CHARACTERIZATION OF HISTAMINE H-3 RECEPTORS REGULATING ACETYLCHOLINE-RELEASE IN RAT ENTORHINAL CORTEX

1 The pharmacological properties and location of H-3 receptors modulat ing acetylcholine release have been investigated in non-superfused sli ces and synaptosomes of rat entorhinal cortex preloaded with [H-3]-cho line. 2 (R)alpha-methylhistamine, an H-3-receptor agonist, potently in hibited the K+-evoked tritium release from slices, an effect antagoniz ed by thioperamide, an H-3-receptor antagonist, with nanomolar potency . 3 The K+-evoked tritium release from synaptosomes remained unaltered in the presence of the potent and selective H-3-receptor agonists, im etit and (R)alpha-methylhistamine, suggesting that H-3 receptors modul ating acetylcholine release are not presynaptically located on choline rgic nerve terminals. 4 Phenylbutanoylhistamine and phenylpropylhistam ine, two H-3-receptor antagonists of moderate potency, failed to antag onize the inhibitory effects of (R)alpha-methylhistamine observed in s lices. Unexpectedly, both compounds when used alone, inhibited tritium release from slices and synaptosomes with micromolar potency and to t he same extent (by approximately 50% when added at a final concentrati on of 200 mu M). This inhibitory effect did not involve H-1, H-2 or H- 3 receptors and was not mediated by an unknown histamine receptor site , since histamine used at a high concentration neither reproduced nor antagonized the effect of phenylbutanoylhistamine. It remained unalter ed in the presence of scopolamine and was neither mimicked nor antagon ized by vasoactive intestinal peptide, previously shown to be colocali zed with acetylcholine in some neurones.5 It is concluded that acetylc holine release in rat entorhinal cortex is modulated by H-3 receptors presumably not located on cholinergic axon terminals. It remains to be established whether these H-3 receptors belong to a receptor subtype different from those previously described since the potency of phenylb utanoylhistamine and phenylpropylhistamine as H-3-receptor antagonists was probably greatly underestimated by additional properties of both drugs.