INHIBITION OF CORTICAL ACETYLCHOLINE-RELEASE AND COGNITIVE PERFORMANCE BY HISTAMINE H-3 RECEPTOR ACTIVATION IN RATS

1 The effects of histamine and agents acting at histamine receptors on spontaneous and 100 mM K+-evoked release of acetylcholine, measured b y microdialysis from the cortex of freely moving rats, and on cognitiv e tests are described. 2 Local administration of histamine (0.1-100 mu M) failed to affect spontaneous but inhibited 100 mM K+-stimulated re lease of acetylcholine up to about 50%. The H-3 receptor agonists (R)- alpha-methylhistamine (RAMH) (0.1-10 mu M), imetit (0.01-10 mu M) and immepip (0.01-10 mu M) mimicked the effect of histamine. 3 Neither 2-t hiazolylethylamine (TEA), an agonist showing some selectivity for H-1 receptors, nor the H-2 receptor agonist, dimaprit, modified 100 mM K+- evoked release of acetylcholine. 4 The inhibitory effect of 100 mu M h istamine was completely prevented by the highly selective histamine H- 3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H-1 and H-2 but not H-3 receptors. 5 The H-3 receptor-induced inhibition of K+-evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX). 6 The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg(-1 )) and RAMH (5 mg kg(-1)) were tested on acetylcholine release and sho rt term memory paradigms. Both drugs reduced 100 mM K+-evoked release of cortical acetylcholine, and impaired object recognition and a passi ve avoidance response. 7 These observations provide the first evidence of a regulatory role of histamine H-3 receptors on cortical acetylcho line release in vivo. Moreover, they suggest a role for histamine in l earning and memory and may have implications for the treatment of dege nerative disorders associated with impaired cholinergic function.