title: GABAB receptor-positive modulators: brain region-dependent effects.
abstract: This study examined the positive modulatory properties of 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) at γ-aminobutyric acid B (GABA(B)) receptors in different brain regions. Using quantitative autoradiography, we measured GABA(B) receptor-stimulated binding of guanosine 5'-O-(3-[³⁵S]thiotriphosphate) ([³⁵S]GTPγS) to G proteins in medial prefrontal cortex (mPFC), hippocampus, and cerebellum. CGP7930 and rac-BHFF enhanced baclofen-stimulated [³⁵S]GTPγS binding similarly in mPFC and hippocampus, but were more effective in cerebellum. CGP7930 (100 μM) increased [³⁵S]GTPγS binding stimulated by baclofen (30 μM) from 29 to 241% above basal in mPFC and from 13 to 1530% above basal in cerebellum. Likewise, rac-BHFF (10 μM) increased baclofen-stimulated [³⁵S]GTPγS binding more in cerebellum (from 13 to 1778% above basal) than in mPFC (from 29 to 514% above basal). rac-BHFF (10 μM) in combination with γ-hydroxybutyrate (20 mM) increased [³⁵S]GTPγS binding in cerebellum but not in mPFC. rac-BHFF also enhanced the effects of 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP35348). Consistent with its partial agonist properties, CGP35348 stimulated [³⁵S]GTPγS binding in mPFC when given alone (to 18% above basal), but less extensively than baclofen (140% above basal), and antagonized baclofen when given together. CGP35348 (1 mM) in combination with rac-BHFF (100 μM) produced an increase in [³⁵S]GTPγS binding that was larger in cerebellum (from 61 to 1260% above basal) than in mPFC (from 18 to 118% above basal). Taken together, the results show that GABA(B) receptor-positive modulators enhance [³⁵S]GTPγS binding stimulated by GABA(B) receptor agonists in a brain region-dependent manner. This regionally selective enhancement is further evidence of pharmacologically distinct GABA(B) receptor populations, possibly allowing for more selective therapeutic targeting of the GABA(B) system.
authors.affiliation: Department of Pharmacology, MC 7764, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. hensler@uthscsa.edu
authors.forename: Julie G
authors.initials: JG
authors.lastname: Hensler
authors.forename: Tushar
authors.initials: T
authors.lastname: Advani
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Burke
authors.forename: Kejun
authors.initials: K
authors.lastname: Cheng
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Wouter
authors.initials: W
authors.lastname: Koek
mesh_terms: D000818:Animals; D001345:Autoradiography; D001418:Baclofen / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D010636:Phenols / Q000494:pharmacology; D018080:Receptors, GABA-B / Q000187:drug effects*; D012978:Sodium Oxybate / Q000494:pharmacology
chemical_list: C532129:(R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one; C438607:2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)phenol; D001572:Benzofurans; D018755:GABA Agonists; D018757:GABA Modulators; D010636:Phenols; D018080:Receptors, GABA-B; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D012978:Sodium Oxybate; D001418:Baclofen