Regional differences in the inhibition of mouse in vivo [H-3]Ro 15-1788 binding reflect selectivity for alpha(1) versus alpha(2) and alpha(3) subunit-containing GABA(A) receptors

The benzodiazepines flunitrazepam, diazepam, and Xo 15-1788 and the beta-ca rboline DMCM bind with equivalent affinity to the benzodiazepine binding si te of GABA(A) receptors containing different alpha subunits (i.e., alpha(1) , alpha(2), alpha(3), or alpha(5)); whereas, the triazolopyridazine CL 218, 872 and imidazopyridine zolpidem have higher affinity for at subunit-contai ning GABAA receptors. In the present study, the in vivo binding of [H-3]Ro 15-1788 in mouse cerebellum and spinal cord was used to establish the occup ancy of the benzodiazepine binding site of GABA(A) receptors containing pri marily alpha(1) and alpha(2)/alpha(3) subunits, respectively. Thus, the non selective compounds flunitrazepam, diazepam, and DMCM all produced a simila r inhibition of binding in cerebellum and spinal card (respective ID50 valu es of 0.2 to 0.3 mg/kg, 2 mg/kg, and 10 mg/kg IP); whereas, the alpha(1) se lective compounds CL 218,872 and zolpidem were move potent at inhibiting [H -3]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). T hus, the reduction of in vivo f [H-3]Ro 15-1788 binding in tissues containi ng a, and a,lcr, receptor populations reflects the in vitro affinities of s ubtype selective compounds and should help to interpret the behavioral prof ile of such compounds. [Neturopsychopharmacology 20:255-262, 1999] (C) 1999 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.