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.

Background: Agomelatine is a melatonergic receptor agonist and a 5HT_2C receptor antagonist that has shown antidepressant efficacy. In order to analyze separately the effect of the two receptorial components, rats were chronically treated with agomelatine, melatonin (endogenous melatonergic agonist), or S32006 (5-HT_2C antagonist), and then subjected to acute footshock-stress. Results: Only chronic agomelatine, but not melatonin or S32006, completely prevented the stress-induced increase of glutamate release in the rat prefrontal/frontal cortex. Conclusions: These results suggest a potential synergy between melatonergic and serotonergic pathways in the action of agomelatine.

It is known that nicotine can activate several subtypes of release‐regulating presynaptic nicotinic receptors (nAChRs) including those situated on central noradrenergic, dopaminergic, cholinergic and glutamatergic axon terminals. The objective of this study was to investigate the effects of chronic administration of (–)nicotine on the function of the above autoreceptors and heteroreceptors using rat superfused synaptosomes. In hippocampal synaptosomes prelabelled with [³H]noradrenaline (NA) the nicotine‐evoked overflow of [³H]NA was higher in rats treated with nicotine for 10 days (via osmotic mini‐pumps) than in vehicle‐treated rats. In striatal synaptosomes, prelabelled with [³H]dopamine (DA), chronic nicotine did not modify the releasing effect of nicotine. No significant change was observed in experiments with synaptosomes from nucleus accumbens prelabelled with [³H]DA. Exposure of hippocampal synaptosomes prelabelled with [³H]choline to nicotine elicited release of [³H]acetylcholine; this effect was almost abolished in synaptosomes from animals administered nicotine for 10 days, suggesting down‐regulation of nicotinic autoreceptors. In hippocampal synaptosomes prelabelled with [³H]d‐aspartate, the releasing effect of epibatidine following chronic nicotine treatment did not differ from that in controls. The K⁺‐evoked exocytotic release of the neurotransmitters tested was not modified by long‐term nicotine administration. The results show that chronic nicotine differentially affects the function of release‐regulating nAChR subtypes.