ACTH-like neurotropic peptides: possible regulators of rat brain cyclic AMP.
The influence of behaviorally active, N-terminal fragments of ACTH on the accumulation of cAMP in rat brain investigated in broken cell preparations of subcortical tissue, in slices of neostriatum and in vivo. ACTH1--24 has a biphasic effect on the activity of adenylate cyclase in broken cell preparations of rat brain subcortical tissue: concentrations below 25 micrometer stimulated, whereas concentrations of 0.1 mM and higher inhibited adenylate cyclase activity. The magnitude of the stimulation was dependent on the concentrations of ATP and Mg2+ in the incubation medium. Structure activity studies revealed that at a concentration of 10(-4) M ACTH1--16-NH2 and ACTH4--7 also inhibited the activity of adenylate cyclase, whereas ACTH11--24, ACTH1--10, ACTH4--10, [D-Phe7]ACTH1--10 and [D-Phe7]ACTH4--10 were inactive in this respect. Addition of 0.8 mM EGTA but not of 0.25 mM Ca2+ prevented the inhibition by 10(-4) M ACTH1--24. GMP-N-P (10(-5) M), naltrexone (10(-3) M) and ergometrine (10(-3) M) did not influence the inhibitory effect. ACTH1--24 enhanced the accumulation of cAMP in slices from rat brain neostriatum in a dose-dependent manner. This effect was already maximal 7.5 min after the addition of the peptide and was potentiated by isobutylmethylxanthine, a potent inhibitor or phosphodiesterase. Intraventricular injection of 1 microgram ACTH1--16-NH2 in rats significantly elevated (+ 27%) the concentration of cAMP in the septal region 60 min after the injection of the peptide. The results are discussed in terms of a possible involvement of cAMP as a second messenger in the central nervous system for N-terminal fragments of ACTH.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000008:administration & dosage / Q000502:physiology*; D000818:Animals; D001931:Brain Mapping; D002118:Calcium / Q000494:pharmacology; D003342:Corpus Striatum / Q000201:enzymology; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology*; D051381:Rats; D011953:Receptors, Cyclic AMP / Q000187:drug effects; D013329:Structure-Activity Relationship
D000067956:Adenylyl Cyclase Inhibitors; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011953:Receptors, Cyclic AMP; D000255:Adenosine Triphosphate; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D008274:Magnesium; D002118:Calcium