ADRENOCORTICOTROPIN ALPHA-MELANOCYTE-STIMULATING HORMONE (ACTH MSH)-LIKE PEPTIDES MODULATE ADENYLATE-CYCLASE ACTIVITY IN RAT-BRAIN SLICES -EVIDENCE FOR AN ACTH MSH RECEPTOR-COUPLED MECHANISM/

The regulation of adenylate cyclase activity by adrenocorticotropin/al pha-melanocyte-stimulating hormone (ACTH/MSH)-like peptides was invest igated in rat brain slices using a superfusion method. Adenylate cycla se activity was concentration-dependently increased by ACTH-(124), alp ha-MSH (EC50 values 16 and 6 nM, respectively), and [Nle4,D-Phe7]alpha -MSH (EC50 value 1.6 nM), in the presence of forskolin (1 muM, optimal concentration). 1-9-Dideoxyforskolin did not augment the response of adenylate cyclase to ACTH-(1-24). Various peptide fragments were teste d for their ability to enhance [H-3]cyclic AMP production. [Nle4,D-Phe 7]alpha-MSH increased [H-3]cyclic AMP formation with a maximal effect of 30% and was more potent than ACTH-(1-24), ACTH-(1-16)-NH2, alpha-MS H, ACTH-(1-13)NH2, [MetO4]alpha-MSH, [MetO2(4),D-Lys8,Phe9]ACTH-(4-9), ACTH-(7-16)-NH2, ACTH-(1-10), and ACTH-(11-24), in order of potency. This structure-activity relationship resembles that found for the prev iously described peptide-induced display of excessive grooming. ACTH-( 1-24) stimulated adenylate cyclase activity in both striatal (maximal effect, approximately 20%) and septal slices (maximal effect, approxim ately 40%), but not in hippocampal or cortical slices. Lesioning of th e dopaminergic projections to the striatum did not result in a diminis hed effect of [Nle4,D-Phe7]alpha-MSH on [H-3]cyclic AMP accumulation, which indicates that the ACTH/MSH receptor-stimulated adenylate cyclas e is not located on striatal dopaminergic terminals. ACTH-(1-24) did n ot affect the dopamine D1 or D2 receptor-mediated modulation of adenyl ate cyclase activity. Based on the present data, we suggest that the b inding of endogenous ACTH or alpha-MSH to a putative ACTH/MSH receptor in certain brain regions leads to the activation of a signal transduc tion pathway using cyclic AMP as a second messenger.