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[摘要]：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-Hbenzofuran-2-one (rac-BHFF) at gamma-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) ([(35)S]GTP gamma S) to G proteins in medial prefrontal cortex (mPFC), hippocampus, and cerebellum. CGP7930 and rac-BHFF enhanced baclofen-stimulated [(35)S]GTP gamma S binding similarly in mPFC and hippocampus, but were more effective in cerebellum. CGP7930 (100 mu M) increased [(35)S]GTP gamma S binding stimulated by baclofen (30 mu M) from 29 to 241% above basal in mPFC and from 13 to 1530% above basal in cerebellum. Likewise, rac-BHFF (10 mu M) increased baclofen-stimulated [35S] GTP gamma S binding more in cerebellum (from 13 to 1778% above basal) than in mPFC (from 29 to 514% above basal). rac-BHFF (10 mu M) in combination with gamma-hydroxybutyrate (20 mM) increased [35S] GTP gamma S 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] GTP gamma S 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 mu M) produced an increase in [35S] GTP gamma S 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] GTP gamma S 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. |
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