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Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ at GABA(A) receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA(A) receptors containing α1 and α5 subunits. In contrast, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA(A) receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA(A) receptor positive modulators are dependent on their relative efficacy and affinity at different GABA(A) receptor subtypes.
Atack,
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.
2006, Pubmed
Atack,
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.
2006,
Pubmed Collinson,
Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor.
2002,
Pubmed Crestani,
Trace fear conditioning involves hippocampal alpha5 GABA(A) receptors.
2002,
Pubmed Dixon,
Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates.
2008,
Pubmed Griffiths,
Benzodiazepine self-administration in humans and laboratory animals--implications for problems of long-term use and abuse.
1997,
Pubmed Kleven,
Effects of different classes of partial benzodiazepine agonists on punished and unpunished responding in pigeons.
1999,
Pubmed Licata,
Contribution of GABAA receptor subtypes to the anxiolytic-like, motor, and discriminative stimulus effects of benzodiazepines: studies with the functionally selective ligand SL651498 [6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyridol[3,4-b]indol-1-one].
2005,
Pubmed Löw,
Molecular and neuronal substrate for the selective attenuation of anxiety.
2000,
Pubmed McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed McKernan,
Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.
2000,
Pubmed Millan,
The neurobiology and control of anxious states.
2003,
Pubmed Nutt,
Overview of diagnosis and drug treatments of anxiety disorders.
2005,
Pubmed Olsen,
International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update.
2008,
Pubmed Platt,
Intravenous self-administration techniques in monkeys.
2005,
Pubmed Pritchett,
Type I and type II GABAA-benzodiazepine receptors produced in transfected cells.
1989,
Pubmed Rivas,
Antiseizure activity of novel gamma-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models.
2009,
Pubmed Rowlett,
Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates.
2005,
Pubmed Rowlett,
Anti-conflict effects of benzodiazepines in rhesus monkeys: relationship with therapeutic doses in humans and role of GABAA receptors.
2006,
Pubmed Rudolph,
Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.
1999,
Pubmed Rudolph,
GABA(A) receptor subtypes: dissecting their pharmacological functions.
2001,
Pubmed Savić,
PWZ-029, a compound with moderate inverse agonist functional selectivity at GABA(A) receptors containing alpha5 subunits, improves passive, but not active, avoidance learning in rats.
2008,
Pubmed
,
Xenbase Spealman,
Comparison of drug effects on responding punished by pressurized air or electric shock delivery in squirrel monkeys: pentobarbital, chlordiazepoxide, d-amphetamine and cocaine.
1979,
Pubmed
