Chronic treatment with DCPCX, an adenosine A(1) antagonist, worsens long-term memory

Abstract

Alzheimer's disease is characterized by progressive cognitive disturbances and neurotransmitter dysfunction. Previous studies targeting the adrenergic A1 pathway suggest that this plays a role in cognitive impairment in Alzheimer's disease. Previous studies have reported that acute treatment with A1 antagonists appears to improve behavioral deficits in rodent models of memory and behavioral impairment. In this study, we addressed whether the chronic administration of 8-cyclopentyl-1,3-dipropylxanthine, a potent and selective adenosine A1 antagonist, could reverse the memory deficits found in aged APPswe/PS1dE9 mice. Chronic treatment did not improve memory in the APPswe/PS1dE9 mouse model and resulted in reduced exploratory behavior, suggestive of reduced anxiety, and a worsening of long-term memory in nontransgenic mice. These results have important implications for understanding the mechanisms of A1 receptor modulation as a target in Alzheimer's disease therapy.

Keywords: Adenosine A(1) antagonist; Alzheimer's disease; Anxiolytic; Chronic treatment; Impaired learning.

Fig. 1. Effect of DPCPX treatment on weight

Mice were weighed on a weekly basis; no change in weight in any group was seen over the 8 week treatment period. Mean ± SEM.

Fig. 2. Effect of DPCPX treatment on non-cognitive behavior

(A) Exploratory behavior measured by the open field activity was unaffected by treatment. (Move: Total activity time; Stereo: time moving in stereotypic fashion; Rest: Time at rest). (B) Motor coordination and balance with accelerating rotarod were unchanged with DCPCX treatment. * p < 0.05; mean ± SEM.

Fig. 3. Effect of DPCPX on anxiety-like behavior

Nontransgenic mice treated with DCPCX spent significantly less time in the margin and more time in the center of the open field, compared to nontransgenic vehicle-treated mice. APP mice showed a similar trend, although the results were non-significant. (Zone A: perimeter of the open field; Zone B: center of the open field). * p < 0.05; mean ± SEM.

Fig. 4. Effect of DPCPX treatment on long-term memory in the Morris Water Maze

(A) APdE9 mice had significantly increased escape latency compared to nontransgenic mice on day 2 and 3 during acquisition trials. (B) Escape latency during visual acuity trials. (C) Platform frequency during short-term memory (STM) probe test. (D) DCPCX treated nontransgenic mice had significantly fewer platform crosses than nontransgenic vehicle indicating impaired memory in the long-term memory (LTM) probe test. * p < 0.05; mean ± SEM.