Hippocampal nNOS inhibition induces an antidepressant-like effect: involvement of 5HT1A receptors.
Systemic as well as hippocampal administration of nNOS inhibitors induces antidepressant-like effects in animal models. However, the mechanisms underlying these effects have not been completely understood. Evidence has suggested that nNOS inhibition increases serotonin signaling in the brain. Moreover, activation of prosencephalic 5HT1A receptors is considered to mediate stress coping and antidepressant effects. On this basis, the aim of this study was to investigate the hypothesis that the antidepressant-like effect induced by nNOS inhibition in the dorsal hippocampus (DH) would involve local serotonergic signaling and 5HT1A receptor activation. Therefore, rats were subjected to the forced swimming test and received microinjections of fluoxetine, NPA (Nω-propyl-L-arginine, selective nNOS inhibitor), WAY100635 (5HT1A antagonist), and vehicle, alone or in combination, into the DH. Exposure to the forced swimming test increased nitric oxide acid levels in the DH. The administration of NPA or fluoxetine in the DH induced dose-dependent antidepressant-like effects. WAY100635 microinjection in the DH did not induce any effect per se, but it counteracted NPA-induced and fluoxetine-induced effects. These results suggest that the antidepressant-like effect induced by the administration of nNOS inhibitors in the DH involves local serotonergic signaling and 5HT1A receptor activation.
aDepartment of Pharmacology, School of Medicine of Ribeirão Preto-FMRP bDepartment of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto-FCFRP cCenter for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Vinicius A
VA
Hiroaki-Sato
Amanda J
AJ
Sales
Caroline
C
Biojone
Sâmia R L
SR
Joca
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013315:Stress, Psychological / Q000188:drug therapy; D013550:Swimming / Q000523:psychology
D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; C109599:N(omega)-propylarginine; D010879:Piperazines; D011725:Pyridines; D012702:Serotonin Antagonists; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D001120:Arginine; D052248:Nitric Oxide Synthase Type I