title: Guanosine Anxiolytic-Like Effect Involves Adenosinergic and Glutamatergic Neurotransmitter Systems.
abstract: Accumulating evidences indicate that endogenous modulators of excitatory synapses in the mammalian brain are potential targets for treating neuropsychiatric disorders. Indeed, glutamatergic and adenosinergic neurotransmissions were recently highlighted as potential targets for developing innovative anxiolytic drugs. Accordingly, it has been shown that guanine-based purines are able to modulate both adenosinergic and glutamatergic systems in mammalian central nervous system. Here, we aimed to investigate the potential anxiolytic-like effects of guanosine and its effects on the adenosinergic and glutamatergic systems. Acute/systemic guanosine administration (7.5 mg/kg) induced robust anxiolytic-like effects in three classical anxiety-related paradigms (elevated plus maze, light/dark box, and round open field tasks). These guanosine effects were correlated with an enhancement of adenosine and a decrement of glutamate levels in the cerebrospinal fluid. Additionally, pre-administration of caffeine (10 mg/kg), an unspecific adenosine receptors' antagonist, completely abolished the behavioral and partially prevented the neuromodulatory effects exerted by guanosine. Although the hippocampal glutamate uptake was not modulated by guanosine (both ex vivo and in vitro protocols), the synaptosomal K+-stimulated glutamate release in vitro was decreased by guanosine (100 μM) and by the specific adenosine A1receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA, 100 nM). Moreover, the specific adenosine A1receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 100 nM) fully reversed the inhibitory guanosine effect in the glutamate release. The pharmacological modulation of A2areceptors has shown no effect in any of the evaluated parameters. In summary, the guanosine anxiolytic-like effects seem closely related to the modulation of adenosinergic (A1receptors) and glutamatergic systems.
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Roberto Farina
authors.initials: RF
authors.lastname: Almeida
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Daniel Diniz
authors.initials: DD
authors.lastname: Comasseto
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Denise Barbosa
authors.initials: DB
authors.lastname: Ramos
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Hansel
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.|Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.
authors.forename: Eduardo R
authors.initials: ER
authors.lastname: Zimmer
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.
authors.forename: Samanta Oliveira
authors.initials: SO
authors.lastname: Loureiro
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil.|Neurobiology Department, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Ganzella
authors.affiliation: Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-anexo, 90035-003, Porto Alegre, RS, Brazil. diogo@ufrgs.br.
authors.forename: Diogo Onofre
authors.initials: DO
authors.lastname: Souza
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D058916:Adenosine A1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006151:Guanosine / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism*
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D014151:Anti-Anxiety Agents; D018377:Neurotransmitter Agents; D043682:Receptor, Adenosine A1; D006151:Guanosine; D018698:Glutamic Acid; D000241:Adenosine
keywords: Adenosine receptors; Anxiety; Glutamate; Glutamate release; Guanosine; Purines