Effects of chronic administration of adenosine A1 receptor agonist and antagonist on spatial learning and memory

Abstract

Spatial memory acquisition in Morris water maze was tested in C57BL/6 mice. Animals were injected once daily with different doses of either N 6 -cyclopentyladenosine (CPA) or 8-cyclopentyl-1,3-dipropylxanthine (CPX). Drugs were administered for 9 days either concurrently with water maze testing (drugs injected 1 h after each trial), or prior to the entire block of trials. In the latter case, 1 day without injections preceded water maze experiments. Chronic administration of CPA resulted in a significant, dose-dependent reduction of target latencies, rapid development of spatial preference, and the absence of animals unable to perform the task. CPX treated animals did not show significant performance changes, and failed to develop spatial preference. Locomotor disturbances were not the cause of the observed effects. Our results indicate that chronic treatment with agents acting at adenosine A 1 receptors results in behavioral effects that are significantly different from those observed following their acute administration. Therefore, particular caution is required in development of adenosine-based strategies targeted at neurodegenerative or cognitive disorders in which chronic treatment is advocated.

Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly

“…The absence of deficits observed in the Morris water maze thus indicates that such life-long administration does not cause any major effects on memory. This is in apparent contrast to a study where chronic administration of the selective A 1 R antagonist CPX was shown to impair performance in the water maze (Von Lubitz et al, 1993), even though no effect was observed after acute administration. In a recent report (2003), Lang et al also confirmed that the deletion of A 1 R does not affect spatial performance during both training and probe trials in a place navigation task in the water maze, although their A 1 R −/− mice showed increased wall hugging, a strategy choice suggested to be a result of their emotional instability.…”

“…The hippocampal formation is enriched with A 1 Rs (Fastbom et al, 1987;Svenningsson et al, 1997) and these receptors may be involved in the development and consolidation of longterm potentiation (LTP) (Arai et al, 1990;de Mendonca and Ribeiro, 1990;Alzheimer et al, 1991;Forghani and Krnjevic, 1995) and in induction of long-term depression (LTD) (de Mendonca et al, 1997;Bon and Garthwaite, 2002;Moore et al, 2003). Selective A 1 R agonists and antagonists have been reported, respectively, to impair and to facilitate learning and memory in passive-avoidance tasks (e.g., Normile et al, 1991;Suzuki et al, 1993;Pereira et al, 2002) and spatial learning in mazes (e.g., Suzuki et al, 1993;Von Lubitz et al, 1993), and have been proposed as therapy in cognitive disorders (reviewed by Erfurth and Schmauss, 1995). However, if given at high doses, antagonists produce an impairment (Zarrindast and Shafaghi, 1994), perhaps reflecting a biphasic action.…”

“…However, if given at high doses, antagonists produce an impairment (Zarrindast and Shafaghi, 1994), perhaps reflecting a biphasic action. Furthermore, chronic administration of selective A 1 R agonists and antagonists may have effects on learning and memory that are opposite the effects elicited by acute administration of the same drugs (Von Lubitz et al, 1993;Hauber and Bareiss, 2001). …”

Carbamazepine-Induced Upregulation of Adenosine A1-Receptors in Astrocyte Cultures Affects Coupling to the Phosphoinositol Signaling Pathway

“…Adenosine A 1 -receptor up and down regulation by chronic treatment with adenosine A 1 -receptor antagonists and agonists, respectively, has been reported to modulate cerebral ischemia, seizures, spatial learning, and memory (Von Lubitz et al 1993a,b, 1994a, but little is known about the physiological consequences of adenosine A 1 -receptor upregulation for their coupling to signal transduction systems. In general, there are only few reports in the literature that examine the consequences of changes in receptor expression for their signal transduction.…”

“…However, we have shown previously that G-protein and PLC contents of all cultures are comparable (measured by a direct activation of Gi/o-proteins by mastoparan) (Biber et al 1997). Moreover, there are no data available at the moment indicating that CBZ might have any effect on G-protein and/or PLC activity or expression or inositol phospholipid metabolism.Adenosine A 1 -receptor up and down regulation by chronic treatment with adenosine A 1 -receptor antagonists and agonists, respectively, has been reported to modulate cerebral ischemia, seizures, spatial learning, and memory (Von Lubitz et al 1993a,b, 1994a, but little is known about the physiological consequences of adenosine A 1 -receptor upregulation for their coupling to signal transduction systems. In general, there are only few reports in the literature that examine the consequences of changes in receptor expression for their signal transduction.…”