Regional specific modulation of neuronal activation associated with nitric oxide synthase inhibitors in an animal model of antidepressant activity.
Behav Brain Res
; 316: 18-28, 2017 01 01.
Article
em En
| MEDLINE
| ID: mdl-27569181
ABSTRACT
OBJECTIVE:
The regional specific modulation of neuronal activation following drug administration is of interest to determine brain areas involved in the behavioural effects of experimental test compounds. In the current investigation the effects of the L-arginine related NOS inhibitor Nω-l-nitroarginine (L-NA) and the structurally unrelated selective neuronal NOS inhibitor 1-(2-Trifluoro-methyl-phenyl) imidazole (TRIM) were assessed in the rat for changes in regional c-FOS immunoreactivity, a marker of neuronal activation, upon exposure to the forced swimming test (FST). Behaviour and regional FOS and FosB/ΔFosB expression was assessed in naive animals and in animals exposed to stress with central serotonin-depletion which exhibit a stress related phenotype in the FST.METHODS:
Male Sprague-Dawley rats (n=5- 6 per group) were treated with the irreversible tryptophan hydroxylase inhibitor, DL-4-p-chlorophenylalanine (pCPA, 150mg/kg, i.p.), to achieve central serotonin-depletion followed by repeated exposures to restraint stress and were then subjected to the FST. 24, 5 and 1h prior to the test, animals were treated with either L-NA (10mg/kg, i.p.), TRIM (50mg/kg, i.p.) or saline vehicle (1mg/kg i.p).RESULTS:
pCPA treatment coupled with restraint stress increased immobility in the FST compared to naïve controls. Both NOS inhibitors decreased immobility time in 5-HT depleted and stressed animals only in keeping with their antidepressant-like properties. Brain regions analyzed for c-FOS immunoreactivity included the pre-limbic cortex, lateral septum (LS), nucleus accumbens, paraventricular hypothalamic nucleus (PVN), central amygdala, hippocampus (dorsal dentate gyrus and ventral CA1), and the dorsal raphe nucleus (DRN). Exposure to the FST increased c-FOS immunoreactivity in the LS, PVN, dentate gyrus, vCA1 and the DRN when compared to non-FST exposed controls. FST-induced c-FOS immunoreactivity was further increased in the LS following treatment with L-NA or TRIM when compared to vehicle-treated FST controls. By contrast, FST-induced c-FOS immunoreactivity was reduced in dorsal dentate gyrus, vCA1 and the DRN following treatment with L-NA or TRIM when compared to vehicle-treated FST controls. There was no difference observed in FST-induced expression of c-FOS between naïve animals and animals exposed to pCPA and restraint stress. This combination however provoked an increase in FosB/ΔFosB immunoreactivity in the infra-limbic cortex and nucleus accumbens with a concomitant reduction in the lateral septum, suggesting alterations to long-term, adaptive neuronal activation.CONCLUSION:
This study identified a pattern of enhanced and reduced FST-related c-FOS immunoreactivity indicative of a NO-regulated network where inhibition of NO leads to activation of the septum with concomitant inhibition of the hippocampus, and the DRN. No link between FST-induced regional expression of c-FOS and increased immobility in the FST was observed in animals exposed to pCPA and stress. However, the 5-HT depletion regime combined with restraint stress provoked regional changes in the expression of ΔFosB which may relate to increased immobility in the FST.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Nitroarginina
/
Depressão
/
Inibidores Enzimáticos
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Behav Brain Res
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Irlanda