Differential contribution of H3R antagonism by LINS01 compounds on memory, anxiety-like behaviour and spontaneous locomotor activity in healthy rats

Autor(es)

Soliani, Andressa ^[1] ; Kubota, Silvia Megumi ^[1] ; Correa, Michelle Fidelis ^[2] ; Cerutti, Suzete Maria ^[1] ; Fernandes, Joao Paulo S. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Biol Sci, Cellular & Behav Pharmacol Lab, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil

^[2] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Behavioural Brain Research; v. 377, JAN 13 2020.
• Citações Web of Science: 0

Resumo

Histamine H-3 receptors (H3R) have attracted interest of research groups as drug target to several CNS disorders. Data suggests that H3R antagonists exert neuroprotective, cognitive enhancement and antidepressant effects in rodents. The LINS01 compounds were reported as selective H3R antagonists, but their effects on memory, anxiety-like behaviour and spontaneous locomotor activity were not evaluated to date. Therefore, this study employed the plus-maze discriminative avoidance task (PM-DAT) to assess concomitantly the effects of LINS01 compounds on short- and long-term memory, anxiety-like behaviour and spontaneous locomotor activity. Thirtyeight adult male Wistar rats were divided into five groups (n= 7-8 per group) according to the treatment. The animals were treated with donepezil (1 mg/kg) and clobenpropit (3 mg/kg) (reference compounds), and with two LINS01 compounds at doses of 5 mg/kg (LINS01003 and LINS01004), and then submitted to the PM-DAT protocol. Saline (vehicle) was used as control group. The behavioural data showed that anxiety-like behaviour, spontaneous locomotor activity and memory effects (short- and long-term) were not affected by the treatment with LINS01004 or clobenpropit. Conversely, treatment with LINS01003 and donepezil impaired the maintenance of discriminative avoidance long-term memory, a hippocampal-dependent memory. Donepezil-treated rats also showed decreased spontaneous locomotor activity and anxiolytic-like effects. In summary, considering that hippocampal damage and memory impairment are associated with Alzheimer's disease (AD), this work brought important findings regarding the contribution of the histamine system to the effects of LINS01 compounds on memory, anxiety and motility, and suggests that H3R antagonism had no effects on anxiety-like behaviour and do not impair discriminative avoidance memory. Furthermore, the findings herein raise new questions about donepezil's function in an ``impaired{''} system such as AD, since it prevented the long-term memory formation in healthy rats. (AU)

• Processo FAPESP: 16/18039-9 - Participação da formação hipocampal na aquisição, consolidação, evocação e extinção da supressão condicionada: caracterização de eventos bioquímicos e correlações clínicas
• Beneficiário: Suzete Maria Cerutti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/25028-3 - Anti-histamínicos H3R/H4R como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/23139-2 - Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: Michelle Fidelis Corrêa
• Modalidade de apoio: Bolsas no Brasil - Doutorado