Abstract
The dorsal raphe nucleus (DRN) is the origin of ascending serotonergic projections and is considered to be an important component of the brain circuit that mediates anxiety- and depression-related behaviors. A large fraction of DRN serotonin-positive neurons contain nitric oxide (NO). Disruption of NO-mediated neurotransmission in the DRN by NO synthase inhibitors produces anxiolytic- and antidepressant-like effects in rats and also induces nonspecific interference with locomotor activity. We investigated the involvement of the 5-HT(1A) autoreceptor in the locomotor effects induced by NO in the DRN of male Wistar rats (280-310 g, N = 9-10 per group). The NO donor 3-morpholinosylnomine hydrochloride (SIN-1, 150, and 300 nmol) and the NO scavenger S-3-carboxy-4-hydroxyphenylglycine (carboxy-PTIO, 0.1-3.0 nmol) were injected into the DRN of rats immediately before they were exposed to the open field for 10 min. To evaluate the involvement of the 5-HT(1A) receptor and the N-methyl-D-aspartate (NMDA) glutamate receptor in the locomotor effects of NO, animals were pretreated with the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 8 nmol), the 5-HT(1A) receptor antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-2-pyridinyl-cyclohexanecarboxamide maleate (WAY-100635, 0.37 nmol), and the NMDA receptor antagonist DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 nmol), followed by microinjection of SIN-1 into the DRN. SIN-1 increased the distance traveled (mean ± SEM) in the open-field test (4431 ± 306.1 cm; F(7,63) = 2.44, P = 0.028) and this effect was blocked by previous 8-OH-DPAT (2885 ± 490.4 cm) or AP7 (3335 ± 283.5 cm) administration (P < 0.05, Duncan test). These results indicate that 5-HT(1A) receptor activation and/or facilitation of glutamate neurotransmission can modulate the locomotor effects induced by NO in the DRN.
Highlights
Inhibition of the nitric oxide (NO) signaling pathway in the brain has been reported to induce anxiolytic- and antidepressant-like effects in animal models
Ulak et al [5] have shown that depletion of endogenous 5-HT or the antagonism of 5-HT2 receptor prevented the antidepressant-like effect of 1-(2-trifluoromethylphenyl)-imidazole (TRIM), an neuronal NOS (nNOS) inhibitor, implying that the antidepressant effects of TRIM might be mediated by an interaction with 5-HT2 receptors. 5-HT2 receptors have been shown to mediate an increase in the hippocampal NO synthase (NOS) activity induced by imipramine withdrawal in rats [6]
These results suggest that 5-HT1A receptors in the dorsal raphe nucleus (DRN) may mediate the effects of NO on locomotor activity
Summary
Inhibition of the nitric oxide (NO) signaling pathway in the brain has been reported to induce anxiolytic- and antidepressant-like effects in animal models. The same compounds and the soluble guanylyl cyclase inhibitors methylene blue [3] dose-dependently reduce immobility time in the forced swimming test, a preclinical behavioral method for detecting antidepressant-like activity of drugs. The behavioral effects of NOS inhibitors appear to depend on endogenous serotonin (5-hydroxytryptamine, 5-HT). Kg potentiate the behavioral effects of imipramine and fluoxetine but not reboxetine, a norepinephrine reuptake inhibitor, in the forced swimming test [4]. Ulak et al [5] have shown that depletion of endogenous 5-HT or the antagonism of 5-HT2 receptor prevented the antidepressant-like effect of 1-(2-trifluoromethylphenyl)-imidazole (TRIM), an nNOS inhibitor, implying that the antidepressant effects of TRIM might be mediated by an interaction with 5-HT2 receptors. 5-HT2 receptors have been shown to mediate an increase in the hippocampal NOS activity induced by imipramine withdrawal in rats [6].
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