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Caffeine has a dual influence on NMDA receptor–mediated glutamatergic transmission at the hippocampus

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Abstract

Caffeine, a stimulant largely consumed around the world, is a non-selective adenosine receptor antagonist, and therefore caffeine actions at synapses usually, but not always, mirror those of adenosine. Importantly, different adenosine receptors with opposing regulatory actions co-exist at synapses. Through both inhibitory and excitatory high-affinity receptors (A1R and A2R, respectively), adenosine affects NMDA receptor (NMDAR) function at the hippocampus, but surprisingly, there is a lack of knowledge on the effects of caffeine upon this ionotropic glutamatergic receptor deeply involved in both positive (plasticity) and negative (excitotoxicity) synaptic actions. We thus aimed to elucidate the effects of caffeine upon NMDAR-mediated excitatory post-synaptic currents (NMDAR-EPSCs), and its implications upon neuronal Ca2+ homeostasis. We found that caffeine (30–200 μM) facilitates NMDAR-EPSCs on pyramidal CA1 neurons from Balbc/ByJ male mice, an action mimicked, as well as occluded, by 1,3-dipropyl-cyclopentylxantine (DPCPX, 50 nM), thus likely mediated by blockade of inhibitory A1Rs. This action of caffeine cannot be attributed to a pre-synaptic facilitation of transmission because caffeine even increased paired-pulse facilitation of NMDA-EPSCs, indicative of an inhibition of neurotransmitter release. Adenosine A2ARs are involved in this likely pre-synaptic action since the effect of caffeine was mimicked by the A2AR antagonist, SCH58261 (50 nM). Furthermore, caffeine increased the frequency of Ca2+ transients in neuronal cell culture, an action mimicked by the A1R antagonist, DPCPX, and prevented by NMDAR blockade with AP5 (50 μM). Altogether, these results show for the first time an influence of caffeine on NMDA receptor activity at the hippocampus, with impact in neuronal Ca2+ homeostasis.

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Abbreviations

A1R:

Adenosine A1 receptor

A2AR:

Adenosine A2A receptor

aCSF:

Artificial cerebrospinal fluid

AD:

Alzheimer’s disease

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AP5:

DL-2-Amino-5-phosphonopentanoic acid

ARs:

Adenosine receptors

CA1 :

Cornu Ammonis 1

Ca2+ :

Calcium ion

CNQX:

6-Cyano-7-nitroquinoxaline-2,3-dione disodium salt hydrate

CNS :

Central nervous system

DIC:

Day in culture

DIC-IR:

Differential interference contrast-infrared

DPCPX:

8-Cyclopentyl-1,3-dipropylxanthine

EDTA:

Ethylenediaminetetraacetic acid

EPSCs:

Excitatory post-synaptic currents

F340/380:

Ratio from excitation wavelength 340 nm and 380 nm

FBS:

Fetal bovine serum

fEPSP:

Field excitatory post-synaptic potential

GABA:

Gamma-aminobutyric acid

HBSS:

Hank’s balanced salt solution

LTD:

Long-term depression

LTP:

Long-term potentiation

mGluR:

Metabotropic glutamate receptors

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptor

NMDAR-EPSCs:

N-Methyl-d-aspartate receptor excitatory post-synaptic potential

PDL:

Poly-d-lysine

PPF:

Paired-pulse facilitation

S.E.M.:

Standard error of the mean

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Acknowledgments

The authors in Portugal are members of an EU twinning action (Project grant 952455). While revising this work, the authors want to make a special tribute to Geoffrey Burnstock for his great contributions to science, for defending and enlarging the knowledge of the purinergic field to the very end of his life, for his friendship and trust even in very difficult circumstances, which will never be forgotten. Thanks Geoff. Your legacy will last forever. We will miss your loud voice and laugh.

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Funding

Robertta Silva Martins was in receipt of a fellowship from Fundação de Amparo à Pesquisa do Estado do Rio de Jan eiro–FAPERJ, Brasil, Bolsa de Doutorado Sanduíche Europa/Oriente (grant number E-26/201.599/2018). The work was supported by Fundação para a Ciência e Tecnologia, Portugal (project grant PTDC/MED-FAR/30933/2017).

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Authors and Affiliations

  1. Instituto de Farmacologia e Neurociências, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    Robertta S. Martins, Diogo M. Rombo, Joana Gonçalves-Ribeiro, Joaquim A. Ribeiro, Sandra H. Vaz & Ana M. Sebastião

  2. Laboratório de Neurofarmacologia, Departamento de Fisiologia e Farmacologia, Pós-Graduação em Neurociências, Universidade Federal Fluminense, Niterói, Brazil

    Robertta S. Martins, Vladimir P. P. Borges-Martins & Regina C. C. Kubrusly

  3. Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

    Diogo M. Rombo, Joana Gonçalves-Ribeiro, Joaquim A. Ribeiro, Sandra H. Vaz & Ana M. Sebastião

  4. Área Departamental de Engenharia de Electrónica e Telecomunicações e de Computadores, Instituto Superior de Engenharia de Lisboa, Lisbon, Portugal

    Carlos Meneses

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All experimental procedures were performed according to European Community Guidelines (Directive 2010/63/EU) and the Portuguese Law (DL 113/2013) for animal care for research purposes and were approved by the “Instituto de Medicina Molecular” Internal Committee and the Portuguese Animal Ethics Committee - Direcção Geral de Veterinária.

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Martins, R.S., Rombo, D.M., Gonçalves-Ribeiro, J. et al. Caffeine has a dual influence on NMDA receptor–mediated glutamatergic transmission at the hippocampus. Purinergic Signalling 16, 503–518 (2020). https://doi.org/10.1007/s11302-020-09724-z

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