KAVAPYRONE ENRICHED EXTRACT FROM PIPER METHYSTICUM AS MODULATOR OF THE GABA BINDING-SITE IN DIFFERENT REGIONS OF RAT-BRAIN

Regional differences in the modulation of [H-3] muscimol binding to GA BA(A) receptor complexes by kavapyrones, compounds of the rhizome of t he plant Piper methysticum which possess sedative activity, were demon strated using membrane fractions obtained from target brain centers of kavapyrone action: hippocampus (HIP), amygdala (AMY) and medulla oblo ngata (MED), and from brain centers outside the main kavapyrone effect s as frontal cortex (FC) and cerebellum (CER). The kava extract enhanc ed the binding of [H-3] muscimol in a concentration-dependent manner w ith maximal potentiation of 358% over control in HIP followed by AMY a nd MED (main target brain centers). Minimal stimulation was observed i n CER followed by FC. In contrast, apart from CER, the potency of kava pyrones was similar in the brain areas investigated with EC(50) values ranging between 200 and 300 mu M kavapyrones. Scatchard analysis reve aled that the observed effects of kavapyrones were due to an increase in the number of binding sites (B-max), rather than to a change in aff inity. At a kavapyrone concentration of 500 mu M the order of enhancem ent in B-max was HIP AMY > MED > FC > CER. When kavapyrones are includ ed together with pentobarbital or HPO the two classes of compounds pro duced a more than additive, i.e., synergetic effect on [H-3] muscimol binding. Our findings suggest that one way kavapyrones might mediate s edative effects in vivo is through effects on GABA(A) receptor binding .