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The nicotinic receptor modulator, lynx2, controls anxiety via regulation of the cholinergic system
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Poster abstracts / Biochemical Pharmacology 97 (2015) 621–636
2.7 Nicotinic modulation of auditory evoked potential electroencephalography in a rodent neurodevelopmental model of schizophrenia Kathy L. Kohlhaas, Holly M. Robb, Victoria A. Roderwald, Lynne E. Rueter AbbVie, Inc., North Chicago, IL, USA Schizophrenia is a chronic disease that has been hypothesized to be linked to neurodevelopmental abnormalities. Schizophrenia patients exhibit impairments in basic sensory processing including sensory gating deficits in P50 and mismatch negativity (MMN). Neuronal nicotinic acetylcholine receptor (nAChR) agonists have been reported to attenuate these deficits. Gestational exposure of rats to methylazoxymethanol acetate (MAM) at embryonic day 17 leads to developmental disruption of the limbic-cortical system. MAM exposed offspring show neuropathological and behavioral changes that have similarities with those seen in schizophrenia. In this study, we aimed to assess whether N40 auditory sensory gating (the rodent form of P50 gating) and MMN deficits as measures of auditory evoked potential (AEP) electroencephalography (EEG) are present in MAM rats and whether nAChR agonists could attend the deficit. E17 male MAM and sham rats were implanted with cortical electrodes at two months of age. EEG recordings evaluating N40 gating and MMN paradigms were done comparing effects of vehicle (saline), nicotine and the a7 agonist ABT-107. Deficits were seen for MAM rats compared to sham animals in both N40 auditory sensory gating and MMN AEP recordings. There was a strong trend for N40 deficits to be attenuated by both nicotine (0.16 mg/kg i.p. base) and ABT-107 (1.0 mg/kg i.p. base). MMN deficits were significantly attenuated by ABT-107 but not by nicotine. These data support the MAM model as a useful tool for translating pharmacodynamic effects in clinical medicine studies of novel therapeutic treatments for schizophrenia. http://dx.doi.org/10.1016/j.bcp.2015.08.032 2.8 The nicotinic receptor modulator, lynx2, controls anxiety via regulation of the cholinergic system Kristin R. Anderson, Huaixing Wang, Julie M. Miwa Department of Biological Sciences, Lehigh University, Bethlehem, PA, USA Among the most disruptive aspects to daily functioning in modern society are a group of anxiety disorders. The anxiety response is a normal and advantageous reaction to a stressor but disorders can develop when individuals cannot return to baseline once the stressor has resolved. Due to a lack of full understanding of the biological underpinnings of anxiety, current anxiety treatments only temporarily relieve the symptoms without treating the cause. Interestingly, many anxiety sufferers selfmedicate by smoking, suggesting a role of the cholinergic system in anxiety modulation. We are using a candidate gene approach to uncover these underpinnings, focusing on the role of a cholinergic modulator, lynx2, highly expressed in the basolateral aspect of the anxiety structure, the amygdala (BLA). Lynx2 proteins bind to and suppress cholinergic receptors (nAChRs). Consistent with its high expression, mice lacking lynx2 (lynx2KO), demonstrate elevated anxiety levels across several assays (light-dark, open-field, etc.). We hypothesize that experience-dependent plasticity in the amygdala plays a role in the return to baseline state, and that this is
subject to cholinergic modulation. To address this, we are performing behavioral pharmacological studies in lynx2KO mice to measure anxiety responses along with electrophysiology studies. Sensitivity to nicotine is augmented in lynx2KO mice in both the light/dark assay and slice physiology. Further investigations into the specific nAChR subtypes are being conducted with several specific inhibitors and uncovering a shift in receptor subtype without lynx2 presence, suggesting a role for lynx2 in receptor subunit composition. Synaptic plasticity is altered in the BLA between wild-type and lynx2KO mice and normalcy could be restored by pharmacological manipulation of nAChRs. These data suggest that addressing synaptic plasticity may be a promising avenue by which to return individuals back to baseline states. To address this further, fear extinction is being used to assess modification of the fear response over time. Understanding of how amygdalar output can be altered by lynx and cholinergic pathways could help in the development of treatments for anxiety disorders such as PTSD. http://dx.doi.org/10.1016/j.bcp.2015.08.033
2.9 Reduction of aggressive behavior in mouse models by the selective a7 nicotinic partial agonist GTS-21 Alan S. Lewis, Katherine Garvey, Yann S. Mineur, Marina R. Picciotto Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Background: Aggressive behavior often complicates the treatment of many neuropsychiatric disorders, especially neurodevelopmental and neurodegenerative disorders. Levels and signaling of nicotinic acetylcholine receptors (nAChRs) are altered in many of these conditions. Previous studies have demonstrated that acute administration of nicotine can reduce aggression in animal models. We therefore hypothesized that pharmacological agents active at specific nAChR subunits might be therapeutic for aggression occurring in these conditions. To that end, we sought to identify the molecular basis for nicotine’s anti-aggressive (‘‘serenic’’) effect, and to characterize the effects of GTS-21, an a7 nAChR partial agonist, on aggression in mouse models. Methods: Aggressive behavior was quantified using socially isolated adult male C57BL/6 and BALB/c mice in a resident-intruder paradigm. Nicotine or GTS-21 was administered i.p. 10 min prior to initiation of resident-intruder tests. Antagonists (DHbE, 3 mg/kg, or MLA, 5 mg/kg) were administered i.p. 15 min prior to nicotine or GTS-21. Social interaction and locomotor testing was performed using a Noldus EthovisionXT system. c-Fos expression was quantified as a marker of neuronal activity. Results: As previously reported, aggressive behavior was dosedependently reduced by nicotine administration, with the serenic effect of a moderate dose (0.25 mg/kg) eliminated by the a7 nAChR antagonist MLA but not by the heteromeric nAChR antagonist DHbE. We further found dose-dependent serenic effects of the a7 nAChR partial agonist GTS-21 in BALB/c mice, a low sociability and moderately aggressive mouse strain. GTS-21 was further evaluated to identify its effects on locomotor activity, sociability with conspecifics, and regulation of neuronal activity in brain regions important for regulation of aggression. Conclusion: Selective activation of the a7 nAChR may be a promising therapeutic avenue for reducing aggressive behavior. Furthermore, as multiple a7 nAChRs agonists are well tolerated in
Poster abstracts / Biochemical Pharmacology 97 (2015) 621–636
2.7 Nicotinic modulation of auditory evoked potential electroencephalography in a rodent neurodevelopmental model of schizophrenia Kathy L. Kohlhaas, Holly M. Robb, Victoria A. Roderwald, Lynne E. Rueter AbbVie, Inc., North Chicago, IL, USA Schizophrenia is a chronic disease that has been hypothesized to be linked to neurodevelopmental abnormalities. Schizophrenia patients exhibit impairments in basic sensory processing including sensory gating deficits in P50 and mismatch negativity (MMN). Neuronal nicotinic acetylcholine receptor (nAChR) agonists have been reported to attenuate these deficits. Gestational exposure of rats to methylazoxymethanol acetate (MAM) at embryonic day 17 leads to developmental disruption of the limbic-cortical system. MAM exposed offspring show neuropathological and behavioral changes that have similarities with those seen in schizophrenia. In this study, we aimed to assess whether N40 auditory sensory gating (the rodent form of P50 gating) and MMN deficits as measures of auditory evoked potential (AEP) electroencephalography (EEG) are present in MAM rats and whether nAChR agonists could attend the deficit. E17 male MAM and sham rats were implanted with cortical electrodes at two months of age. EEG recordings evaluating N40 gating and MMN paradigms were done comparing effects of vehicle (saline), nicotine and the a7 agonist ABT-107. Deficits were seen for MAM rats compared to sham animals in both N40 auditory sensory gating and MMN AEP recordings. There was a strong trend for N40 deficits to be attenuated by both nicotine (0.16 mg/kg i.p. base) and ABT-107 (1.0 mg/kg i.p. base). MMN deficits were significantly attenuated by ABT-107 but not by nicotine. These data support the MAM model as a useful tool for translating pharmacodynamic effects in clinical medicine studies of novel therapeutic treatments for schizophrenia. http://dx.doi.org/10.1016/j.bcp.2015.08.032 2.8 The nicotinic receptor modulator, lynx2, controls anxiety via regulation of the cholinergic system Kristin R. Anderson, Huaixing Wang, Julie M. Miwa Department of Biological Sciences, Lehigh University, Bethlehem, PA, USA Among the most disruptive aspects to daily functioning in modern society are a group of anxiety disorders. The anxiety response is a normal and advantageous reaction to a stressor but disorders can develop when individuals cannot return to baseline once the stressor has resolved. Due to a lack of full understanding of the biological underpinnings of anxiety, current anxiety treatments only temporarily relieve the symptoms without treating the cause. Interestingly, many anxiety sufferers selfmedicate by smoking, suggesting a role of the cholinergic system in anxiety modulation. We are using a candidate gene approach to uncover these underpinnings, focusing on the role of a cholinergic modulator, lynx2, highly expressed in the basolateral aspect of the anxiety structure, the amygdala (BLA). Lynx2 proteins bind to and suppress cholinergic receptors (nAChRs). Consistent with its high expression, mice lacking lynx2 (lynx2KO), demonstrate elevated anxiety levels across several assays (light-dark, open-field, etc.). We hypothesize that experience-dependent plasticity in the amygdala plays a role in the return to baseline state, and that this is
subject to cholinergic modulation. To address this, we are performing behavioral pharmacological studies in lynx2KO mice to measure anxiety responses along with electrophysiology studies. Sensitivity to nicotine is augmented in lynx2KO mice in both the light/dark assay and slice physiology. Further investigations into the specific nAChR subtypes are being conducted with several specific inhibitors and uncovering a shift in receptor subtype without lynx2 presence, suggesting a role for lynx2 in receptor subunit composition. Synaptic plasticity is altered in the BLA between wild-type and lynx2KO mice and normalcy could be restored by pharmacological manipulation of nAChRs. These data suggest that addressing synaptic plasticity may be a promising avenue by which to return individuals back to baseline states. To address this further, fear extinction is being used to assess modification of the fear response over time. Understanding of how amygdalar output can be altered by lynx and cholinergic pathways could help in the development of treatments for anxiety disorders such as PTSD. http://dx.doi.org/10.1016/j.bcp.2015.08.033
2.9 Reduction of aggressive behavior in mouse models by the selective a7 nicotinic partial agonist GTS-21 Alan S. Lewis, Katherine Garvey, Yann S. Mineur, Marina R. Picciotto Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Background: Aggressive behavior often complicates the treatment of many neuropsychiatric disorders, especially neurodevelopmental and neurodegenerative disorders. Levels and signaling of nicotinic acetylcholine receptors (nAChRs) are altered in many of these conditions. Previous studies have demonstrated that acute administration of nicotine can reduce aggression in animal models. We therefore hypothesized that pharmacological agents active at specific nAChR subunits might be therapeutic for aggression occurring in these conditions. To that end, we sought to identify the molecular basis for nicotine’s anti-aggressive (‘‘serenic’’) effect, and to characterize the effects of GTS-21, an a7 nAChR partial agonist, on aggression in mouse models. Methods: Aggressive behavior was quantified using socially isolated adult male C57BL/6 and BALB/c mice in a resident-intruder paradigm. Nicotine or GTS-21 was administered i.p. 10 min prior to initiation of resident-intruder tests. Antagonists (DHbE, 3 mg/kg, or MLA, 5 mg/kg) were administered i.p. 15 min prior to nicotine or GTS-21. Social interaction and locomotor testing was performed using a Noldus EthovisionXT system. c-Fos expression was quantified as a marker of neuronal activity. Results: As previously reported, aggressive behavior was dosedependently reduced by nicotine administration, with the serenic effect of a moderate dose (0.25 mg/kg) eliminated by the a7 nAChR antagonist MLA but not by the heteromeric nAChR antagonist DHbE. We further found dose-dependent serenic effects of the a7 nAChR partial agonist GTS-21 in BALB/c mice, a low sociability and moderately aggressive mouse strain. GTS-21 was further evaluated to identify its effects on locomotor activity, sociability with conspecifics, and regulation of neuronal activity in brain regions important for regulation of aggression. Conclusion: Selective activation of the a7 nAChR may be a promising therapeutic avenue for reducing aggressive behavior. Furthermore, as multiple a7 nAChRs agonists are well tolerated in