to naloxone-precipitated morphine withdrawal, mutants showed decreased number of jumps, indicating attenuated physical signs of opioid withdrawal. What is more, astrocytic GR knockout mice did not acquire naloxone-induced CPA, suggesting alternations in behavioral response to naloxone-evoked aversion. CONCLUSIONS: Our data indicate that astrocytic GR may be involved in regulation of naloxone-induced aversion and morphine withdrawal. However, knockout of GR in astrocytes does not influence pain sensitivity, morphine analgesia, tolerance and reward-associated memory. In conclusion, our results shed a light on the causal role of GR-dependent signaling in astrocytes in mediating behavioral effects of opioids. FINANCIAL SUPPORT: Funding for this study was provided by Polish National Science Centre Grant: 2013/08/A/ NZ3/00848.
4

Analysis of morphine-induced gene expression in the mouse hippocampus

76%
Barut J., Skupio U., Marut L., Tertil M., Golda S., Przewlocki R.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Exposure to drugs of abuse initiates molecular alterations in the central nervous system that lead to an increased overall tenderness to addiction with subsequent drug exposures. These drug-induced alterations employ changes in gene expression, which may underlie the behavioral aberrancy that define a state of addiction. AIM(S): To identify the specific transcriptional alterations in different stages of morphine addiction in the hippocampus (Hip), brain region which play a role in the acquisition and extinction of memories associated with drug seeking behavior. METHOD(S): C57BL/6J male mice were injected twice daily for 3 weeks with morphine (increasing doses, 20-100 mg/kg i.p.). Animals were observed for spontaneous signs of withdrawal and behavior was measured in first and third week of abstinence. Morphine induced gene expression in the Hip was analyzed, using the qPCR technology. RESULTS: 24 h after chronic treatment we have observed spontaneous withdrawal syndrome and the peak of corticosterone levels in blood. Morphine-abstinent mice exhibited a variety of depression-like behaviors and cognitive deficits. Analyzes of Hip transcriptional responses to morphine indicated that most of genes regulated by morphine injection are GR-dependent, with a number of them being astrocyte‑specific (Gjb6, Plin4, Slc1a3, Gfap, Gja1). Analyzed genes clustered into few co-expressed groups, i.a. GR-dependent (Fkbp5, Tsc22d3, Zbtb16, Plin4) and activity-dependent (Fos, Fosl2) both upregulated in single and chronic exposure to morphine. Interestingly, 3-weeks abstinent mice didn’t exhibit any significant difference in transcription, but single dose of morphine (relapse) trigger sensitization of expression of some interesting genes (camk1g, Fosl2, Arc). CONCLUSIONS: Our results reveal that morphine induces drug‑specific transcriptional signatures in the Hip. Stress systems in Hip may modify the reward circuit through GR-dependent molecular pathways and this mechanism may be a fundamental for addiction therapy research. FINANCIAL SUPPORT: Polish National Science Centre Grant number 2013/08/A/NZ3/00848.
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