Oral administration of guanosine impairs inhibitory avoidance performance in rats and mice

Abstract

Extracellular guanine-based purines, mainly the nucleoside guanosine, have recently been shown to exert neuroprotective effects, which seem to be related to antagonism of the glutamatergic system. In this study, we investigated the effects of acute oral administration of guanosine on inhibitory avoidance task in rats and mice. We also studied its effects on locomotor activity, anxiety-related behaviors and mechanisms of action involving the purinergic system. Guanosine (2.0 and 7.5 mg/kg, per os), administered 75 min pretraining, dose-dependently impaired retention of the inhibitory avoidance task in rats and mice, an effect not prevented by the adenosine receptor antagonist caffeine. Guanosine presented no effects on locomotor activity and anxiety-related behaviors. This amnesic effect of guanosine may be compatible with inhibition of glutamatergic system and seems to be not mediated by adenosine.

Introduction

Glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS) (Ozawa, Kamiya, & Tsuzuki, 1998), modulates several brain functions, and is also implicated in acute and chronic brain disturbances, both in animals and humans (Lipton & Rosemberg, 1994; Rathbone et al., 1999). Physiologically, glutamate plays a crucial role in learning and memory processes. Specifically, NMDA receptors are essential to the initiation of cellular and molecular mechanisms responsible for memory formation (Izquierdo & Medina, 1997; Morris & Davis, 1994), as evidenced by the amnesic effect of NMDA antagonists on inhibitory avoidance (Izquierdo & Medina, 1997; Miserendino, Sananes, Melia, & Davis, 1990; Morris, Anderson, Lynch, & Baudry, 1986).

Intracellular guanine-based purines (GBPs) have been shown to modulate cell transmembrane signals via G-proteins activity (Gudermann, Schorneberg, & Schultz, 1997; Morris & Malbon, 1999). More recently, extracellular GBPs (mainly the nucleoside guanosine) were shown to exert biological effects without a direct interaction with G-proteins, including trophic role in neural cells (Rathbone et al., 1999) and antagonism of the glutamatergic activity (Baron et al., 1989; Frizzo et al., 2001; Frizzo et al., 2002; Frizzo et al., 2003; Lara et al., 2001; Malcon et al., 1997; Paas, Devillers-Thiery, Changeux, Medevielle, & Teichberg, 1996; Paz, Ramos, Ramirez, & Souza, 1994; Roesler et al., 2000; Rubin et al., 1996; Schmidt, Lara, Maraschin, Perla, & Souza, 2000; Tasca, Wofchuk, Souza, Ramirez, & Rodnight, 1995). Concerning the neuroprotective role of GBPs, in vivo studies have shown that guanosine administered intraperitoneally (i.p.) or orally (p.o.) in mice, prevented seizures induced by quinolinic acid and α-dendrotoxin (compounds that overstimulate the glutamatergic system) (Lara et al., 2001; Schmidt et al., 2000; Vinadé et al., 2003), whereas intrastriatal GMP protected against quinolinic acid-induced cell death in rats (Malcon et al., 1997). These results point to a neuroprotective role of GBPs, mainly guanosine, possibly by modulating the glutamatergic neurotransmission.

We have previously shown that i.p. guanosine exerted an amnesic effect on inhibitory avoidance task in rats (Roesler et al., 2000), similar to NMDA antagonists (Izquierdo & Medina, 1997), that was present when guanosine was administered before training, but not after training or before testing. In this study, we investigated the effect of guanosine on inhibitory avoidance task, performing an acute oral administration of the drug, a more promising therapeutic route. We further investigated the role of adenosine and its receptor antagonist caffeine in the mechanism of action of guanosine, since there is evidence that guanosine might act by releasing adenosine (Rathbone et al., 1999). We also studied the effects of p.o. guanosine on locomotor activity (hole board to mice and open-field to rats) and anxiety-related behaviors (hole board to mice and elevated plus-maze to rats).