Nitric oxide synthase inhibitors have antidepressant-like properties in mice. 2. Chronic treatment results in downregulation of cortical beta-adrenoceptors.
Down-regulation of cortical beta-adrenoceptors is observed in rodents following chronic treatment with many clinically effective antidepressant therapies. [3H]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 [3H]dihydroalprenolol binding to cortical membranes without affecting Kd. 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 [3H]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 [3H]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.
Department of Psychiatry, University of Mississippi Medical Center, Jackson 39216-4505, USA. bkarolewicz@psychiatry.umsmed.edu
B
B
Karolewicz
K H
KH
Bruce
B
B
Lee
I A
IA
Paul
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D004082:Dihydroalprenolol / Q000494:pharmacology; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D019335:Nitroarginine / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*
D018759:Adrenergic Uptake Inhibitors; D000319:Adrenergic beta-Antagonists; D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D011943:Receptors, Adrenergic, beta; D019335:Nitroarginine; D004082:Dihydroalprenolol; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D007099:Imipramine