The Experts below are selected from a list of 89313 Experts worldwide ranked by ideXlab platform

John R Atack - One of the best experts on this subject based on the ideXlab platform.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for alpha2 and alpha3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Spencer J Tye, Cyrille Sur, Fran Bromidge
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for α2 and α3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Fran Bromidge, Ian Ragan, Julie Kerby
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • anxiogenic properties of an inverse agonist selective for α3 subunit containing gabaa receptors
    British Journal of Pharmacology, 2005
    Co-Authors: John R Atack, Neil Collinson, P H Hutson, George R Marshall, Graham D Bentley, Christopher Moyes, Susan M Cook, Ian Collins, Keith A Wafford, Ruth M Mckernan
    Abstract:

    Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of alpha3IA are most probably mediated by the alpha3 subtype. Alpha3IA has good CNS penetration in rats and mice as measured using a [(3)H]Ro 15-1788 in vivo binding assay. At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. alpha1-containing receptors), alpha3IA (30 mg kg(-1) i.p.), like the nonselective partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). Neurochemically, alpha3IA (30 mg kg(-1) i.p.) as well as FG 7142 (15 mg kg(-1) i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. Taken together, these data demonstrate that an inverse agonist selective for GABA(A) receptors containing an alpha3 subunit is anxiogenic, and suggest that since alpha3-containing GABA(A) receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.

Fran Bromidge - One of the best experts on this subject based on the ideXlab platform.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for α2 and α3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Fran Bromidge, Ian Ragan, Julie Kerby
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for alpha2 and alpha3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Spencer J Tye, Cyrille Sur, Fran Bromidge
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

Susan M Cook - One of the best experts on this subject based on the ideXlab platform.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for alpha2 and alpha3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Spencer J Tye, Cyrille Sur, Fran Bromidge
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for α2 and α3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Fran Bromidge, Ian Ragan, Julie Kerby
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • anxiogenic properties of an inverse agonist selective for α3 subunit containing gabaa receptors
    British Journal of Pharmacology, 2005
    Co-Authors: John R Atack, Neil Collinson, P H Hutson, George R Marshall, Graham D Bentley, Christopher Moyes, Susan M Cook, Ian Collins, Keith A Wafford, Ruth M Mckernan
    Abstract:

    Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of alpha3IA are most probably mediated by the alpha3 subtype. Alpha3IA has good CNS penetration in rats and mice as measured using a [(3)H]Ro 15-1788 in vivo binding assay. At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. alpha1-containing receptors), alpha3IA (30 mg kg(-1) i.p.), like the nonselective partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). Neurochemically, alpha3IA (30 mg kg(-1) i.p.) as well as FG 7142 (15 mg kg(-1) i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. Taken together, these data demonstrate that an inverse agonist selective for GABA(A) receptors containing an alpha3 subunit is anxiogenic, and suggest that since alpha3-containing GABA(A) receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.

Keith A Wafford - One of the best experts on this subject based on the ideXlab platform.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for alpha2 and alpha3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Spencer J Tye, Cyrille Sur, Fran Bromidge
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • tpa023 7 1 1 dimethylethyl 6 2 ethyl 2h 1 2 4 triazol 3 ylmethoxy 3 2 fluorophenyl 1 2 4 triazolo 4 3 b pyridazine an agonist selective for α2 and α3 containing gabaa receptors is a nonsedating anxiolytic in rodents and primates
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: John R Atack, Susan M Cook, Keith A Wafford, Bindi Sohal, Andrew Pike, David Melillo, Linda J Bristow, Fran Bromidge, Ian Ragan, Julie Kerby
    Abstract:

    7-(1,1-Dimethylethyl)-6-(2-ethyl-2 H -1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3- b ]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABAA receptors containing an α1, α2, α3, or α5 subunit but has partial agonist efficacy at the α2 and α3 subtypes and essentially antagonist efficacy at the α1 and α5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1–3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N -methyl-β-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel α2/α3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

  • anxiogenic properties of an inverse agonist selective for α3 subunit containing gabaa receptors
    British Journal of Pharmacology, 2005
    Co-Authors: John R Atack, Neil Collinson, P H Hutson, George R Marshall, Graham D Bentley, Christopher Moyes, Susan M Cook, Ian Collins, Keith A Wafford, Ruth M Mckernan
    Abstract:

    Alpha3IA (6-(4-pyridyl)-5-(4-methoxyphenyl)-3-carbomethoxy-1-methyl-1H-pyridin-2-one) is a pyridone with higher binding and functional affinity and greater inverse agonist efficacy for GABA(A) receptors containing an alpha3 rather than an alpha1, alpha2 or alpha5 subunit. If doses are selected that minimise the occupancy at these latter subtypes, then the in vivo effects of alpha3IA are most probably mediated by the alpha3 subtype. Alpha3IA has good CNS penetration in rats and mice as measured using a [(3)H]Ro 15-1788 in vivo binding assay. At doses in rats that produce relatively low levels of occupancy (12%) in the cerebellum (i.e. alpha1-containing receptors), alpha3IA (30 mg kg(-1) i.p.), like the nonselective partial inverse agonist N-methyl-beta-carboline-3-carboxamide (FG 7142), not only caused behavioural disruption in an operant, chain-pulling assay but was also anxiogenic in the elevated plus maze, an anxiogenic-like effect that could be blocked with the benzodiazepine antagonist Ro 15-1788 (flumazenil). Neurochemically, alpha3IA (30 mg kg(-1) i.p.) as well as FG 7142 (15 mg kg(-1) i.p.) increased the concentration of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in rat medial prefrontal cortex by 74 and 68%, respectively, relative to vehicle-treated animals, a response that mimicked that seen following immobilisation stress. Taken together, these data demonstrate that an inverse agonist selective for GABA(A) receptors containing an alpha3 subunit is anxiogenic, and suggest that since alpha3-containing GABA(A) receptors play a role in anxiety, then agonists selective for this subtype should be anxiolytic.

Christopher A Lowry - One of the best experts on this subject based on the ideXlab platform.

  • Anxiogenic drug administration and elevated plus-maze exposure in rats activate populations of relaxin-3 neurons in the nucleus incertus and serotonergic neurons in the dorsal raphe nucleus.
    Neuroscience, 2015
    Co-Authors: Adam J. Lawther, Christopher A Lowry, Andrew L Gundlach, M.l. Clissold, Stephen Kent, Matthew W. Hale
    Abstract:

    Abstract Anxiety is a complex and adaptive emotional state controlled by a distributed and interconnected network of brain regions, and disruption of these networks is thought to give rise to the behavioral symptoms associated with anxiety disorders in humans. The dorsal raphe nucleus (DR), which contains the majority of forebrain-projecting serotonergic neurons, is implicated in the control of anxiety states and anxiety-related behavior via neuromodulatory effects on these networks. Relaxin-3 is the native neuropeptide ligand for the G i/o -protein-coupled receptor, RXFP3, and is primarily expressed in the nucleus incertus (NI), a tegmental region immediately caudal to the DR. RXFP3 activation has been shown to modulate anxiety-related behavior in rodents, and RXFP3 mRNA is expressed in the DR. In this study, we examined the response of relaxin-3-containing neurons in the NI and serotonergic neurons in the DR following pharmacologically induced anxiety and exposure to an aversive environment. We administered the anxiogenic drug FG-7142 or vehicle to adult male Wistar rats and, 30 min later, exposed them to either the elevated plus-maze or home cage control conditions. Immunohistochemical detection of c-Fos was used to determine activation of serotonergic neurons in the DR and relaxin-3 neurons in the NI, measured 2 h following drug injection. Analysis revealed that FG-7142 administration and exposure to the elevated plus-maze are both associated with an increase in c-Fos expression in relaxin-3-containing neurons in the NI and in serotonergic neurons in dorsal and ventrolateral regions of the DR. These data are consistent with the hypothesis that relaxin-3 systems in the NI and serotonin systems in the DR interact to form part of a network involved in the control of anxiety-related behavior.

  • development environment interactions control tph2 mrna expression
    Neuroscience, 2013
    Co-Authors: Jodi L Lukkes, Matthew W. Hale, Jared M Kopelman, Nina C Donner, Christopher A Lowry
    Abstract:

    Adverse early life experience is thought to increase an individual's susceptibility to mental health disorders, including anxiety and affective disorders, later in life. Our previous studies have shown that post-weaning social isolation of female rats during a critical period of development sensitizes an anxiety-related serotonergic dorsal raphe nucleus (DR) system in adulthood. Therefore, we investigated how post-weaning social isolation, in combination with a challenge with the anxiogenic drug, N-methyl-beta-carboline-3-carboxamide (FG-7142; a partial inverse agonist at the benzodiazepine allosteric site on the GABAA receptor), affects home cage behavior and serotonergic gene expression in the DR of female rats using in situ hybridization histochemistry. Juvenile female rats were reared in isolation or groups of three for a 3-week period from weaning (postnatal day (PD) 21 to mid-adolescence (PD42)), after which all rats were group-reared for an additional 16 days until adulthood. Among vehicle-treated rats, isolation-reared rats had decreased rodent tryptophan hydroxylase 2 (tph2) mRNA expression in ventral and ventrolateral subdivisions of the DR, a pattern observed previously in a rat model of panic disorder. Isolation-reared rats, but not group-reared rats, responded to FG-7142 with increased duration of vigilance and arousal behaviors. In addition, FG-7142 decreased tph2 expression, measured 4h following treatment, in multiple subregions of the DR of group-reared rats but had no effect in isolation-reared rats. No treatment effects were observed on 5-HT1A receptor or serotonin transporter gene expression. These data suggest that adolescent social isolation alters tph2 expression in specific subregions of the DR and alters the effects of stress-related stimuli on behavior and serotonergic systems.

  • multiple anxiogenic drugs recruit a parvalbumin containing subpopulation of gabaergic interneurons in the basolateral amygdala
    Progress in Neuro-psychopharmacology & Biological Psychiatry, 2010
    Co-Authors: Matthew W. Hale, Jolane K Abrams, Anantha Shekhar, Christopher A Lowry, Philip L Johnson, Alex M Westerman
    Abstract:

    Abstract The basolateral amygdala is a nodal structure within a distributed and interconnected network that regulates anxiety states and anxiety-related behavior. Administration of multiple anxiogenic drugs increases cellular responses (i.e., increases c-Fos expression) in a subregion of the basolateral amygdala, but the neurochemical phenotypes of these cells are not known. The basolateral amygdala contains glutamatergic projection neurons and several populations of γ-aminobutyric acid-synthesizing (GABAergic) interneurons, including a population of parvalbumin (PV)-expressing GABAergic interneurons that co-express the excitatory 5-HT 2A receptor. The role for these PV-expressing GABAergic interneurons in anxiety-states is unclear. In this experiment we examined the effects of multiple anxiogenic drugs including the 5-HT 2C/2A receptor agonist m -chlorophenyl piperazine (mCPP), the adenosine receptor antagonist caffeine, the α 2 -adrenoreceptor antagonist yohimbine and the partial inverse agonist at the benzodiazepine allosteric site on the GABA A receptor, N -methyl-beta-carboline-3-carboxamide (FG-7142), on c-Fos expression in PV-immunoreactive (PV-ir) interneurons in subdivisions of the basolateral amygdala. All drugs with the exception of mCPP increased c-Fos expression in PV-ir neurons in the basolateral amygdaloid nucleus, anterior part (BLA). The numbers of c-Fos-immunoreactive (c-Fos-ir)/PV-ir GABAergic interneurons in the BLA were positively correlated with the numbers of c-Fos-ir serotonergic neurons in the mid-rostrocaudal dorsal raphe nucleus (DR) and with a measure of anxiety-related behavior. All four drugs increased c-Fos expression in non-PV-ir cells in most of the subdivisions of the basolateral amygdala that were sampled, compared with vehicle-injected controls. Together, these data suggest that the PV/5-HT 2A receptor expressing GABAergic interneurons in the basolateral amygdala are part of a DR-basolateral amygdala neuronal circuit modulating anxiety-states and anxiety-related behavior.

  • pharmacology of the β carboline fg 7142 a partial inverse agonist at the benzodiazepine allosteric site of the gabaa receptor neurochemical neurophysiological and behavioral effects
    Cns Drug Reviews, 2007
    Co-Authors: Andrew K. Evans, Christopher A Lowry
    Abstract:

    Given the well-established role of benzodiazepines in treating anxiety disorders, beta-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABA(A) receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related physiology and behavior. FG-7,142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the alpha1 subunit-containing GABA(A) receptor, although it is not selective. FG-7,142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the alpha1 subunit-containing GABA(A) receptor. FG-7,142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7,142 has been shown to induce anxiety-related behavioral and physiological responses in a variety of experimental paradigms across numerous mammalian and non-mammalian species, including humans. FG-7,142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7,142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and beta-carboline agonists, and increase the effectiveness of subsequent GABA(A) receptor antagonists and beta-carboline inverse agonists. FG-7,142, as a partial inverse agonist, can help to elucidate individual components of full agonism of benzodiazepine binding sites and may serve to identify the specific GABA(A) receptor subtypes involved in specific behavioral and physiological responses.

  • pharmacology of the beta carboline fg 7 142 a partial inverse agonist at the benzodiazepine allosteric site of the gaba a receptor neurochemical neurophysiological and behavioral effects
    Cns Drug Reviews, 2007
    Co-Authors: Andrew K. Evans, Christopher A Lowry
    Abstract:

    Given the well-established role of benzodiazepines in treating anxiety disorders, beta-carbolines, spanning a spectrum from full agonists to full inverse agonists at the benzodiazepine allosteric site for the GABA(A) receptor, can provide valuable insight into the neural mechanisms underlying anxiety-related physiology and behavior. FG-7,142 is a partial inverse agonist at the benzodiazepine allosteric site with its highest affinity for the alpha1 subunit-containing GABA(A) receptor, although it is not selective. FG-7,142 also has its highest efficacy for modulation of GABA-induced chloride flux mediated at the alpha1 subunit-containing GABA(A) receptor. FG-7,142 activates a recognized anxiety-related neural network and interacts with serotonergic, dopaminergic, cholinergic, and noradrenergic modulatory systems within that network. FG-7,142 has been shown to induce anxiety-related behavioral and physiological responses in a variety of experimental paradigms across numerous mammalian and non-mammalian species, including humans. FG-7,142 has proconflict actions across anxiety-related behavioral paradigms, modulates attentional processes, and increases cardioacceleratory sympathetic reactivity and neuroendocrine reactivity. Both acute and chronic FG-7,142 treatment are proconvulsive, upregulate cortical adrenoreceptors, decrease subsequent actions of GABA and beta-carboline agonists, and increase the effectiveness of subsequent GABA(A) receptor antagonists and beta-carboline inverse agonists. FG-7,142, as a partial inverse agonist, can help to elucidate individual components of full agonism of benzodiazepine binding sites and may serve to identify the specific GABA(A) receptor subtypes involved in specific behavioral and physiological responses.