Abstract
The benzodiazepines flunitrazepam, diazepam, and Ro 15-1788 and the β-carboline DMCM bind with equivalent affinity to the benzodiazepine binding site of GABAA receptors containing different α subunits (i.e., α1, α2, α3, or α5); whereas, the triazolopyridazine CL 218,872 and imidazopyridine zolpidem have higher affinity for α1 subunit-containing GABAA receptors. In the present study, the in vivo binding of [3H]Ro 15-1788 in mouse cerebellum and spinal cord was used to establish the occupancy of the benzodiazepine binding site of GABAA receptors containing primarily α1 and α2/α3 subunits, respectively. Thus, the nonselective compounds flunitrazepam, diazepam, and DMCM all produced a similar inhibition of binding in cerebellum and spinal cord (respective ID50 values of 0.2 to 0.3 mg/kg, 2 mg/kg, and 10 mg/kg IP); whereas, the α1 selective compounds CL 218,872 and zolpidem were more potent at inhibiting [3H]Ro 15-1788 binding in the cerebellum (ID50 values 4.5 mg/kg and 10 mg/kg IP) compared to the spinal cord (ID50 values 12 mg/kg and >30 mg/kg IP). Thus, the reduction of in vivo f [3H]Ro 15-1788 binding in tissues containing α1 and α2/α3 receptor populations reflects the in vitro affinities of subtype selective compounds and should help to interpret the behavioral profile of such compounds.
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Atack, J., Smith, A., Emms, F. et al. Regional Differences in the Inhibition of Mouse In Vivo [3H]Ro 15-1788 Binding Reflect Selectivity for α1 versus α2 and α3 Subunit-Containing GABAA Receptors. Neuropsychopharmacol 20, 255–262 (1999). https://doi.org/10.1016/S0893-133X(98)00052-9
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DOI: https://doi.org/10.1016/S0893-133X(98)00052-9
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