Adrenoceptor subtype‐specific acceleration of the hypoxic depression of excitatory synaptic transmission in area CA1 of the rat hippocampus

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Abstract
The depression of excitatory synaptic transmission by hypoxia in area CA1 of the hippocampus is largely dependent upon the activation of adenosine A1 receptors on presynaptic glutamatergic terminals. As well as adenosine, norepinephrine levels increase in the hypoxic/ischemic hippocampus. We sought to determine the influence of α‐ and β‐adrenoceptor (AR) activation on the hypoxic depression of synaptic transmission utilizing electrophysiological, pharmacological and adenosine sensor techniques. Norepinephrine depressed synaptic transmission and significantly accelerated the hypoxic depression of synaptic transmission. The α‐AR agonist 6‐fluoronorepinephrine mimicked both of these effects whilst the α2‐AR antagonist yohimbine, but not the α1‐AR antagonist urapidil, prevented the actions of 6‐fluoronorepinephrine. In contrast, the β‐AR agonist isoproterenol enhanced synaptic transmission and only accelerated the hypoxic depression of transmission in hypoxia‐conditioned slices in which the hypoxic release of adenosine is reduced. The effects of isoproterenol were blocked by the non‐selective β‐AR antagonist propranolol and the selective β1‐AR antagonist betaxolol. Using an enzyme‐based adenosine sensor we observed that the application of the β‐AR agonist resulted in increased extracellular adenosine during repeated hypoxia. Our results suggest that α2‐AR activation facilitates the hypoxic depression of synaptic transmission probably via the known α2‐AR‐mediated inhibition of presynaptic calcium channels whereas β1‐AR activation does so via increased extracellular adenosine and greater activation of inhibitory adenosine A1 receptors.

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