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Prenatal stress induces vulnerability to nicotine addiction and alters D2 receptors’ expression in the nucleus accumbens in adult rats
Abstracts – XIX Congress PTF / Pharmacological Reports 67S (2015) 2–45
the nociceptive pathways of the central and peripheral nervous systems, modulate the perception of pain of different modalities, including inflammatory and neuropathic pain. However, the role of group III mGlu receptors’ signaling in visceral pain processing is still largely unknown. And yet, visceral pain is associated with a wide variety of chronic functional disorders including irritable bowel syndrome and painful bladder syndrome. Interestingly, stress has recently been shown as one of the most significant risk factors increasing the prevalence of these disorders and exacerbating the severity of pain symptoms. We utilised the Wistar Kyoto (WKY) rat strain, as a model of stress-sensitive visceral hypersensitivity, to investigate the involvement of group III mGlu receptors in stress-associated visceral pain disorders. WKY rats are known to display a stress-hyper-responsive phenotype along with innate hypersensitivity to noxious colon and urinary bladder distension as compared to stress-resilient Sprague Dawley rats. Here we show that WKY rats exhibit an altered pattern of group III mGlu receptors expression in certain regions of brain limbic system, which are tightly associated with emotional processes including visceral pain. Moreover, WKY rats display a profound upregulation of mGlu7 receptors’ expression on the periphery, namely in bladder tissue, while pharmacological inhibition of this receptor effectively reduces visceral hypersensitivity in the animals. Altogether, these data suggest that altered group III mGlu receptor signaling may be one of the mechanisms underlying visceral hypersensitivity in stress-prone individuals. To this end, pharmacological modulation of these receptors might be an attractive approach for the management of stress-induced visceral pain. http://dx.doi.org/10.1016/j.pharep.2015.06.023 The mechanism of antipsychotic-like action of the mGlu receptor activators: Focus on GABAergic signaling Joanna M. Wieron´ska 1,*, Monika Woz´niak 1, Francine Acher 2, Andrzej Pilc 1 1
Institute of Pharmacology, Polish Academy of Sciences, Krako´w, Poland 2 Universite´ Paris Descartes, Paris, France *Corresponding author. The GABAergic/glutamatergic imbalance in the brain is thought to be one of the main causes that leads to development of schizophrenia. Therefore it seems that the pharmacological manipulations within those two systems may restore the homeostasis in the brain, thus exerting antipsychotic efficacy. Both glutamatergic and GABAergic compounds were shown to possess antipsychotic-like effects in animal models of positive, negative and cognitive symptoms of schizophrenia. However, the interesting thing is, that the compounds may complement eachothers action, and as a result the sub effective doses of two or more drugs can be administered at the same time to achieve therapeutic effect. This could decrease the risk of inducing the unwanted adverse effects. In our research we investigated, if the parallel administration of GABAB positive allosteric modulators together with metabotropic glutamate receptors ligands in a sub effective doses induced antipsychotic-like effects in animal models of schizophrenia. We showed that the concomitant administration of mGlu5 and GABAB PAMs is effective in the models of negative and cognitive, but not positive symptoms, while the co-administration of GABAB-mGlu4 activators exerts positive effect in the models of positive symptoms, only.
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The study was supported by the Statutory Funds of the Polish Academy of Science and by the National Science Centre, Grant no. 2012/6/ 06/A/NZ7/00014 (MAESTRO) given to A. Pilc. http://dx.doi.org/10.1016/j.pharep.2015.06.024 Alterations in brain mGluR5 and D2 receptor density during MDMA abstinence in different living conditions in rats Małgorzata Frankowska 1,*, Lucyna Pomierny-Chamioło 2, Joanna Miszkiel 1, Bartosz Pomierny 2, Małgorzata Filip 1,2 1
Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krako´w, Poland 2 Department of Toxicology, Faculty of Pharmacy, Jagiellonian University, Medical College, Krako´w, Poland *Corresponding author. MDMA (3,4-methylenedioxymethylamphetamine; ecstacy) is a psychostimulant currently considered as most popular drug of abuse in Europe. Accumulative evidence suggests that the dopamine and glutaminergic transmission and the corresponding dopamine D2 (D2R) and glutamate mGlu5 (mGluR5) receptors are involved in MDMA-evoked seeking and relapse behaviors. The aim of study was to uncover the role of D2R and mGluR5 in craving-related brain neuroadaptations in the rats exposed to MDMA. With using the titrated receptor antagonists [cH]raclopride and [cH]MPEP, several binding assays were performed to evaluate D2R and mGluR5 densities in the neural circuitry of rats trained to self-administer MDMA (0.5 mg/kg/infusion; FR5) that were subsequently assigned to live in either isolation conditions (home cage; HC), or exposed to experimental cage (EC) or exposed to enriched environment (EE) during a period of forced abstinence. To create control groups, a ‘yoked’ procedure was employed. EC resulted in a significant decrease in density of D2R in the hippocampus (by 29%) and an increase in the nucleus accumbens (23%) of rats previously self-administered MDMA, while ‘yoked’ MDMA animals displayed opposite results with a significant increase in the hippocampus (28%) and decreases in the nucleus accumbens and dorsal striatum (by 20–24%). Abstinence in EE resulted in a significant rise (by 16–27%) in D2R in the limbic structures (the prefrontal cortex, nucleus accumbens and hippocampus) in rats with history of MDMA self-administration. MDMA ‘yoked’ animals resulted in ca. 40% increase in the hippocampus in receptor density. In the brains of rats self-administered MDMA and MDMA ‘yoked’ controls housed in HC, a significant increase (by 33 and 127%) in [cH]raclopride binding to D2R in the nucleus accumbens and prefrontal cortex was found. Moreover, MDMA self-administration and subsequent HC isolation produced increases in D2R density in the dorsal striatum (by 85%), with decreased in MDMA ‘yoked’ animals (by 36%). EC evoked a significant decrease (>25%) in density of mGluR5 in the prefrontal cortex of rats previously exposured to MDMA. Neither EE nor HC induced significant changes in mGluR5 in rat repeated treated with history MDMA. Since EE and EC reduce relapse to MDMA on the behavioural level, the present observations seem to indicate the importance of accumbal D2R and mGluR5 interaction and may refer them as molecular targets to control drug seeking and relapse. This study was supported by the grant no. 2011/03/D/NZ7/06295 by the NCN (Krako´w, Poland) and by the statutory activity of Institute of Pharmacology PAS. http://dx.doi.org/10.1016/j.pharep.2015.06.025
the nociceptive pathways of the central and peripheral nervous systems, modulate the perception of pain of different modalities, including inflammatory and neuropathic pain. However, the role of group III mGlu receptors’ signaling in visceral pain processing is still largely unknown. And yet, visceral pain is associated with a wide variety of chronic functional disorders including irritable bowel syndrome and painful bladder syndrome. Interestingly, stress has recently been shown as one of the most significant risk factors increasing the prevalence of these disorders and exacerbating the severity of pain symptoms. We utilised the Wistar Kyoto (WKY) rat strain, as a model of stress-sensitive visceral hypersensitivity, to investigate the involvement of group III mGlu receptors in stress-associated visceral pain disorders. WKY rats are known to display a stress-hyper-responsive phenotype along with innate hypersensitivity to noxious colon and urinary bladder distension as compared to stress-resilient Sprague Dawley rats. Here we show that WKY rats exhibit an altered pattern of group III mGlu receptors expression in certain regions of brain limbic system, which are tightly associated with emotional processes including visceral pain. Moreover, WKY rats display a profound upregulation of mGlu7 receptors’ expression on the periphery, namely in bladder tissue, while pharmacological inhibition of this receptor effectively reduces visceral hypersensitivity in the animals. Altogether, these data suggest that altered group III mGlu receptor signaling may be one of the mechanisms underlying visceral hypersensitivity in stress-prone individuals. To this end, pharmacological modulation of these receptors might be an attractive approach for the management of stress-induced visceral pain. http://dx.doi.org/10.1016/j.pharep.2015.06.023 The mechanism of antipsychotic-like action of the mGlu receptor activators: Focus on GABAergic signaling Joanna M. Wieron´ska 1,*, Monika Woz´niak 1, Francine Acher 2, Andrzej Pilc 1 1
Institute of Pharmacology, Polish Academy of Sciences, Krako´w, Poland 2 Universite´ Paris Descartes, Paris, France *Corresponding author. The GABAergic/glutamatergic imbalance in the brain is thought to be one of the main causes that leads to development of schizophrenia. Therefore it seems that the pharmacological manipulations within those two systems may restore the homeostasis in the brain, thus exerting antipsychotic efficacy. Both glutamatergic and GABAergic compounds were shown to possess antipsychotic-like effects in animal models of positive, negative and cognitive symptoms of schizophrenia. However, the interesting thing is, that the compounds may complement eachothers action, and as a result the sub effective doses of two or more drugs can be administered at the same time to achieve therapeutic effect. This could decrease the risk of inducing the unwanted adverse effects. In our research we investigated, if the parallel administration of GABAB positive allosteric modulators together with metabotropic glutamate receptors ligands in a sub effective doses induced antipsychotic-like effects in animal models of schizophrenia. We showed that the concomitant administration of mGlu5 and GABAB PAMs is effective in the models of negative and cognitive, but not positive symptoms, while the co-administration of GABAB-mGlu4 activators exerts positive effect in the models of positive symptoms, only.
7
The study was supported by the Statutory Funds of the Polish Academy of Science and by the National Science Centre, Grant no. 2012/6/ 06/A/NZ7/00014 (MAESTRO) given to A. Pilc. http://dx.doi.org/10.1016/j.pharep.2015.06.024 Alterations in brain mGluR5 and D2 receptor density during MDMA abstinence in different living conditions in rats Małgorzata Frankowska 1,*, Lucyna Pomierny-Chamioło 2, Joanna Miszkiel 1, Bartosz Pomierny 2, Małgorzata Filip 1,2 1
Laboratory of Drug Addiction Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krako´w, Poland 2 Department of Toxicology, Faculty of Pharmacy, Jagiellonian University, Medical College, Krako´w, Poland *Corresponding author. MDMA (3,4-methylenedioxymethylamphetamine; ecstacy) is a psychostimulant currently considered as most popular drug of abuse in Europe. Accumulative evidence suggests that the dopamine and glutaminergic transmission and the corresponding dopamine D2 (D2R) and glutamate mGlu5 (mGluR5) receptors are involved in MDMA-evoked seeking and relapse behaviors. The aim of study was to uncover the role of D2R and mGluR5 in craving-related brain neuroadaptations in the rats exposed to MDMA. With using the titrated receptor antagonists [cH]raclopride and [cH]MPEP, several binding assays were performed to evaluate D2R and mGluR5 densities in the neural circuitry of rats trained to self-administer MDMA (0.5 mg/kg/infusion; FR5) that were subsequently assigned to live in either isolation conditions (home cage; HC), or exposed to experimental cage (EC) or exposed to enriched environment (EE) during a period of forced abstinence. To create control groups, a ‘yoked’ procedure was employed. EC resulted in a significant decrease in density of D2R in the hippocampus (by 29%) and an increase in the nucleus accumbens (23%) of rats previously self-administered MDMA, while ‘yoked’ MDMA animals displayed opposite results with a significant increase in the hippocampus (28%) and decreases in the nucleus accumbens and dorsal striatum (by 20–24%). Abstinence in EE resulted in a significant rise (by 16–27%) in D2R in the limbic structures (the prefrontal cortex, nucleus accumbens and hippocampus) in rats with history of MDMA self-administration. MDMA ‘yoked’ animals resulted in ca. 40% increase in the hippocampus in receptor density. In the brains of rats self-administered MDMA and MDMA ‘yoked’ controls housed in HC, a significant increase (by 33 and 127%) in [cH]raclopride binding to D2R in the nucleus accumbens and prefrontal cortex was found. Moreover, MDMA self-administration and subsequent HC isolation produced increases in D2R density in the dorsal striatum (by 85%), with decreased in MDMA ‘yoked’ animals (by 36%). EC evoked a significant decrease (>25%) in density of mGluR5 in the prefrontal cortex of rats previously exposured to MDMA. Neither EE nor HC induced significant changes in mGluR5 in rat repeated treated with history MDMA. Since EE and EC reduce relapse to MDMA on the behavioural level, the present observations seem to indicate the importance of accumbal D2R and mGluR5 interaction and may refer them as molecular targets to control drug seeking and relapse. This study was supported by the grant no. 2011/03/D/NZ7/06295 by the NCN (Krako´w, Poland) and by the statutory activity of Institute of Pharmacology PAS. http://dx.doi.org/10.1016/j.pharep.2015.06.025