Nitric oxide synthase inhibitors have antidepressant-like properties in mice 2.: Chronic treatment results in downregulation of cortical β-adrenoceptors

Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [H-3]dihydroalprenolol binding to cortical beta-adrenoceptors was examined in mice treated with the nitric oxide (NO) synthase antagonist N-G-nitro-L-arginine (L-NNA). Administration of L-NNA (0.1, 0.3 mg/kg) for 21 days produced a significant reduction (28%, 31%, respectively, P < 0.05) in [H-3]dihydroalprenolol binding to cortical membranes without affecting K-d. Dose 1 mg/kg of L-NNA given chronically also produced a 20% decrease in beta-adrenoceptor density, but this effect was not statistically significant. While chronic treatment with imipramine (15 and 30 mg/kg) produced respectively a 30% and 25% (P < 0.05) reduction in the density of [H-3]dihydroalpenolol, single injection of either imipramine (15 and 30 mg/kg) or L-NNA (0.1, 0.3, and 1 mg/kg) had no effect on [H-3]dihydroalprenolol binding. These findings are consistent with the hypothesis that drugs which can affect the Ca2+-calmodulin/nitric oxide synthase/guanylyl cyclase signaling pathway may represent a novel approach to the treatment of depression and are congruent with our previous observation, which has demonstrated the antidepressant-like properties of NO synthase inhibitors in the forced swim test. (C) 1999 Elsevier Science B.V. All rights reserved.