In vivo Quinolinic Acid Increases Synaptosomal Glutamate Release in Rats: Reversal by Guanosine Rejane G. Tavares, 1 Andre´ P. Schmidt, 1 Jamile Abud, 1 Carla I. Tasca, 2 and Diogo O. Souza 1,3 (Accepted March 8, 2005) Glutamate, the main excitatory neurotransmitter in the mammalian central nervous system (CNS), plays important role in brain physiological and pathological events. Quinolinic acid (QA) is a glutamatergic agent that induces seizures and is involved in the etiology of epilepsy. Guanine-based purines (GBPs) (guanosine and GMP) have been shown to exert neuropro- tective effects against glutamatergic excitotoxic events. In this study, the influence of QA and GBPs on synaptosomal glutamate release and uptake in rats was investigated. We had previously demonstrated that QA ‘‘in vitro’’ stimulates synaptosomal L-[ 3 H]glutamate release. In this work, we show that i.c.v. QA administration induced seizures in rats and was able to stimulate synaptosomal L-[ 3 H]glutamate release. This in vivo neurochemical effect was prevented by i.p. guanosine only when this nucleoside prevented QA-induced seizures. I.c.v. QA did not affect synaptosomal L-[ 3 H]glutamate uptake. These data provided new evidence on the role of QA and GBPs on glutamatergic system in rat brain. KEY WORDS: Glutamate release and uptake; Guanosine; Quinolinic acid; Synaptosomal preparations; Seizures. INTRODUCTION Quinolinic acid (QA), an endogenous metabolite of tryptophan, and the importance as a neurotoxin was first evident from work by Lapin (1978), who demonstrated that the administration of QA to mice caused convulsion (1). QA is an agonist of N-methyl- D-aspartate (NMDA) receptors, a synaptosomal glutamate releaser and an inhibitor of vesicular and astrocytic glutamate uptake (2–4). Thus, QA over- stimulates the glutamatergic system, induces seizures and is involved in the etiology of epilepsy (5,6). Additionally, accumulation of QA in the brain seems to be involved in the ethiopathology of convulsions and occurs in patients with hepatic encephalopathy, acquired immune deficiency syndrome (AIDS)-re- lated neurological disorders, and Huntington’s dis- ease (4). In the mammalian central nervous system (CNS), glutamate is the principal neurotransmitter mediating excitatory synaptic events, being essential for normal brain functions (7). The removal of glutamate from the synaptic cleft is an important mechanism for modulating glutamate actions, and also for maintaining its extracellular concentration below neurotoxic levels (8,9). Glutamate uptake processes involve two transport systems located at distinct cellular levels: high affinity Na + -dependent carriers located mainly at astrocytic cell membranes (8–11), and a low affinity Na + -independent carrier 1 Department of Biochemistry, ICBS, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil. 2 Department of Biochemistry, CCB, Federal University of Santa Catarina, Floriano´polis, SC, Brazil. 3 Address reprint requests to: Mr. Diogo O. Souza, Avenida Ramiro Barcelos, 2600-Anexo, CEP 90035-003, Porto Alegre-Rs- Brazil. Tel.: +55-51-3316-5535, Fax: +55-51-3316-5540/55-51- 3316-5535; E-mail: diogo@ufrgs.br Neurochemical Research, Vol. 30, No. 4, April 2005 (Ó 2005), pp. 439–444 DOI: 10.1007/s11064-005-2678-0 439 0364-3190/05/0400–0439/0 Ó 2005 Springer Science+Business Media, Inc.