The effects of adenosine A_2A and A₁ receptor activation on the release of glutamate were studied in rat cerebral cortex synaptosomes exposed in superfusion to adenosine receptor ligands. Adenosine (0.1 μM) produced a significant potentiation of the Ca²⁺‐dependent K⁺(15 mM)‐evoked [³H]‐D‐aspartate overflow (20.4±3.5%), which was blocked by A_2A blocker SCH58261 (0.1 μM). At higher concentrations (10 – 1000 μM) adenosine inhibited in a DPCPX‐sensitive manner the Ca²⁺‐dependent K⁺‐evoked [³H]‐D‐aspartate overflow. The inhibitory effect of adenosine at 1000 μM was significantly increased by SCH58261. This inhibition was antagonized by 1 μM DPCPX. Adenosine did not produce any effect on basal release. The A_2A receptor agonist CGS 21680 was ineffective on basal release, but stimulated the Ca²⁺‐dependent K⁺‐evoked overflow of [³H]‐D‐aspartate (EC₅₀ ≃ 1 pM). The effect of 0.01 nM CGS 21680 was totally sensitive to the A_2A receptor antagonist SCH58261 (IC₅₀ ≃5 nM). The A₁ receptor agonist CCPA inhibited the Ca²⁺‐dependent K⁺‐evoked [³H]‐D‐aspartate overflow (EC₅₀ ≃ 20 nM). The effect of 100 nM CCPA was abolished by 100 nM of the A₁ receptor antagonist DPCPX. The K⁺(15 mM)‐evoked overflow of endogenous glutamate was enhanced by CGS 21680 (0.01 nM) and inhibited by CCPA (0.1 μM). The effect of CGS 21680 was abolished by SCH58261 (0.1 μM) and that of CCPA by DPCPX (0.1 μM). It is concluded that adenosine and adenosine receptor agonists modulate glutamate release by activating inhibitory A₁ and excitatory A_2A receptors present on glutamatergic terminals of the rat cerebral cortex. British Journal of Pharmacology (2002) 136, 434–440; doi:10.1038/sj.bjp.0704712

We previously showed that beta-amyloid (Aβ), a peptide considered as relevant to Alzheimer's Disease, is able to act as a neuromodulator affecting neurotransmitter release in absence of evident sign of neurotoxicity in two different rat brain areas. In this paper we focused on the hippocampus, a brain area which is sensitive to Alzheimer's Disease pathology, evaluating the effect of Aβ (at different concentrations) on the neurotransmitter release stimulated by the activation of pre-synaptic cholinergic nicotinic receptors (nAChRs, α4β2 and α7 subtypes). Particularly, we focused on some neurotransmitters that are usually involved in learning and memory: glutamate, aspartate and GABA. We used a dual approach: in vivo experiments (microdialysis technique on freely moving rats) in parallel to in vitro experiments (isolated nerve endings derived from rat hippocampus). Both in vivo and in vitro the administration of nicotine stimulated an overflow of aspartate, glutamate and GABA. This effect was greatly inhibited by the highest concentrations of Aβ considered (10 µM in vivo and 100 nM in vitro). In vivo administration of 100 nM Aβ (the lowest concentration considered) potentiated the GABA overflow evoked by nicotine. All these effects were specific for Aβ and for nicotinic secretory stimuli. The in vitro administration of either choline or 5-Iodo-A-85380 dihydrochloride (α7 and α4β2 nAChRs selective agonists, respectively) elicited the hippocampal release of aspartate, glutamate, and GABA. High Aβ concentrations (100 nM) inhibited the overflow of all three neurotransmitters evoked by both choline and 5-Iodo-A-85380 dihydrochloride. On the contrary, low Aβ concentrations (1 nM and 100 pM) selectively acted on α7 subtypes potentiating the choline-induced release of both aspartate and glutamate, but not the one of GABA. The results reinforce the concept that Aβ has relevant neuromodulatory effects, which may span from facilitation to inhibition of stimulated release depending upon the concentration used.