br Conclusions The present data suggest

Conclusions The present data suggest that homeostatic balance of the cortical/hippocampal adenosinergic tone is necessary for normal working memory function and any deviation appears to impair performance – either as a consequence of A2AR under-activation when adenosine levels are reduced or due to enhanced A1R-mediated inhibition when adenosine levels are elevated. Either of these represents also an imbalance between cortical/hippocampal and striatal adenosinergic regulation due to the differential expression of the two receptor subtypes in the striatum and cortex/hippocampus. Indeed, this particular regional imbalance may explain the stronger memory impairment seen in fb-Adk-def mice compared with Adk-tg mice. It therefore follows that (i) rebalancing or stabilizing cortical/hippocampal adenosinergic tone might be beneficial in correcting working memory deficiency in a number of cognitive disorders where adenosine homeostasis may be disturbed (for a review, see Boison, 2008), and (ii) boosting A2AR-mediated signalling in the striatum may independently confer additional pro-cognitive benefits possibly via an independent mechanism. More specific manipulations in terms of bupropion hydrochloride regions (cortical vs. striatal) and AR subtypes (A1R vs. A2AR) are needed to verify our novel hypothesis regarding adenosine’s multiple regulatory roles in learning and memory.
Acknowledgements The present study was funded by the National Institutes of Health (MH083973) with additional support from the Swiss Federal Institute of Technology Zurich. The authors thank Peter Schmid for the maintenance of the equipment and software maintenance, and the animal husbandry staffs for their excellent services. We are also indebted to Joram Feldon for providing access to the animal keeping and behavioural testing facilities necessary for the reported experiments.
Introduction Recent studies have suggested that the immunosuppressants, cyclosporin A and tacrolimus (FK506) mimic cardioprotective effects of ischemic preconditioning. Cyclosporin A has been shown to preserve post-ischemic left ventricular function in isolated rat hearts, with inhibition of mitochondrial ion pore opening in cardiomyocytes implicated as a mechanism of the action (Duchen et al., 1993). Cyclosporin A treatment also preserved myocardial function and nitric oxide production in isolated guinea pig hearts during ischemia–reperfusion (Massoudy et al., 1997). In addition, both cyclosporin A and its analog FK506 have been shown to reduce post-ischemic myocardial infarct size in isolated rabbit hearts (Weinbrenner et al., 1998). FK506 also improved post-ischemic cardiac function in isolated rat hearts (Haines et al., 2000). This finding raised the possibility of a role for calcineurin, a known target of both cyclosporin A and FK506. In brain and liver where both cyclosporin A and FK506 induce ischemic preconditioning, these drugs reduced infarct size in animal models of ischemia–reperfusion injury Bochelen et al., 1999, Garcia-Criado et al., 1997, Toung et al., 1999. However, the mechanisms underlying the protective effect remain unclear. Both cyclosporin A and FK506 can induce an increase in adenosine plasma levels in kidney transplant recipients, and the plasma levels of cyclosporin A and adenosine are closely correlated. The mechanism of action of the two drugs is not clear but a reduction in adenosine uptake by red blood cells has been observed (Guieu et al., 1998). Because adenosine also has a potent immunosuppressive effect, it has been proposed that endogenous adenosine action participates in cyclosporin A- and FK506-mediated immunosuppression (Guieu et al., 1998). In addition, adenosine is a mediator of ischemic preconditioning (Millar et al., 1996), and it also has anti-inflammatory and anti-thrombotic effects Bouma et al., 1997b, Kitakaze et al., 1991. Therefore, it is possible that cyclosporin A- and FK506-induced organ protection is mediated by endogenous adenosine.