Untitled

Abstract

We have considerable evidence that increased amounts of an endogenous monoamine oxidase inhibitor, which we have called tribulin (Sandler, 1982), are generated in conditions of stress and anxiety. In this study we have investigated the effects of the anxiogenic drugs pentylenetetrazole (PTZ) and ephedrine on tribulin levels in rat brain and heart. Female Wistar ra~ts (approximately 250g) were injected (i.p.) with PTZ (20mg/kg), ephedrine (20mg/kg) or water, 30 min prior to death, or diazepam (1 and 2.5mg/kg) or propranolol (5mg/kg) 60 min before death. When two drugs were administered, a 30 min preadministration period was employed. Rat brains and hearts were rapidly removed, weighed and homogenised (20% w/v) in cold 2M HCl, using an Ultraturrax homogenizer. Homogenates were centrifuged for 10 min at 3,000g and the supernatant extracted into two volumes of redistilled ethyl acetate. The organic layer was removed and dried under nitrogen. Acid blanks were run in parallel throughout the procedure. Residues were reconstituted in 100V1 of 100mM phosphate buffer, pH 7.4 and incubated with 20p1 MAO preparation (1% w/v rat liver homogenate) and 10P1 14C-tyramine (New England Nuclear Corporation); diluted with unlabelled tyramine to give a final concentration of 83pM for 30 min at 37 C. MAO inhibitory activity in rat brain. Diazepam, which had no intrinsic activity, was able to prevent this. Similarly, ephedrine adminiistration brought about raised MAO inhibitory activity in rat brain which could be prevented by prior administration of propranolol. Similar results were found in the heart, although ephedrine did not cause increased MAO I in the heart. We have shown previously that rat urinary tribulin is increased by cold restraint stress, an effect attenuated by benzodiazepines (Glover et al., 1981). These results show that anxiogenic agents can also increase levels of this endogenous MAO inhibitor in rat brain and heart, an effect similarly attenuated by anxiolytic agents. [4,5]decan-7,9-dione methane sulphonate) evolved frpm a programme aimed at the rational design of 5-HTlA receptor ligands using graphics computer assisted technology (Hibert et al., 1986). This report describes the characterisation of MDL 73005EF as a potent and highly selective ligand for 5-HTIA receptors and its activity in a variety of in vitro and in vivo test systems.In a variety of radioligand binding assays (for details see Fozard et al., 1987) MDL 73005EF proved a highly selective displacer of binding to the 5-HTlA recognition site (Table 1). In functional tests the agonist and antagonist activity of MDL 73005EF has been evaluated by its ability to either mimic or reverse the effects of the selective 5-HTIA receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin . On the transmurally stimulated guinea-pig ileum (Fozard and Kilbinger, 1985), MDL 73005EF blocked the 8-OH-DPAT-induced inhibition of the contractile response with a -log KB value of 8.5. The compound was a weak inhibitor of the contractile response (pICl5, 6.7) but achieve...