title: Ethanol withdrawal induces anxiety-like effects: Role of nitric oxide synthase in the dorsal raphe nucleus of rats.
abstract: Nitric oxide (NO) mediated transmission in the dorsal raphe nucleus (DRN) has been shown to be involved in the modulation of anxiety-like behaviors. We investigated whether inhibition of nitric oxide synthase (NOS) in the DRN would prevent anxiety-like behavior induced by ethanol withdrawal. Male Wistar rats were treated with ethanol 2-6% (v/v) for a period of 21 days. Ethanol withdrawal was induced by abrupt discontinuation of the treatment. Experiments were performed 48 h after ethanol discontinuation. Rats with a guide cannula aimed at the DRN received intra-DRN injections of the non-selective NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME), selective neuronal NOS (nNOS) inhibitor N(ω)-propyl-l-arginine (NPLA), or selective inhibitor of inducible NOS (iNOS) N-([3-(aminomethyl)phenyl] methyl) ethanimidamidedihydrochloride (1400W). Five minutes later, the animals were tested in the elevated plus maze (EPM). Plasma ethanol levels were determined by gas chromatography. There was a reduction in plasma ethanol levels 48 h after ethanol withdrawal. Rats from the ethanol withdrawal group showed decreased exploration of the open arms of the EPM with no change in the exploration of enclosed arms. Intra-DRN treatment with l-NAME (100 nmoles/0.2 μL) and 1400W (1 nmol/0.2 μL), but not NPLA (10 nmoles/0.2 μL) in the DRN attenuated the decrease in the exploration of the open arms of the EPM induced by ethanol withdrawal. The major new finding of the present study is that iNOS in the DRN plays a role in the anxiety-like behavior induced by ethanol withdrawal.
authors.affiliation: Laboratório de Neurobiologia do Estresse e da Depressão, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-901 Ribeirão Preto, SP, Brazil; Programa de Pós-graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-900, Ribeirão Preto SP, Brazil.
authors.forename: Natália Almeida
authors.initials: NA
authors.lastname: Gonzaga
authors.affiliation: Laboratório de Neurobiologia do Estresse e da Depressão, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Melissa Resende
authors.initials: MR
authors.lastname: Batistela
authors.affiliation: Laboratório de Neurobiologia do Estresse e da Depressão, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Diego
authors.initials: D
authors.lastname: Padovan
authors.affiliation: Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-901 Ribeirão Preto, SP, Brazil.
authors.forename: Bruno Spinosa
authors.initials: BS
authors.lastname: de Martinis
authors.affiliation: Programa de Pós-graduação em Farmacologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-900, Ribeirão Preto SP, Brazil; Escola de Enfermagem de Ribeirão Preto - Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-902 Ribeirão Preto, SP, Brazil; Instituto de Neurociências e Comportamento (INeC), Avenida Bandeirantes, 3900, 14049-901 Ribeirão Preto, SP, Brazil.
authors.forename: Carlos Renato
authors.initials: CR
authors.lastname: Tirapelli
authors.affiliation: Laboratório de Neurobiologia do Estresse e da Depressão, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-901 Ribeirão Preto, SP, Brazil; Instituto de Neurociências e Comportamento (INeC), Avenida Bandeirantes, 3900, 14049-901 Ribeirão Preto, SP, Brazil; Núcleo de Pesquisa em Neurobiologia das Emoções (NUPNE), Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Avenida Bandeirantes, 3900, Cidade Universitária, 14040-900 Ribeirão Preto, SP, Brazil. Electronic address: cpadovan@usp.br.
authors.forename: Cláudia Maria
authors.initials: CM
authors.lastname: Padovan
mesh_terms: D000818:Animals; D001007:Anxiety / Q000201:enzymology* / Q000523:psychology; D065847:Dorsal Raphe Nucleus / Q000187:drug effects / Q000201:enzymology*; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D007276:Injections, Intraventricular; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013375:Substance Withdrawal Syndrome / Q000201:enzymology* / Q000523:psychology
chemical_list: D000431:Ethanol; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
keywords: Anxiety; Dorsal raphe nucleus; Ethanol withdrawal; Nitric oxide