Elsevier

Neurobiology of Aging

Volume 26, Issue 6, June 2005, Pages 957-964
Neurobiology of Aging

Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats: Involvement of adenosine A1 and A2A receptors

https://doi.org/10.1016/j.neurobiolaging.2004.08.012Get rights and content

Abstract

Caffeine, a non-selective adenosine receptor antagonist, has been suggested as a potential drug to counteract age-related cognitive decline since critical changes in adenosinergic neurotransmission occur with aging. In the present study, olfactory discrimination and short-term social memory of 3, 6, 12 and 18 month-old rats were assessed with the olfactory discrimination and social recognition tasks, respectively. The actions of caffeine (3.0, 10.0 and 30.0 mg/kg, i.p.), the A1 receptor antagonist DPCPX (1.0 and 3.0 mg/kg, i.p.) and the A2A receptor antagonist ZM241385 (0.5 and 1.0 mg/kg, i.p.) in relation to age-related effects on olfactory functions were also studied. The 12 and 18 month-old rats exhibited significantly impaired performance in both models, demonstrating deficits in their odor discrimination and in their ability to recognize a juvenile rat after a short period of time. Acute treatment with caffeine or ZM241385, but not with DPCPX, reversed these age-related olfactory deficits. The present results suggest the participation of adenosine receptors in the control of olfactory functions and confirm the potential of caffeine for the treatment of aged-related cognitive decline.

Introduction

In recent years, a growing body of research has emphasized the age-related deficits in human olfactory function. In part, this increased interest stems from a close relationship between olfactory dysfunction and various age-related neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's chorea [16], [31], [32], [33]. Recent evidence suggests that areas in the central nervous system processing olfactory information are affected at the early stages of these diseases, even before the development of their classical symptoms, such as cognitive decline for Alzheimer's disease and motor disruption for Parkinson's disease [24], [33]. Consequently, olfactory dysfunction might be an early indicator of these age-related disorders and the development of specific olfactory testing may represent an important tool in the clinical diagnosis of early-stages of these diseases [15], [24].

Previous studies have shown that although less marked than in humans, similar age-related decline in olfactory functions can be seen in rodents, including deficits in olfactory perception [34] and impairment in olfactory learning and memory [7], [21], [44], [46], [50]. Thus, rats present marked age-related deficits in their ability to form odor reward associations [44] and to perform olfactory delayed nonmatching-to-sample [53] and olfactory reversal learning [46]. For this reason, olfactory memory tasks may be of interest in the study of the neurobiological changes involved in age-related deficits and for testing potential therapeutic treatments for age-related cognitive declines.

On the other hand, many studies suggest that the methylxanthine caffeine, a popular CNS stimulant present in coffee and other frequently used beverages such as tea and cola, improves learning and memory processes both in rodents [1], [5], [19], [37], [45] and in humans [38], [42], [43]. Because of its cognition-enhancing properties, caffeine has been suggested as a potential drug to counteract age-related cognitive decline [43].

However, results from previous clinical studies on the efficacy of caffeine to counteract or reverse age-related cognitive decline have been inconsistent. Jarvis [26] investigated the effects of habitual coffee consumption on the cognition of 9,003 British adults and demonstrated a greater improvement in cognitive performance among the oldest men and women. Rees et al. [41] described a small but significant improvement of psychomotor and cognitive performance induced by caffeine in older subjects. A recent study with 1,538 participants (mean range 72.6 and 73.3 years for women and men, respectively) has indicated that lifetime coffee intake may be beneficial for cognitive performance, with a prominent caffeine-improved performance in women aged ≥80 years [27]. In disagreement with these results, longitudinal studies have demonstrated that the effects of habitual caffeine intake are limited and do not support the idea that prolonged caffeine use reduces cognitive decline in aging individuals [23], [51].

Central effects of caffeine are mediated by binding in a non-selective way to adenosine receptors in the brain. Four adenosine receptor subtypes (A1, A2A, A2B and A3) have been cloned and characterized from several mammalian species including humans and rats, and they all belong to the G-protein-coupled receptor (GPCR) family [18]. The physiological actions of adenosine are exerted by activation of the high affinity receptors A1 and A2A that are highly expressed in diverse brain areas, while the low affinity receptors A2B might be relevant in pathological conditions. The A3 receptor is a high affinity receptor in humans but has a low density in most tissues [14], [47]. Recently, Kaelin-Lang et al. [28] have demonstrated the high expression of the A2A receptor genes in the granular cells of the accessory olfactory bulb of rodents. However, the functional importance of these receptors is still unknown.

In addition, an increasing number of studies have demonstrated critical age-related changes in adenosinergic neurotransmission. Adenosine concentration in many brain areas, such as the hippocampus and limbic cortex, is significantly increased in aging rats, in part by a more efficient formation of adenosine from ATP and by a decreased removal (nearly 50%) of extracellular adenosine [8], [9]. Furthermore, many authors have demonstrated age-related alteration in the adenosine A1 and A2A receptor's balance, with an increase in the number of A2A receptors, as well as an increase in their G protein coupling and in the efficiency of A2A receptor activation to increase cAMP [10], [30]. The number of A1 receptors decreases in aging rats [36], [10], [49], although there is an increase in the G protein coupling to A1 receptors [11].

In the light of these considerations, the purpose of the present study was to evaluate the age-related effects on olfactory discrimination and social recognition memory in rats. Furthermore, to investigate the possible involvement of adenosine receptors on olfactory functions, we injected intraperitoneally caffeine, the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or the A2A receptor antagonist 4-(2-[7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385).

Section snippets

Animals

Subjects were adult male Wistar rats, 3, 6, 12 or 18 month old, and juvenile male Wistar rats (25–30 days old) from our own colony. Juvenile rats were kept in groups of ten per cage and served as social stimuli for the adult rats. The animals were maintained in a room under controlled temperature (23 ± 1 °C) and subject to a 12 h light cycle (lights on 7:00 a.m.) with free access to food and water. All tests were carried out between 13:00 and 18:00 h. All procedures used in the present study

Age-related effects on olfactory discrimination and social recognition memory in rats

The results of the olfactory discrimination abilities of 3, 6, 12 and 18 month-old rats are summarized in Fig. 1. One-way ANOVA revealed a significant effect for the age factor (F(3,28) = 9.52, p < 0.0001). Subsequent Newman–Keuls test indicated that both 3 and 6 month-old groups were able to discriminate between the familiar and the non-familiar compartments, spending much more time in the familiar compartment. However, 12 and 18 month-old rats presented disruption in the olfactory discrimination

Discussion

The present findings demonstrate age-related deficits in olfactory discrimination and social recognition memory in rats and that single intraperitoneal administration of caffeine (10.0 or 30.0 mg/kg) or the adenosine A2A receptor antagonist ZM241385 (0.5 or 1.0 mg/kg), but not the adenosine A1 receptor antagonist DPCPX (1.0 or 3.0 mg/kg), reversed these age-related deficits in olfactory functions.

As described in the Introduction section, an increasing number of studies have demonstrated that areas

Acknowledgements

The authors are grateful to Prof. Giles A. Rae and Dr. Nelson De-Mello for their expert comments. This work was supported, in part, by CNPq-Brazil.

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