title: Tolerance to repeated stress in rats with lesions of the serotoninergic neurons of the Median Raphe Nucleus and chronically treated with imipramine.
abstract: Repeated exposure to aversive events leads to the development of tolerance to stress, which involves the serotonergic pathway originated in the Median Raphe Nucleus (MnRN) to the Dorsal Hippocampus (DH). However, it is not clear whether these lesion-induced deficits can be attenuated by treatment with antidepressants. Therefore, the aim of this work was to investigate the effects of chronic treatment with Imipramine (IMI) in rats with lesions in the MnRN and exposed to restraint stress. Male Wistar rats with or without neurochemical lesions of the MnRN serotonergic neurons with the neurotoxin 5,7-DHT were submitted to acute (2h) or chronic restraint (2h/day/seven consecutive days) and treated with saline (1 ml/kg) or imipramine (15 mg/kg) via intraperitoneal twice a day during the same period. In acutely restrained rats, stress occurred on the last day of treatment. Test in the elevated plus maze (EPM) was performed 24h later. After EPM test, animals were sacrificed and had their brains removed. Dorsal hippocampus and striatum were dissected and the levels of 5-HT and 5-hydroxy-indoleacetic acid (5-HIAA) measured by HPLC analysis. Our results showed that in control rats exposure to acute restraint stress decreased exploration of the open and enclose arms of the EPM, an effect that was attenuated by imipramine. In rats with 5,7-DHT lesions, acute restraint did not change the exploration of the EPM, independently of the treatment. On the other hand, when chronically restrained, saline treated rat with 5,7-DHT lesion showed a reduced exploration of the open arms of the EPM. This effect was attenuated by simultaneous treatment with imipramine. HPLC analysis showed significantly decreases on 5-HT and 5-HIAA levels in the hippocampus, but not in the striatum. These later results confirm that 5,7-DHT lesions of the MnRN had significant impact on the serotonergic projections to the dorsal hippocampus which seems to be essential for the development of tolerance to repeated stress in the absence of any pharmacological treatment.
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: K
authors.initials: K
authors.lastname: Silva
authors.affiliation: Instituto de Neurociências e Comportamento (INeC), Avenida Bandeirantes, 3900, Ribeirão Preto, SP 14049-901, 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; Laboratório de Psicofarmacologia, 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: M C
authors.initials: MC
authors.lastname: Carvalho
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, Ribeirão Preto, SP 14049-901, 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: C M
authors.initials: CM
authors.lastname: Padovan
mesh_terms: D015115:5,6-Dihydroxytryptamine / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use; D015306:Biogenic Monoamines / Q000378:metabolism; D004361:Drug Tolerance; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D011903:Raphe Nuclei / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D059326:Serotonergic Neurons / Q000187:drug effects*; D018490:Serotonin Agents / Q000633:toxicity; D013315:Stress, Psychological / Q000188:drug therapy*
chemical_list: D000929:Antidepressive Agents, Tricyclic; D015306:Biogenic Monoamines; D018490:Serotonin Agents; D007099:Imipramine; D015115:5,6-Dihydroxytryptamine
keywords: Median raphe nucleus; Restraint stress; Serotonin; Tolerance to stress