Hypoxia markedly depresses synaptic transmission in hippocampal slices of the rat. This depression is attributed to presynaptic inhibition of
glutamate release and is largely mediated by
adenosine released during
hypoxia acting through presynaptic
adenosine A(1) receptors. Paired pulse facilitation studies allowed us to confirm the presynaptic nature of the depression of synaptic transmission during
hypoxia. We tested the hypothesis that activation of heterosynaptic inhibitory receptors localized in glutamatergic presynaptic terminals in the hippocampus, namely
gamma-aminobutyric acid subtype B (
GABA(B)) receptors, alpha(2)-adrenergic receptors, and
muscarinic receptors might contribute to the
hypoxia-induced depression of synaptic transmission. Field excitatory postsynaptic potentials were recorded in the CA1 area of hippocampal slices from young adult (5-6 weeks) Wistar rats. Neither the selective antagonist for alpha(2)-adrenergic receptors,
rauwolscine (10 microM), nor the antagonist for the
GABA(B) receptors,
CGP 55845 (10 microM), modified the response to
hypoxia. The selective
adenosine A(1) receptor antagonist,
DPCPX (50 nM), reduced the
hypoxia-induced depression of synaptic transmission to 59.2+/-9.6%, and the
muscarinic receptor antagonist,
atropine (10 microM), in the presence of
DPCPX (50 nM), further attenuated the depression of synaptic transmission to 49.4+/-8.0%. In the same experimental conditions, in the presence of
DPCPX (50 nM), the
muscarinic M(2) receptor antagonist
AF-DX 116 (10 microM), but not the M(1) receptor antagonist
pirenzepine (1 microM), also attenuated the
hypoxia-induced depression to 41.6+/-6.6%. Activation of
muscarinic M(2) receptors contributes to the depression of synaptic transmission upon
hypoxia. This effect should assume particular relevance during prolonged periods of
hypoxia when other mechanisms may become less efficient.