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 was 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 μM 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 of phosphodiesterase. Intraventricular injection of 1 μg 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. © 1979.