Modification by Arachidonic Acid of Extracellular Adenosine Metabolism and Neuromodulatory Action in the Rat Hippocampus

Abstract

Adenosine and arachidonate (AA) fulfil opposite modulatory roles, arachidonate facilitating and adenosine inhibiting cellular responses. To understand if there is an inter-play between these two neuromodulatory systems, we investigated the effect of AA on extracellular adenosine metabolism in hippocampal nerve terminals. AA (30 M) facilitated by 67% adenosine evoked release and by 45% ATP evoked release. These effects were not significantly modified upon blockade of lipooxygenase or cyclooxygenase and were attenuated (52-61%) by the protein kinase C inhibitor, chelerythrine (6 M).

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…Note that in purified nerve terminals, which only account for 1%Y2% of the volume of more integrated preparations [129], spatial restrains are decreased and it is the only preparation where it has been demonstrated that ecto-5 0 -nucleotidase was the predominant enzymatic activity responsible for the formation of extracellular adenosine from adenine nucleotides [130]. Thus, in nerve terminals, a,b-methylene ADP is able to decrease the formation of extracellular adenosine [107,108,112,117,118].…”

“…Two main mechanisms have been identified in nerve terminals for the generation of extracellular adenosine: one is based on the release of adenosine as such through bi-directional non-concentrative (or equilibrative) nucleoside transporters [106]. In fact, inhibition of equilibrative nucleoside transporters can actually decrease the extracellular levels of adenosine in nerve terminals [107,108], in accordance with a build-up of extracellular adenosine involving its release through equilibrative nucleoside transporters in this particular compartment of the brain. The second mechanism for the extracellular build-up of adenosine is its formation from released ATP, after its extracellular catabolism by ecto-nucleotidases (reviewed in [109]).…”

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

“…Although this is the most widely accepted hypothesis for the build-up of extracellular adenosine, it has only received episodic experimental confirmation (e.g. Cunha et al, 2000;MacDonald and White, 1985). Oddly, the effect of pharmacologically manipulating these nucleoside transporters is an increase of the extracellular levels of adenosine implying that their role is to take-up rather than release adenosine (see Fredholm et al, 2005).…”

ATP is released from nerve terminals and from activated muscle fibres on stimulation of the rat phrenic nerve

“…In central nervous system (CNS) synapses like in the hippocampus, ATP can act as a neurotransmitter [10,11] and the release of ATP is enriched in presynaptic preparations (cf. [3,6]). In contrast, at motor nerve endings, albeit the extracellular levels of ATP are also increased on stimulation of nerve afferents [16,17,19], there seems to be a considerably larger contribution of post-synaptically released adenine nucleotides [5,19].…”

“…refs. [3,6]). But the relevant question from the functional point of view is what might be the role of extracellular ATP in the control of neuromuscular transmission.…”