Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induce...d behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.
TY - JOUR
AU - Piantadosi, Sean C.
AU - French, Beverly J.
AU - Poe, Michael M.
AU - Timić, Tamara
AU - Marković, Bojan
AU - Pabba, Mohan
AU - Seney, Marianne L.
AU - Oh, Hyunjung
AU - Orser, Beverley A.
AU - Savić, Miroslav
AU - Cook, James M.
AU - Sibille, Etienne
PY - 2016
UR - http://farfar.pharmacy.bg.ac.rs/handle/123456789/2633
AB - Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.
PB - Frontiers Media Sa, Lausanne
T2 - Frontiers in Pharmacology
T1 - Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator
VL - 7
DO - 10.3389/fphar.2016.00446
ER -
@article{
author = "Piantadosi, Sean C. and French, Beverly J. and Poe, Michael M. and Timić, Tamara and Marković, Bojan and Pabba, Mohan and Seney, Marianne L. and Oh, Hyunjung and Orser, Beverley A. and Savić, Miroslav and Cook, James M. and Sibille, Etienne",
year = "2016",
url = "http://farfar.pharmacy.bg.ac.rs/handle/123456789/2633",
abstract = "Rationale: Current first-line treatments for stress related disorders such as major depressive disorder (MDD) act on monoaminergic systems and take weeks to achieve a therapeutic effect with poor response and low remission rates. Recent research has implicated the GABAergic system in the pathophysiology of depression, including deficits in interneurons targeting the dendritic compartment of cortical pyramidal cells. Objectives: The present study evaluates whether SH-053-2'F-R-CH3 (denoted "alpha 5-PAM"), a positive allosteric modulator selective for (alpha 5-subunit containing GABA(A) receptors found predominantly on cortical pyramidal cell dendrites, has anti stress effects. Methods: Female and male C57BL6/J mice were exposed to unpredictable chronic mild stress (UCMS) and treated with alpha 5-PAM acutely (30 min prior to assessing behavior) or chronically before being assessed behaviorally. Results: Acute and chronic alpha 5-PAM treatments produce a pattern of decreased stress induced behaviors (denoted as "behavioral emotionality") across various tests in female, but not in male mice. Behavioral Z-scores calculated across a panel of tests designed to best model the range and heterogeneity of human symptomatology confirmed that acute and chronic alpha 5-PAM treatments consistently produce significant decreases in behavioral emotionality in several independent cohorts of females. The behavioral responses to alpha 5-PAM could not be completely accounted for by differences in drug brain disposition between female and male mice. In mice exposed to UCMS, expression of the Gabra5 gene was increased in the frontal cortex after acute treatment and in the hippocampus after chronic treatment with alpha 5-PAM in females only, and these expression changes correlated with behavioral emotionality. Conclusion: We showed that acute and chronic positive modulation of alpha 5 subunit containing GABA(A) receptors elicit anti-stress effects in a sex-dependent manner, suggesting novel therapeutic modalities.",
publisher = "Frontiers Media Sa, Lausanne",
journal = "Frontiers in Pharmacology",
title = "Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator",
volume = "7",
doi = "10.3389/fphar.2016.00446"
}
Piantadosi SC, French BJ, Poe MM, Timić T, Marković B, Pabba M, Seney ML, Oh H, Orser BA, Savić M, Cook JM, Sibille E. Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator. Frontiers in Pharmacology. 2016;7
Piantadosi, S. C., French, B. J., Poe, M. M., Timić, T., Marković, B., Pabba, M., Seney, M. L., Oh, H., Orser, B. A., Savić, M., Cook, J. M.,& Sibille, E. (2016). Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator.
Frontiers in PharmacologyFrontiers Media Sa, Lausanne., 7.
https://doi.org/10.3389/fphar.2016.00446
Piantadosi Sean C., French Beverly J., Poe Michael M., Timić Tamara, Marković Bojan, Pabba Mohan, Seney Marianne L., Oh Hyunjung, Orser Beverley A., Savić Miroslav, Cook James M., Sibille Etienne, "Sex-Dependent Anti-Stress Effect of an alpha 5 Subunit Containing GABA(A) Receptor Positive Allosteric Modulator" 7 (2016),
https://doi.org/10.3389/fphar.2016.00446 .
