GABAB Receptor-Positive Modulators: Brain Region-Dependent Effects

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-3 H -benzofuran-2-one (rac-BHFF) at γ-aminobutyric acid B (GABAB) receptors in different brain regions. Using quantitative autoradiography, we measured GABAB 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 GABAB receptor-positive modulators enhance [35S]GTPγS binding stimulated by GABAB receptor agonists in a brain region-dependent manner. This regionally selective enhancement is further evidence of pharmacologically distinct GABAB receptor populations, possibly allowing for more selective therapeutic targeting of the GABAB system.